Itaconic acid

Last updated
Itaconic acid
2-methylenesuccinic acid 200.svg
Itaconic-acid-3D-balls.png
Names
Preferred IUPAC name
Methylidenebutanedioic acid
Other names
2-Methylenesuccinic acid
Methylenesuccinic acid [1]
1-Propene-2,3-dicarboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.002.364 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C5H6O4/c1-3(5(8)9)2-4(6)7/h1-2H2,(H,6,7)(H,8,9) Yes check.svgY
    Key: LVHBHZANLOWSRM-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C5H6O4/c1-3(5(8)9)2-4(6)7/h1-2H2,(H,6,7)(H,8,9)
    Key: LVHBHZANLOWSRM-UHFFFAOYAS
  • O=C(O)C(=C)CC(=O)O
Properties
C5H6O4
Molar mass 130.099 g·mol−1
AppearanceWhite solid
Density 1.63 g/cm3 [1]
Melting point 162 to 164 °C (324 to 327 °F; 435 to 437 K) (decomposes) [1]
1 g/12 mL [1]
Solubility in ethanol 1 g/5 mL [1]
-57.57·10−6 cm3/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Itaconic acid (also termed methylidenesuccinic acid and 2-methylidenebutanedioic acid [2] ) is a fatty acid containing five carbons (carbon notated as C), two of which are in carboxyl groups (notated as -CO2H) and two others which are double bonded together (i.e., C=C). (itaconic acid's chemical formula is C5H6O4, see adjacent figure and dicarboxylic acids). At the strongly acidic pH levels below 2, itaconic acid is electrically neutral because both of its carboxy residues are bound to hydrogen (notated as H); at the basic pH levels above 7, it is double negatively charged because both of its carboxy residues are not bound to H, i.e., CO2 (its chemical formula is C5H4O42-); and at acidic pH's between 2 and 7, it exists as a mixture with none, one, or both of its carboxy residues bound to hydrogen. In the cells and most fluids of living animals, which generally have pH levels above 7, itaconic acid exists almost exclusively in its double negatively charged form; this form of itaconic acid is termed itaconate. [3] Itaconic acid and itaconate exist as cis and trans isomers (see cis–trans isomerism). Cis-itaconic acid and cis-itaconate isomers have two H's bound to one carbon and two residues (noted as R) bound to the other carbon in the double bound (i.e., H2C=CR2) whereas trans-itaconic acid and trans-itaconate have one H and one R residue bound to each carbon of the double bound. The adjacent figure shows the cis form of itaconic acid. Cis-aconitic acid spontaneously converts to its thermodynamically more stable (see chemical stability) isomer, trans-aconitic acid, at pH levels below 7. [4] The medical literature commonly uses the terms itaconic acid and itaconate without identifying them as their cis isomers. This practice is used here, i.e., itaconic acid and itaconate refer to their cis isomers while the trans isomer of itaconate (which has been detected in fungi but not animals [4] ) is here termed trans-itaconate (trans-itaconic acid is not further mentioned here).

Contents

Animal cells make itaconate by an enzyme-catalyzed reaction from cis-aconitate (see aconitic acid), an intermediate metabolite in the tricarboxylic acid cycle, (i.e., TCA cycle). This cycle operates in the mitochondria of virtually all the cells of animals, plants, fungi, and some microorganisms. [5] The itaconate-producing reaction is stimulated when cells undergo stressful conditions that suppress the TCA cycle's operation. [6] Studies examining the actions of itaconate and/or itaconate-like compounds suggest that the itaconate formed in this reaction acts on its cell of origin and other cells to regulate the potentially deleterious inflammation responses caused by various microorganisms, viruses, autoimmune diseases, oxidative stress, and other types of tissue injury. [6] They also suggest that it may inhibit the development and/or progression of certain cancers. [7] Itaconate is also a bactericidal agent, i.e., an agent that acts directly on certain types of bacteria to inhibit their viability and/or disease-causing abilities. [8] [9]

In 1836, Samuel Baup discovered a previously unknown by-product in a distillate of citric acid; this by-product was later named itaconic acid. [6] In the late 1920s, itaconic acid was isolated from a fungus in the Aspergillus genus of fungi [6] and in the 1930s itaconate was shown to have bactericidal actions. [8] [9] During this time, itaconic acid proved to be useful for synthesizing a wide range of products required by agricultural, textile, and other industries. Since then, the use of itaconic acid for industrial and manufacturing purposes has grown. [10] In 2011, Strelko et al. [11] reported that itaconate was produced by two mammalian immortalized cell lines, cultured mouse VM-M3 brain tumor cells and RAW 264.7 mouse macrophages, and by macrophages isolated from mice. This group also showed that stimulation of mouse macrophages with the bacterial toxin, lipopolysaccharide (i.e., LPS, also termed endotoxin), increased their production and secretion of itaconate. [7] In 2013, Michelucci et al. [12] revealed the biosynthesis pathway that makes itaconate in mammals. These publications were followed by numerous others focused on the biology of itaconate and certain itaconate-like compounds as regulars of various cellular responses in animals and possibly humans. [7] [13]

The following section, titled "Biology of Itaconate," details preclinical studies that analyzed the effects of itaconate and itaconate-like compounds on human cells, animal cells, and animals used as models of specific diseases. These studies sought to a) define itaconate's physiological and pathological functions as well as its mechanisms of action in health and disease; b) define the actions and mechanisms of action of various itaconate-like compounds; and c) determine which actions of itaconate and itaconate-like compounds support conducting further studies to determine if it or they would be useful therapeutic agents in humans. [6] [7] [14] The last section, titled "Commercial production and uses of itaconic acid," reports on the changing methods for making large amounts, and the many commercial uses, of itaconic acid. [3] [15]

Biology of Itaconate

Cells making itaconate

While many cell types can be manipulated to produce itaconate, the major cell types that normally make itaconate in response to stressful conditions are hematological cells such as the macrophages located in various tissues and the monocytes located in the bone marrow and blood. These cells are phagocytes, i.e., cells that ingulf microorganisms, dead or seriously injured cells, and foreign particles all of which cause inflammatory responses. [14] Itaconate is also produced by certain myeloid-derived suppressor cells [16] such as highly mature neutrophils [17] [18] [19] which are often termed granulocyte myeloid-derived suppressor cells or granulocyte MDSCs. [16] Unlike other types of itaconate-forming cells, however, these neutrophils, which are phagocytes, tend to retain rather than release itaconate to the extracellular space. [18]

Itaconate-forming metabolic pathway

Itaconate is a by-product of the tricarboxylic acid cycle. This cycle consists of eight successive enzyme-catalyzed biochemical reactions that occur in the cell's mitochondria. These reactions sequentially metabolize (indicated by →) citrate through eight intermediate metabolites and then converts the eighth intermediate metabolite, i.e. oxaloacetate, back to citate:

citrate → cis-aconitate → isocitrate → α-ketoglutarate → succinyl-CoA → succinate → fumarate → malate → oxaloacetate → citrate

This cyclical metabolic pathway serves the vital function of releasing the energy stored in nutrients to its cell of origin and in multicellular organisms' other cells throughout the body. [6] [20] Recent studies have found that some of the metabolites in the tricarboxylic acid cycle stimulate physiological and pathological responses, i.e., they are bioactive metabolites. For example, cells undergoing stress suppress the tricarboxylic acid cycle's operation. This causes succinate to accumulate. [20] [21] [22] The accumulating succinate stimulates a wide range of mostly pathological (e.g., cardiac ventricular hypertrophy) [22] ) and pro-inflammatory [23] (e.g., Crohn's disease) [24] disorders. High levels of succinate do have some beneficial actions such as promoting the neovascularization of tissues suffering vascular occlusions. [25] Succinate produces these effects by activating its G protein-coupled receptor, i.e., SUCNR1, in cells bearing this receptor but also by stimulating cells not bearing SUCNR1 as well as SUCNR1-bearing cells by receptor-independent mechanisms. [21] [26] Itaconate is also a bioactive metabolite. When operation of the tricarboxylic acid cycle is suppressed, one of its metabolites, cis-aconitate, accumulates. Aconitate decarboxylase (also termed ACOD1, cis-aconitate decarboxylase, immune-responsive gene 1, immune response gene 1, immunoregulatory gene 1, and IRG1 [27] [28] [29] [30] ) metabolizes cis-aconitate to itaconate and carbon dioxide (CO2) in the following decarboxylation reaction: [14] [24]

cis-aconitate → itaconate + CO2

This itaconate is transported across the mitochondrial membrane into the cell's cytosol by the mitochondrial dicarboxylate carrier protein, mitochondrial 2-oxoglutarate/malate carrier protein, and citrate–malate shuttle. [31] The cytosolic itaconate may then move form the cytosol through the patients' cells' surface membranes to the extracellular space (this trans-membrane movement may involve a specific transport protein such as the major facilitator superfamily transport protein (i.e., MfsA) in fungi. [32] ) This itaconate has mostly anti-inflammatory actions. [19] [23] It acts on its parent cell, other cells, and certain microorganism [6] by stimulating or inhibiting the activity of various response-regulating pathways in its parent cell, other cells, and bacteria. Itaconate's actions on its parent and other cells were considered as entirely independent of any receptor. Very recently, however, itaconate has been reported to stimulate certain mammalian cells by activating the OXGR1 receptor. [33] [34]

OXGR1 receptor

OXGR1 (also known as GPR99) is a G protein-coupled receptor that was identified in 2004 as a receptor for the tricarboxylic cycle intermediate, α-ketoglutarate. [33] In 2013, it was found to also be a receptor for leukotriene E4 and to lesser extents leukotriene C4 and D4. [35] [36] AZeng et al. [33] reported in 2023 that: a) among a set of cultured human embryonic kidney HEK 293 cells made to express any one of 351 different human G protein-coupled receptors, only cells expressing OXGR1 responded to itaconate by raising their cytosolic Ca2+ levels; b) HEK 293 cells expressing any of the other 350 receptors did not consistently alter their cytosolic Ca2+ levels in response to itaconate; c) respiratory epithelium cells isolated from control mice (i.e., these cells naturally express OXGR1) but not from Oxgr1 gene knockout mice (i.e., these cells lacked OXRG1) responded to itaconic acid by raising their cytosolic Ca2+ levels and stimulating their mucociliary clearance (equivalent to stimulating the secretion of mucus); d) application of itaconate in the noses of control mice but not Oxgr1 gene knockout mice stimulated nasal secretion of mucus; e)Oxgr1 gene knockout mice and Irg1 gene knockout mice (mice lacking the itaconate-producing protein, IRG1) that were intranasally infected with Pseudomonas aeruginosa had increased numbers of these bacteria in their lung tissue and bronchoalveolar lavage fluid (i.e., airway washing) than control mice that respectively expressed OXGR1 and IRG1; and f) α-ketoglutarate and itaconate, which have similar structures, activated OXGR1-exressing HEK293 cells at similar concentrations, i.e., between 200–300 μM/liter. [33] [34] These findings are the first to indicate that itaconate stimulates human HEK 293 and mouse respiratory epithelial cells by activating their OXGR1 receptors. Since OXGP1 is expressed in a wide range of tissues and mediates the allergic and inflammatory responses to the cited leukotrienes, [34] it may be involved in the inflammatory responses detailed in the following "Actions of itaconate and its analogs" section. That is, itaconate, like succinate (see previous paragraph), may stimulate cells by receptor-dependent and receptor independent mechanisms. Future studies need to determine the extent to which OXGR1 contributes to the various actions of itaconate and itaconate-like compounds (see next section) as well as the potencies of each of these agents in activating OXGR1. [23] [33] [34]

Itaconate and itaconate-like compounds

4-Octyl itaconate, dimethyl itaconate, [9] and 4-ethyl itaconate [6] have been used to mimic the biological effects of itaconate. These functional analogs of itaconate are often used in place of itaconate because of their presumed greater ability to pass through the surface membranes of, and thereby enter, cells. In should be noted that many studies have examined the actions of itaconate analogs rather than itaconate itself and that itaconate and these three analogs have on occasion shown significantly different biological activities. [7] [14] [19] [37] [38]

The anionic forms of mesaconic and citraconic acids, i.e., mesaconate and citraconate, are isomers of itaconate that differ from itaconate by the location of their internal carbon to carbon double bonds (i.e., C=C). [39] The two isomers have recently been found to have some but not all of the biological activities of itaconate. [7] [19] [40] (Meconate is a natural product made by mouse macrophages. [37] ) Other compounds have been synthesized that enter cells and then breakdown into itaconate plus a second inflammation-inhibiting agent, carbon monoxide. These compounds, termed itaCORMs, have recently been shown to activate some of the anti-inflammatory pathways activated by itaconate but also to have the anti-inflammatory activity of carbon monoxide in suppressing production of the pro-inflammatory cytokine, interleukin-23. The itaCORMs require further study. [41] Analyses of itaconate as well as each of the itaconate analogs, itaconate isomers, and itaCORM may be useful for selecting the agent(s) best suited to treat the human disorders which preclinical studies suggest are improved by itaconate or an itaconate-like compound(s). [6]

Dietary sources of itaconate and its isomers

Itaconic acid and its two isomers, mesaconic and citraconic acids, were found in rye and wheat breads with appreciably higher concentrations of itaconic and citraconic acids in their crusts (i.e., outer bread layer) than crumbs (i.e., soft inner part of the bread). Based on the average consumption of bread and bread-related baked goods in Germany, the daily intake of itaconate plus its two isomers was estimated to be from 7 to 20 micrograms. Rats have been shown to absorb the itaconic acid that was added to their diet. Further studies are needed to determine the levels of these compounds in other foods, the extent to which itaconic acid and itaconic acid-like compounds are absorbed by humans, and the usefulness of treating itaconate-suppressing disorders with oral itaconic acid or the acidic forms of the itaconic acid-like compounds. [39]

Actions of itaconate and its analogs

Itaconate and its analogs can operate concurrently through multiple pathways to induce their effects. [42] [43] [44] Relevant to this, future studies must determine the role of the newly defined receptor for itaconate, OXGR1, in contributing to the mediation of the following actions of itaconate and itaconate-like compounds. [33]

Inhibit succinate dehydrogenase

Succinate dehydrogenase (i.e., SDH) is an enzyme complex of six proteins in the mitochondrial tricarboxylic acid cycle that metabolizes succinate to fumarate. [27] (Although bacteria generally lack mitochondria, [45] their surface membranes have a similar SDH system. [46] ) Itaconate inhibits SDH's activity thereby blocking succinate's oxidation to fumarate and causing succinate levels to increase. Itaconate has been reported to increase succinate levels in a wide variety of cells including cultured mouse RAW264.7 macrophages, macrophages differentiated from human monocytes, [37] Huh7 human liver carcinoma cells, human MCF-7 breast cancer cells, human A549 lung adenocarcinoma cells, and the brain neurons and astrocytes generated from rat embryo brain tissue. [47] This succinate stimulates various responses in its parent and other cells as detailed elsewhere (see SUCNR1 and succinic acid). [20] [21] [48]

Inactivate KEAP1

KEAP1 (i.e., Kelch-like ECH-associated protein 1) resides in the cytoplasm of cells. It binds the transcription factor nuclear factor erythroid 2-related factor 2 (i.e., NFE2L2 or Nrf2) thereby holding it in the cytosol and unable to enter the cell nucleus where it would inhibit the expression of certain genes. Retention of Nrf2 in the cell's cytosol also promotes its degradation by E3 ubiquitin ligase. Nrf2: a) inhibits its target genes from expressing their pro-inflammatory cytokines, Interleukin 1 beta, i.e., IL-1β (which is enzymatically cleaved to its active form by caspase 1 [49] ) and tumor necrosis factor; b) inhibits its target genes expression of hypoxia-inducible factor 1-alpha which is converted enzymatically to an active form [50] that stimulates the pro-inflammatory actions of macrophages (i.e., by inducing them to assume the MI macrophage subtype), dendritic cells, T cells, and neutrophils; [51] and c) increases the cellular and tissue levels of pro-inflammatory reactive oxygen species. 4-Octyl itaconate, dimethyl itaconate, and itaconate inactivate KEAP1 thereby increasing Nrf2's entry into the cell nucleus and inhibiting production of the cited pro-inflammatory cytokines and various reactive oxygen species. [6] [31] [50] [52]

In a model of intracellular inflammation, LPS stimulated mouse bone marrow-derived macrophages to increase their levels of IL-1β, tumor necrosis factor, hypoxia-inducible factor 1-alpha, and reactive oxygen species. 4-Octyl itaconate suppressed all of these LPS-induced responses. It also reduced the production of IL-1β and tumor necrosis factor in LPS-stimulated human peripheral blood monocytes. And, in a model of LPS-induced septic shock, mice injected intraperitoneally with LPS plus 4-octyl itaconate had fewer physical symptoms of shock, lower serum levels of the pro-inflammatory cytokines, IL-1β and tumor necrosis factor, unchanged levels of the anti-inflammatory cytokine interleukin 10, and longer survival times compared to mice treated with LPS but not 4-octyl itaconate. Thus, the inhibitory effects of 4-octyl itaconate, dimethyl itaconate, and itaconate on cells appear due to their inactivation of KEAP1 and resulting movement of cytosolic Nrf2 into the cell nucleus where it inhibits its target genes from producing reactive oxygen species and the cited inflammation-promoting proteins. This mechanism may also underlie 4-octyl itaconate's ability to reduce the severity of LPS-induced shock in mice. [31]

Inhibit NLRP3

The NLRP3-containing inflammasome, like the other types of inflammasomes, is a cytosolic multiprotein complex that when activated promotes inflammatory reactions. The NLRP3-containing inflammasome forms in response to danger signals (e.g., LPS, pathogens, etc.). These signals cause cytosolic NLRP3 (i.e., NLR family pyrin domain containing 3) to bind PYCARD (i.e., apoptosis-associated speck-like protein containing a CARD) which in turn binds and activates the enzyme caspase 1 to form the functional NLRP3-containing inflammasome. This inflammasome's activated caspase 1 cleaves a) the protein precursors of IL-1β and interleukin 18 into their active pro-inflammatory cytokine forms and b) gasdermin D (also termed GSDMD) into its active form that triggers its parent cell's pyroptosis response. Pyroptosis is a form of programmed cell death which causes parent cell swelling, Lysis (i.e., the breakdown of their surface membranes), and the release of IL-1β and interleukin 18 into the extracellular space where they stimulate other cells to mount inflammatory responses. [14] [49] [53]

In one study, cultured bone marrow-derived mouse macrophages were treated with LPS for 3 hours, 4-octyl itaconate or buffer for the next 45 minutes, nigericin or adenosine triphosphate (both agents activate NLRP3) for the next 45 minutes, and then assayed for extracellular IL-1β, interleukin 18, gasdermin D, and a protein not released by cells unless they had died, lactate dehydrogenase. Compared to cells not treated with 4-octyl itaconate, 4-octyl itaconate-treated cells released less IL-1β, interleukin 18, gasdermin D, and lactate dehydrogenase. Thus, 4-octyl itaconate suppressed the release of the two pro-inflammatory cytokines by, and reduced the death rate of, these cells. Dimethyl itaconate and itaconate likewise inhibited these cells from releasing IL-1β (release of the other proteins not reported). Similar results occurred in studies on mononuclear cells isolated from the blood of persons who did or did not have the cryopyrin-associated periodic syndrome, i.e., CAPS. CAPS is an autoinflammatory disease due to any one of several different mutations in the NLRP3 gene; these mutations cause cells to release excessive amounts of IL-1β. 4-Octyl itaconate inhibited the release of IL-1β from LPS- or Pam3CSK4-stimulated (Pam3CSK4a mimics LPS's actions [54] ), nigericin-activated mononuclear cells isolated from the blood of persons who did or did not have CAPS. [55] Finally, the injection of monosodium urate crystals (a form of uric acid that activates the NLRP3 inflammasome) into the peritoneum of mice caused peritonitis (i.e., inflammation of the serous membrane that lines the abdominal cavity and the cavity's organs (e.g., intestines, liver, etc.). Injection of 4-octyl itaconate along with the uric acid crystals significantly reduced this inflammation response as indicated by the lower levels of IL-1β and another pro-inflammatory cytokine, interleukin 6 (i.e., IL-6), and fewer inflammation-inducing neutrophils in the peritoneum compared to 4-octyl itaconate-untreated mice. These studies indicate that itaconate, dimethyl itaconate, and 4-octyl itaconate inhibit NLRP3 and thereby the formation of the active NLRP3 inflammasome. This inhibition appears responsible for the ability of itaconate, dimethyl itaconate, and 4-octyl itaconate to suppress the pro-inflammatory responses of mouse macrophages and human mononuclear cells to LPS as well as the ability of 4-octyl itaconate to suppress the peritoneal inflammatory response of mice to urate crystals. [14] [55]

Increase ATF3 levels

ATF3 (i.e., cyclic AMP-dependent transcription factor ATF-3) is a transcription factor that inhibits the NFKBIZ gene's expression of NF-kappa-B inhibitor zeta (i.e., IκBζ), a protein located in the cell nucleus that promotes the production of certain pro-inflammatory cytokines such as IL-6, [14] [43] interferon gamma, and granulocyte-macrophage colony-stimulating factor. [43] [44] Itaconate and dimethyl itaconate stimulate the production of ATF3 thereby suppressing the cellular levels of IκBζ and IL-6 as well as IL-6-promoted inflammatory responses. [7] [14] [56]

Studies have shown that: a)Atf3 gene knockout embryonic mouse fibroblasts [6] and bone marrow-derived mouse macrophages [57] (these cells lack ATF3 protein) had higher levels of IκBζ and pro-inflammatory cytokines (including IL-6 in the macrophage study) than control (i.e., ATF3 protein-expressing) fibroblasts and macrophages; b)Irg1 gene knockout peritoneal macrophages (i.e., macrophages lacking the itaconate-forming enzyme, IRK1) had lower levels of ATF3 than control mice but 4-oleyl itaconate treatment increased their ATF3 levels; c) dimethyl itaconate inhibited the ability of LPS to increase the levels of IκBζ protein and IL-6 in mouse bone marrow-derived macrophages; [56] d)Atf3 gene knockout mice with experimentally-induced inflammation of their hearts caused by either myocardial infarction due to the ligation of their left anterior descending coronary artery or by intraperitoneal injections of the heart-injuring drug, doxorubicin, developed greater levels of cardiac tissue inflammation, larger cardiac infarction (i.e., dead tissue) sizes, more cardiac fibrosis, poorer cardiac function, and higher blood serum levels of IL-6 than ATF3-expressing control mice; and e) 4-octyl itaconate reduced the IL-6 serum levels, cardiac inflammation, cardiac fibrosis, infarction size, and cardiac dysfunction caused by myocardial infarction or doxorubicin in Atf3 gene knockout mice. [58] These findings suggest that 4-octyl itaconate and dimethyl itaconate have anti-inflammatory actions in these cited models of inflammation and do so by increasing ATF3 and/or decreasing IκBζ levels which in turn reduces the levels of inflammation-promoting cytokines. [6] [59] [56]

Inhibit Tet methylcytosine dioxygenase 2

Tet methylcytosine dioxygenase 2 (i.e., TET2) is an enzyme that is activated by the tricarboxylic acid cycle intermediate metabolite, α-ketoglutarate. Itaconate blocks this activation. [19] Activated TET2 hydroxylates, i.e. adds a hydride group (notated as OH−), to the methyl group (notated as -CH3) of 5-methylcytosine on the cytosine (i.e., C) in the CpG sites of the DNA in its target genes. The 5-hydroxymethylcytosine DNA formed by this hydroxylation may inhibit or stimulate some of these target genes' production of the proteins they direct to be made (see Gene expression). [60] In addition, TET2 binds to two histone deacetylases, HDAC1 and HDAC2, which are thereby activated. The gene expression-regulating and HDAC1/2 activation effects of itaconate have anti-inflammatory actions. For example, they suppress the levels of the proinflammatory cytokines, IL-6 and IL-1β, in dendritic cells and macrophages. [40] [60] [61] [62]

Studies have shown that: a) itaconate blocked α-ketoglutarate from binding to and thereby activating the isolated TET2 protein in a cell-free system; b)TET2 gene knockout bone marrow-derived macrophages (i.e., BMDMs) had far lower levels of hydroxymethylcytosine in their DNA than control macrophages; c) itaconate and 4-octyl itaconate lowered the amount of hydroxymethylcytosine in the DNA of control but not in TET2 gene knockout BMDMs; d) LPS stimulation of mouse macrophage RAW264.7 cells (these cells express TET2) caused increases in their levels of the messenger RNA (and presumably therefore the protein levels) of three proinflammatory chemokines (i.e., proteins that among other functions mobilize inflammation-promoting leukocytes), CXCL9, CXCL10, and CXCL11, but did not do so in Tet2 gene knockout RAW264.7 cells; e) itaconate reduced the ability of LPS to stimulate rises in the messenger RNA levels for IL-6 and IL-1β in RAW264.7 cells; f) 4-octyl itaconate reduced the ability of LPS to raise the messenger RNA levels of IκBζ, Il-6, CXCL9, CXCL10, and CXCL11 in the RAW264 cells; g) in a model of LPS-induced septic shock, LPS-treated Irg1 gene knockout mice (i.e., mice lacking the itaconate-forming protein, IRG1), had higher serum levels of IL-6, greater lung damage, and poorer survival times than control (i.e. IRG1-expressing) LPS-treated mice; h) compared to LPS-treated control mice, LPS-treated mice that were made to express an inactive TET2 protein (termed Tet2HxD) in place of active TET2 protein had lower serum levels of pro-inflammatory cytokines IL-6 and tumor necrosis factor, lower serum levels of the proinflammatory chemokine CXCL9, lower serum levels of alanine transaminase and aspartate transaminase (i.e., liver proteins that are released in the circulation by damaged livers), less severe pulmonary edema and lung tissue injury, and longer survival times; and i) the intraperitoneal injection of itaconate 12 hours before LPS treatment of in mice expressing active TET2 likewise had lower serum levels of IL-6, tumor necrosis factor, CXCL9, alanine transaminase, and aspartate transaminase, less severe pulmonary edema and lung tissue injury, and longer survival times. [7] [63] These findings indicate that 4-octyl itaconate and itaconate inhibit the activation of TET2 and thereby the production of various proinflammatory cytokines and chemokines. At least some of these itaconate and 4-octyl itaconate actions appear to suppress the sepsis shock-like actions of LPS in mice. Further studies are needed to determine in itaconate and/or itaconate-like compounds suppress other inflammatory conditions. [7] [63] (Since TET2 inactivating gene mutations in humans have been associated the development of various cancers such as acute myeloid leukemia, the possibility that itaconate's inhibition of TET2's catalytic activity may lead to these cancers requires investigation. [7] )

Inhibit interleukin 17A

Interleukin 17 (i.e., IL-17) refers to any one of 6 different but closely related subtypes, IL-17A to IL17F. IL-17A is a pro-inflammatory cytokine that is commonly elevated in cells undergoing inflammatory responses. [59] (Some studies used the term IL-17 when referring to IL-17A or when the subtype of IL-17 measured was undefined.) Excessive IL-17A production appears to contribute to the development of various autoimmune diseases [64] by stabilizing the messenger RNA for IκBζ and thereby increasing cellular levels of IκBζ protein and IL-6. [42] [59]

A study focusing on models of the skin autoimmune disease psoriasis reported that: a) cultured mouse and human keratinocytes, i.e., skin cells, treated with IL-17A increased their levels of IκBζ; b) pretreatment of these skin cells with dimethyl itaconate inhibited this increase; c) the application of imiquimod to the skin of mouse ears daily for 7 days caused psoriasis-like ear skin scaling (i.e., thickening of the skin's stratum corneum due to dry or greasy laminated masses of keratin) and edema in control mice but not do so in mice treated injected intraperitoneally with dimethyl itaconate 24 hours before application of imiquimod; and d) analysis of the ear skin of these mice found significant stimulation of various IκBζ-targeted genes in control mice but not in dimethyl itaconate-treated mice. These results suggest that dimethyl itaconate inhibited IL-17A's ability to increase IκBζ levels and thereby reduced the levels of IL-6 in mouse and human keratinocytes; this mechanism may have been responsible for the ability of dimethyl itaconate to block the psoriasis-like skin response of mice to imiquimod. [59] [56] Elevated levels of IL-17 (assumed to be IL-17A unless future studies define it as another IL-17 subtype) occur in the cells involved in other human autoimmune inflammatory disorders besides psoriasis. [65] These other disorders include ankylosing spondylitis; [66] rheumatoid arthritis; [67] spondyloarthritis diseases (i.e., rheumatoid factor-antibody negative ankylosing spondylitis, psoriatic spondylitis, certain forms of reactive arthritis, inflammatory bowel disease-associated spondylitis, and unclassifiable spondylitis); [68] Crohn's disease; [67] ulcerative colitis, [69] and Sjögren’s syndrome. [42] [43] The effects of itaconate or one of its analogs in animal models of these autoimmune diseases should be examined in a manner similar to the studies in psoriasis. [59]

Antibacterial actions

Itaconate can act directly on certain types of bacteria to limit their growth and disease-causing abilities. The enzyme isocitrate lyase is required for the glyoxylate cycle to operate in many bacteria. This cycle is a vital metabolic pathway that uses compounds containing 2 carbon atoms such as acetate to meet bacterial carbon needs when simple sugars, e.g., glucose, are unavailable. [70] Itaconate inhibits isocitrate lyase and thereby the functioning of the glycolate cycle and the growth of cultured and/or phagocytosed Staphylococcus aureus (including multiple drug resistant Staphyoocccus aureus), Vogesella indigofera (also termed Pseudomonas indigofera ), Legionella pneumophila , Mycobacterium avium , Salmonella enterica, Coxiella burnetii , Francisella tularensis , and Acinetobacter baumannii. [8] [14] [19] [40] [48] [71]

Studies examining the effects of itaconate and itaconate-like compounds on phagocytosed bacterial have reported that: a) mouse bone marrow-derived macrophages exposed to live or heat-killed Staphylococcus aureus rapidly (i.e., within 1 hour) developed increases in their levels of IRG1 and IRG1's metabolite, itaconate; b ) human Müller retinal glia IO-M1 cells exposed to these live or heat-killed bacterial likewise showed rapid increases in their IRG1 levels (itaconate not measured); c) 4-octyl itaconate and dimethyl itaconate suppressed the growth of Staphylococcus aureus in mouse bone marrow-derived macrophages and Müller retinal glial IO-M1 cells by inhibiting these cells formation of the NLRP3 inflammasome and thereby the production of pro-inflammatory cytokines such as IL-1β; [14] [28] and d) itaconate suppressed the growth of Salmonella typhimurium in mouse macrophage-like RAW264.7 cells by stimulating these cells to produce reactive oxygen species. [72] In a study of bacteria-induced endophthalmitis (i.e., eye inflammation): a) mice injected with live Staphylococcus aureus into their eye's aqueous humor developed increased retina tissue levels of the itaconate-forming enzyme, IRG1, as well as itaconate; b)Irg1 gene knockout mice (i.e., mice lacking IRG1 protein) that had interocular injections of these bacteria developed severer disease than control (i.e., IRG1-exressing) mice receiving these bacteria injections; c) Mice intraocularly injected with these bacteria plus itaconate, 4-octyl itaconate, or dimethyl itaconate developed less severe eye damage and fewer interocular bacteria than mice injected with these bacteria without getting injected with itaconate or the itaconate analogs; d) adding antibiotics to the itaconate treatment further reduced the severity of these eye infections; and e) analysis of the aqueous humor in the eyes of 22 patients with bacterial eye infections (i.e., 12 gram-positive and 10 gram-negative bacteria) found significantly higher levels of itaconate than those in the eyes of 10 patients with non-infectious eye problems (e.g., retinal detachment). These findings suggest that itaconate functions to suppress the growth of the cited bacteria in mice and may also do so in humans. They also support studies to determine if itaconate or itaconate-like compounds are useful for treating human Staphylococcus aureus eye infections, other types of bacterial eye infections in animals and humans, and animal and human infections in other tissue sites besides the eye. [14] [28] It should be noted, however, that Staphylococcus aureus and at least one other bacterial species, Pseudomonas aeruginosa, can use host cell-derived itaconate to form a biofilm that covers their surfaces and thereby increases their survival and pathogenicity. [40] [73]

Antiviral actions

Itaconate suppresses the growth of certain disease-causing viruses. Zika virus causes the mosquito-transmitted human disease, Zika fever. The virus produces symptomatic disease in only 20% of infected humans. These symptoms, which are usually mild, include rashes, fevers, conjunctivitis, muscle pains, joint pains, malaise, and headaches lasting for 2–7 days. However, the virus can cause severe nervous system birth defects in babies when it is transmitted from infected mothers to their embryos. These "congenital zika syndrome" defects include microcephaly, craniosynostosis (i.e., premature closure of the skull's fontanels), cerebellar hypoplasia, ventriculomegaly, and various other nervous system malformations. Zika virus also causes severe non-congenital nervous system inflammatory disorders such as the Guillain-Barré syndrome, encephalitis, disseminated encephalomyelitis, and transverse myelitis; in rare cases, it also causes cerebrovascular strokes. As of 2023, there were no vaccines or antiviral medications available to treat Zika fever. [74] In cell culture studies, human A549 lung adenocarcinoma cells and Huh7 human hepatocyte-derived cancer cells were treated with buffer or 4-octyl itaconate for 2 days and then infected with Zika virus for 4 days. 4-Octyl itaconate suppressed the growth of this virus in both cancer cell types. [75] In a model of neurological Zika disease, mice were injected intracranially with Zika virus plus or minus 4-octyl itaconate. 4-Ocyl itaconate significantly reduced the number of brain tissue Zika viruses. This study also indicated that the antiviral action of 4-octyl itaconate was associated with its inhibition of the succinate dehydrogenase enzyme and the resulting rises in brain tissue levels of succinate. Further studies are needed to determine if itaconate and/or its analogs will prove useful for treating Zika fever in humans. [14] [76]

4-Octyl itaconate also suppresses the proliferation of COVID-19. Treating cultured Vero cells (i.e., cells originally isolated from an African green monkey) with 4-octyl itaconate before infecting them with SARS-CoV-2 (strain #291.3 FR-4286) greatly reduced their content of this virus's RNA, the number of viral particles released by the Vero cells, and the number of Vero cells killed by the virus. 4-Octyl itaconate had similar anti-viral effects on cultured SARS-CoV-2-infected human lung cancer Calu-3 cells, human epithelial NuLi cells, and human airway epithelial cells. Further studies strongly suggested that these anti-viral actions of 4-octyl itaconate were due to its stimulating increases in the activity of the Nrf2 transcription factor (see the above section termed "Inhibit KEAP1"). [40] [75] Studies have also been conducted on cultured cells challenged with other disease-causing viruses. One or more of the itaconate analogs was shown to inhibit the growth of: a) Herpes simplex viruses types 1 and 2 in cultured human HaCaT keratinocyte skin cells; b) Vaccinia virus in human HaCaT T keratinocyte skin cells and mouse bone marrow-derived macrophages; [75] and c) Zika virus in A549 and Huh-7 cells (see previous paragraph). [75] Notably, however, 4-octyl itaconate enhanced rather than inhibited the growth of vesicular stomatitis virus in cultured 4T1 mouse breast cancer and 786-O human kidney carcinoma cells; it also reduced the inflammatory response to, and improved the survival of, influenza A virus but did not inhibit this virus's growth in mice. [29]

Anti-cancer actions

Individuals with inflammatory bowel diseases, i.e., ulcerative colitis and Crohn's disease, have an increased risk of developing cancer in the afflicted areas of their colons and other parts of their gastrointestinal tracts. [77] In a murine model of inflammatory bowel disease leading to colon cancer, mice were given an intraperitoneal injection of the cancer-causing agent azomethane on day 0, on day 5 were given an intraperitoneal injection of dimethyl itaconate or the vehicle used to dissolve dimethyl itaconate, on days 5 through 9 were given drinking water containing the colitis-causing agent dextran sodium sulfate, and on days 10 through 25 were given normal drinking water. After repeating this cycle three times, the mice were euthanized. Compared to mice treated with the vehicle, mice treated with dimethyl itaconate showed; a) less thickened and hyperplastic colons; b) fewer inflammatory cells in their colons; c) lower colon tissue levels of the proinflammatory cytokines, IL-1β and IL-6 as well as the proinflammatory chemokines, CCL2, CCL17, and Interleukin 8; and d) far fewer colon tumors. These findings indicate that dimethyl itaconate inhibited colon inflammatory responses to dextran sodium sulfate and presumably thereby colon cancer responses to azomethane in mice. They also support further preclinical studies to determine if itaconate-like compounds suppress human inflammation-related colon cancers. [7] [78]

Retinoblastoma is a cancer that develops in the retinas of individuals who are most often children under 4–5 years old. It is caused by inheriting or acquiring an inactive gene in both of their retinoblastoma genes, i.e., RB1 genes. In the absence of a functional RB1 gene, immature cells in the retina commonly become retinoblastomas. High-risk retinoblastomas, e.g., those that have invaded tissues outside of the eyeball and/or metastasized to distant tissues, are treated aggressively with long-term chemotherapy regimens that frequently include carboplatin. [79] [80] The retinoblastomas of patients treated with this regimen often become resistant to carboplatin as well as other chemotherapy drugs such as etoposide and vincristine, i.e., they are multiple drug resistant retinoblastomas. A recent study reported several key findings. First, cultured Y79 cells (a human retinoblastoma-derived cell-line [81] ) were made resistant to carboplatin by a limiting dilution method. That is, Y29 cells were incubated with carboplatin to allow overgrowth and isolation of carboplatin-resistant Y79 cells. These carboplatin-resistant cells, termed Y79-CR cells, were also resistant to etoposide and vincristine. Second, compared to Y79 cells, Y79-CR cells had far higher levels of autophagy, i.e., degradation of cell components by a lysosome-dependent mechanism. Third, treating Y79-CR cells with agents that suppress autophagy restored their sensitivity to the cell-killing actions of carboplatin, etoposide, and vincristine. Fourth, carboplatin inhibited Y79-CR cell growth in part by causing them to die by a programmed cell death mechanism. Erastin, a compound that triggers a form of programed cell death termed ferroptosis, stimulated Y79-CR cell death but was much less effective in doing so in Y79 cells. Ferroptosis increases the cellular levels of ferrous, a highly reactive form of iron which stimulates the production of cell-toxic reactive oxygen species and peroxidized lipids. Fifth, 4-octyl itaconate induced Y79-CR cells to die, apparently by ferroptosis, i.e., it increased these cells ferrous and lipid peroxidation levels. And sixth, nude mice (i.e., immunodefient mice) were implanted with Y79-CR or Y79 cells in the subcutaneously issue of their flanks; one week later were interperitoneally injected with 4-octyl itaconate or the vehicle used to dissolve 4-octyl itaconate once every other day for 2 weeks; and were euthanized 21 days later. Tumor masses in mice given Y79-CL cells were far less in 4-octyl itaconate-treated than vehicle-treated mice. Also, the differences in tumor masses between 4-octyl itaconate-treated and vehicle-treated mice transplanted with Y79 cells were much less than that in mice transplanted with Y19-CR cells. These results indicate that 4-octyl itaconate selectively kills multiple drug resistant Y79-CR cells that are cultured or implanted in mice and does so by triggering ferroptosis. They also support studies to learn if itaconate and itaconate-like compounds would be useful for treating humans with carboplatin-resistant or other forms of multiple drug resistant retinoblastomas and perhaps other multiple drug resistant cancers. [7] [79] [80]

Thymic carcinoma is a form of thymus gland cancer. In more advanced cases, it is commonly treated with platinum-based antineoplastic drugs and lenvatinib, an inhibitor of vascular endothelial growth factor receptors. However, patients often are or develop resistant to these drugs. Consequently, other agents are being evaluated as treatments for thymic carcinomas. A recent preclinical study reported that dimethyl itaconate decreased the proliferation of cultured Ty82 human thymic carcinoma cells but had relatively little effect on the proliferation of cultured non-cancerous human fibroblasts. Dimethyl itaconate treatment of the Ty82 cells decreased the activity of their mTOR protein as well as PI3K/AKT/mTOR pathway (This pathway promotes the development and/or progression of many cancers including some thymus gland cancers.) Temsirolimus, a specific inhibitor of mTOR, mimicked the action of dimethyl itaconate in suppressing the proliferation of Ty82 cells. [7] [82] [83] [84] These findings suggest that dimethyl itaconate inhibits the proliferation of Ty82 mouse cells by suppressing the activity of their mTOR protein and I3K/AKT/mTOR pathway. Further studies are needed to determine the effects of dimethyl itaconate, other itaconate-like compounds, and/or itaconate treating animals models of thymic carcinomas. [7] [82]

Varying actions of itaconate and its analogs

One study [38] reported that dimethyl itaconate and 4-octyl itaconate stimulated mouse bone marrow-derived macrophages to produce pro-interferon-β (i.e., the precursor to the proinflammatory cytokine IFN-β as well as to secrete IL-6, interleukin 10, and IFN-β whereas itaconate and 4-ethyl itaconate had far less ability to or did not stimulate these responses. This result suggests that future studies should examine the actions of itaconate along with those of each of its analogs. [14] [38]

Commercial production and uses of itaconic acid

Itaconic acid is a non-toxic [15] white solid that is soluble in water, ethanol, and acetone. Historically, it was obtained in relatively small quantities by the dry distillation of citric acid to form itaconic anhydride which then is hydrolyzed, i.e., broken down by water, to form itaconic acid. [85] Since the 1960s, however, it has been produced for industry in the far larger amounts they need by fermenting glucose, molasses, or another carbohydrate by a fungus such as Aspergillus itaconicus, [86] Aspergillus terreus , or Ustilago maydis. [87] One generally accepted route by which fungi make itaconate is through their tricarboxylic acid cycle pathway. This pathway forms cis-aconitate which is converted to itaconate by cis-aconitate-decarboxylase (i.e., IRG1; see above section titled "Itaconate-forming metabolic pathway"). The itaconate made in this fermentation mixture is isolated in the form of itaconic acid. [88] Ustilago maydis ( a species of Ustilago that causes the plant disease smut fungus) uses a different route to form itaconic acid. Its fermentation makes cis-aconitate which is converted to the thermodynamically favored product, trans-aconitate, by the enzyme aconitate delta-isomerase. The trans-aconitate product is decarboxylated to itaconate by trans-aconitate decarboxylase (i.e., TAD1, an enzyme found in Ustilago maydis [89] ). The itaconate in this fermentation mixture is isolated in its itaconic acid form. [90] Itaconate has also been obtained by: a) fermenting the fungi Yarrowia lipolytica with glucose, various species of Candida fungi with glucose, Ustilago vetiveriae fungus with glycerol, and various species of Aspergillus niger fungi with glucose, sorbitol, or sorbitol plus xylose mixture and b) fermenting Escherichia coli bacteria with glucose, xylose, glycerol, or starch and Corynebacterium glutamicum bacteria with glucose or urea. [91] Among the fungi, Aspergillus terreus has been the organism of choice for industrial itaconic acid production in part because it gives relatively high yields of itaconic acid. Recently, however, Ustilago maydis has been genetically engineered to increase its itaconic acid production and is being studied for its usefulness in mass-producing itaconic acid. [92]

Itaconic acid's chemical structure consists of one unsaturated double bond and two carboxyl groups (see carboxylic acid}. This structure renders it readily converted to many valuable bio-based materials (i.e., materials derived from a living or once-living organism). For many years, these materials were commonly produced in the large amounts needed for industrial purposes from various types of carbohydrates. [3] [93] More recently, itaconic acid has also been used to make these materials. In doing so, it is a comonomer, i.e., a precursor monomer, that is readily polymerized to various desired polymers that are further altered to form some of the same or similar products made from the polymerization of carbohydrates. The products made from itaconate include synthetic styrene-butadiene-based rubber, synthetic latexes, various plastics, superabsorbent polymers that absorb large amounts of liquids (for use in, e.g., baby diapers), unsaturated polyester resins that are used to make glass fiber-reinforced plastics (e.g., fiberglass), detergents, [3] and biofuels (i.e., fuels made from organic materials such as itaconic acid). [94] It is also converted to methyl methacrylate, [91] a product that has many commercial and some medical applications (see uses of methyl methacrylate). Fields using the products of itaconate include those that manufacture paint, lacquers (i.e., coatings for covering the surfaces of various objects), plasticizers, plastics, chemical fibers, hygienic materials, construction materials, [3] and environmentally-friendly fuels that can be substituted for pollution-causing, non-renewable fuels such as coal, oil, and natural gas. [94] Itaconic acid itself may be mass-produced if it or any of the analogs synthesized from it are found to be useful for treating medical disorders. [3]

Recently, the demand for itaconic acid has grown to such an extent that it is projected to reach a market value of 177 million dollars per year in United States of American currency by 2028. Consequently, alternate methods for making products with properties similar or identical to those made from itaconic acid by using less costly substitutes for itaconic acid and/or methods that are more productive, less expensive, and/or more environmental-friendly than those used for itaconic acid are being evaluated. [15] Betulin, for example, is an abundant, naturally occurring diol triterpene that is readily isolated from the bark of birch trees. Betulin forms polymers that have some of the biochemical properties found in itaconate polymers. Consequently, botulin is being studied to determine if it can be used in place of itaconic acid to form products with properties similar to those made from itaconic acid but doing so in economically and/or environmentally more favorable ways. [15]

Related Research Articles

α-Ketoglutaric acid Chemical compound

α-Ketoglutaric acid is a dicarboxylic acid, i.e., a short-chain fatty acid containing two carboxyl groups with C, O, and H standing for carbon, oxygen, and hydrogen, respectively. However, almost all animal tissues and extracellular fluids have a pH above 7. At these basic pH levels α-ketoglutaric acid exists almost exclusively as its conjugate base. That is, it has two negative electric charges due to its release of positively charged hydrogen from both of its now negatively charged carboxy groups, CO−2. This double negatively charge molecule is referred to as α-ketoglutarate or 2-oxoglutarate.

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

<span class="mw-page-title-main">Interleukin 18</span> Protein-coding gene in the species Homo sapiens

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, and liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

The enzyme aconitate decarboxylase (EC 4.1.1.6) (i.e., ACOD1, also termed cis-aconitate decarboxylase, immune-responsive gene 1, immune response gene 1, and IRK1) is a protein enzyme that in humans is encoded by the decarboxylase 1 aconitate decarboxylase 1 gene located at position 22.3 on the long arm (i.e., p-arm) of chromosome 13. ACOD1 catalyzes the following reversible (i.e., runs in both directions, as indicated by ) decarboxylation chemical reaction:

<span class="mw-page-title-main">OXGR1</span> Protein-coding gene in the species Homo sapiens

OXGR1, i.e., 2-oxoglutarate receptor 1 is a G protein-coupled receptor located on the surface membranes of certain cells. It functions by binding one of its ligands and thereby becoming active in triggering pre-programmed responses in its parent cells. OXGR1 has been shown to be activated by α-ketoglutarate, itaconate, and three cysteinyl-containing leukotrienes, leukotriene E4, LTC4, and LTD4. α-Ketoglutarate and itaconate are the dianionic forms of α-ketoglutaric acid and itaconic acid, respectively. α-Ketoglutaric and itaconic acids are short-chain dicarboxylic acids that have two carboxyl groups both of which are bound to hydrogen. However, at the basic pH levels in virtually all animal tissues, α-ketoglutaric acid and itaconic acid exit almost exclusively as α-ketoglutarate and itaconate, i.e., with their carboxy residues being negatively charged, because they are not bound to H+. It is α-ketoglutarate and itaconate, not α-ketoglutaric or itaconic acids, which activate OXGR1.

<span class="mw-page-title-main">GPR132</span> Protein-coding gene in the species Homo sapiens

G protein coupled receptor 132, also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e. GPR4, GPR68 (OGR1), and GPR65 (TDAG8), G2A is a G protein coupled receptor that resides in the cell surface membrane, senses changes in extracellular pH, and can alter cellular function as a consequence of these changes. Subsequently, G2A was suggested to be a receptor for lysophosphatidylcholine (LPC). However, the roles of G2A as a pH-sensor or LPC receptor are disputed. Rather, current studies suggest that it is a receptor for certain metabolites of the polyunsaturated fatty acid, linoleic acid.

<span class="mw-page-title-main">GPR84</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.

<span class="mw-page-title-main">SUCNR1</span> Protein-coding gene in the species Homo sapiens

Succinate receptor 1 (SUCNR1), previously named G protein-coupled receptor 91 (GPR91), is a receptor that is activated by succinate, i.e., the anionic form of the dicarboxylic acid, succinic acid. Succinate and succinic acid readily convert into each other by gaining (succinate) or losing (succinic acid) protons, i.e., H+ (see Ions). Succinate is by far the predominant form of this interconversion in living organisms. Succinate is one of the intermediate metabolites in the citric acid cycle (also termed the TCA cycle or tricarboxylic acid cycle). This cycle is a metabolic pathway that operates in the mitochondria of virtually all eucaryotic cells. It consists of a series of biochemical reactions that serve the vital function of releasing the energy stored in nutrient carbohydrates, fats, and proteins. Recent studies have found that some of the metabolites in this cycle are able to regulate various physiological and pathological functions in a wide range of cell types. The succinyl CoA in this cycle may release its bound succinate; succinate is one of these mitochondrial-formed bioactive metabolites.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.

<span class="mw-page-title-main">Free fatty acid receptor 4</span> Protein-coding gene in the species Homo sapiens

Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1, FFAR2, and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.

<span class="mw-page-title-main">NFKBIZ</span> Protein-coding gene in the species Homo sapiens

NF-kappa-B inhibitor zeta (IκBζ) is a protein that in humans is encoded by the NFKBIZ gene. This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-κB proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Adipose tissue macrophages (ATMs) comprise resident macrophages present in adipose tissue. Besides adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells that includes pre-adipocytes, fibroblasts, vascular endothelial cells, and a large variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in obese leptin deficient mice, and up to 40% in obese humans. ATMs comprise nearly 50% of all immune cells in normal conditions, suggesting an important role in supporting normal functioning of the adipose tissue. Increased number of adipose tissue macrophages may correlate with increased production of pro-inflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity, although is becoming recognized that in healthy conditions tissue-resident macrophages actively support a variety of critical physiological functions in nearly all organs and tissues, including adipose tissue.

<span class="mw-page-title-main">NFKBID</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, delta also known as IκBNS is a protein in humans that is encoded by the NFKBID gene.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

References

  1. 1 2 3 4 5 Merck Index , 11th Edition, 5130
  2. ↑ Tretter L, Patocs A, Chinopoulos C (August 2016). "Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1857 (8): 1086–1101. doi: 10.1016/j.bbabio.2016.03.012 . PMID   26971832.
  3. 1 2 3 4 5 6 Kuenz A, Krull S (May 2018). "Biotechnological production of itaconic acid-things you have to know". Applied Microbiology and Biotechnology. 102 (9): 3901–3914. doi:10.1007/s00253-018-8895-7. PMID   29536145.
  4. 1 2 Nie Z, Wang L, Zhao P, Wang Z, Shi Q, Liu H (November 2023). "Metabolomics reveals the impact of nitrogen combined with the zinc supply on zinc availability in calcareous soil via root exudates of winter wheat (Triticum aestivum)". Plant Physiology and Biochemistry. 204: 108069. doi:10.1016/j.plaphy.2023.108069. PMID   37852066.
  5. ↑ Xie LY, Xu YB, Ding XQ, Liang S, Li DL, Fu AK, Zhan XA (November 2023). "Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle". Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 167: 115487. doi: 10.1016/j.biopha.2023.115487 . PMID   37713987.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 Shi X, Zhou H, Wei J, Mo W, Li Q, Lv X (December 2022). "The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases". Redox Biology. 58: 102553. doi:10.1016/j.redox.2022.102553. PMC   9713374 . PMID   36459716.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Yang W, Wang Y, Tao K, Li R (December 2023). "Metabolite itaconate in host immunoregulation and defense". Cellular & Molecular Biology Letters. 28 (1): 100. doi: 10.1186/s11658-023-00503-3 . PMC   10693715 . PMID   38042791.
  8. 1 2 3 Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R, Hiller K (May 2013). "Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production". Proceedings of the National Academy of Sciences of the United States of America. 110 (19): 7820–5. Bibcode:2013PNAS..110.7820M. doi: 10.1073/pnas.1218599110 . PMC   3651434 . PMID   23610393.
  9. 1 2 3 Murphy MP, O'Neill LA (August 2018). "Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers". Cell. 174 (4): 780–784. doi: 10.1016/j.cell.2018.07.030 . PMID   30096309.
  10. ↑ Boondaeng A, Suwanruji P, Vaithanomsat P, Apiwatanapiwat W, Trakunjae C, Janchai P, Apipatpapha T, Chanka N, Chollakup R (July 2021). "Bio-synthesis of itaconic acid as an anti-crease finish for cellulosic fiber fabric". RSC Advances. 11 (42): 25943–25950. Bibcode:2021RSCAd..1125943B. doi:10.1039/d1ra05037k. PMC   9037204 . PMID   35479465.
  11. ↑ Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC, Rabinowitz JD, Roberts MF (October 2011). "Itaconic acid is a mammalian metabolite induced during macrophage activation". Journal of the American Chemical Society. 133 (41): 16386–9. doi:10.1021/ja2070889. PMC   3216473 . PMID   21919507.
  12. ↑ Lewis RN, Sykes BD, McElhaney RN (June 1987). "Thermotropic phase behavior of model membranes composed of phosphatidylcholines containing dl-methyl anteisobranched fatty acids. 1. Differential scanning calorimetric and 31P NMR spectroscopic studies". Biochemistry. 26 (13): 4036–44. doi:10.1021/bi00387a044. PMID   3651434.
  13. ↑ Wu R, Chen F, Wang N, Tang D, Kang R (August 2020). "ACOD1 in immunometabolism and disease". Cellular & Molecular Immunology. 17 (8): 822–833. doi:10.1038/s41423-020-0489-5. PMC   7395145 . PMID   32601305.
  14. 1 2 3 4 5 6 7 8 9 10 11 12 13 Peace CG, O'Neill LA (January 2022). "The role of itaconate in host defense and inflammation". The Journal of Clinical Investigation. 132 (2). doi:10.1172/JCI148548. PMC   8759771 . PMID   35040439.
  15. 1 2 3 4 Lehman-Chong AM, Cox CL, Kinaci E, Burkert SE, Dodge ML, Rosmarin DM, Newell JA, Soh L, Gordon MB, Stanzione JF (September 2023). "Itaconic Acid as a Comonomer in Betulin-Based Thermosets via Sequential and Bulk Preparation". ACS Sustainable Chemistry & Engineering. 11 (38): 14216–14225. doi:10.1021/acssuschemeng.3c04178. PMC   10526528 . PMID   37771764.
  16. 1 2 Zhao H, Teng D, Yang L, Xu X, Chen J, Jiang T, Feng AY, Zhang Y, Frederick DT, Gu L, Cai L, Asara JM, Pasca di Magliano M, Boland GM, Flaherty KT, Swanson KD, Liu D, Rabinowitz JD, Zheng B (December 2022). "Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth". Nature Metabolism. 4 (12): 1660–1673. doi:10.1038/s42255-022-00676-9. PMC   10593361 . PMID   36376563.
  17. ↑ Tomlinson KL, Riquelme SA, Baskota SU, Drikic M, Monk IR, Stinear TP, Lewis IA, Prince AS (February 2023). "Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst". Cell Reports. 42 (2): 112064. doi:10.1016/j.celrep.2023.112064. PMC   10387506 . PMID   36724077.
  18. 1 2 Crossley JL, Ostashevskaya-Gohstand S, Comazzetto S, Hook JS, Guo L, Vishlaghi N, Juan C, Xu L, Horswill AR, Hoxhaj G, Moreland JG, Tower RJ, Levi B (October 2023). "Itaconate-producing neutrophils regulate local and systemic inflammation following trauma". JCI Insight. 8 (20). doi:10.1172/jci.insight.169208. PMC   10619500 . PMID   37707952.
  19. 1 2 3 4 5 6 Lang R, Siddique MN (2024). "Control of immune cell signaling by the immuno-metabolite itaconate". Frontiers in Immunology. 15: 1352165. doi: 10.3389/fimmu.2024.1352165 . PMC   10938597 . PMID   38487538.
  20. 1 2 3 Arnold PK, Finley LW (February 2023). "Regulation and function of the mammalian tricarboxylic acid cycle". The Journal of Biological Chemistry. 299 (2): 102838. doi: 10.1016/j.jbc.2022.102838 . PMC   9871338 . PMID   36581208.
  21. 1 2 3 Fernández-Veledo S, Ceperuelo-Mallafré V, Vendrell J (September 2021). "Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis". Trends in Endocrinology and Metabolism. 32 (9): 680–692. doi:10.1016/j.tem.2021.06.003. PMID   34301438. S2CID   236097682.
  22. 1 2 Aguiar CJ, Rocha-Franco JA, Sousa PA, Santos AK, Ladeira M, Rocha-Resende C, Ladeira LO, Resende RR, Botoni FA, Barrouin Melo M, Lima CX, Carballido JM, Cunha TM, Menezes GB, Guatimosim S, Leite MF (December 2014). "Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation". Cell Communication and Signaling. 12: 78. doi: 10.1186/s12964-014-0078-2 . PMC   4296677 . PMID   25539979.
  23. 1 2 3 Peace CG, O'Carroll SM, O'Neill LA (November 2023). "Fumarate hydratase as a metabolic regulator of immunity". Trends in Cell Biology. doi:10.1016/j.tcb.2023.10.005. PMID   37940417.
  24. 1 2 Wu KK (July 2023). "Extracellular Succinate: A Physiological Messenger and a Pathological Trigger". International Journal of Molecular Sciences. 24 (13): 11165. doi: 10.3390/ijms241311165 . PMC   10342291 . PMID   37446354.
  25. ↑ Moyon A, Garrigue P, Balasse L, Fernandez S, Brige P, Bouhlel A, Hache G, Dignat-George F, Taïeb D, Guillet B (April 2021). "Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study". Cells. 10 (4): 795. doi: 10.3390/cells10040795 . PMC   8066129 . PMID   33918298.
  26. ↑ Krzak G, Willis CM, Smith JA, Pluchino S, Peruzzotti-Jametti L (January 2021). "Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation". Trends in Immunology. 42 (1): 45–58. doi:10.1016/j.it.2020.11.004. PMID   33279412. S2CID   227522279.
  27. 1 2 Dalla Pozza E, Dando I, Pacchiana R, Liboi E, Scupoli MT, Donadelli M, Palmieri M (February 2020). "Regulation of succinate dehydrogenase and role of succinate in cancer". Seminars in Cell & Developmental Biology. 98: 4–14. doi:10.1016/j.semcdb.2019.04.013. PMID   31039394.
  28. 1 2 3 Singh S, Singh PK, Jha A, Naik P, Joseph J, Giri S, Kumar A (May 2021). "Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection". Cell Reports. Medicine. 2 (5): 100277. doi:10.1016/j.xcrm.2021.100277. PMC   8149370 . PMID   34095879.
  29. 1 2 Sohail A, Iqbal AA, Sahini N, Chen F, Tantawy M, Waqas SF, Winterhoff M, Ebensen T, Schultz K, Geffers R, Schughart K, Preusse M, Shehata M, Bähre H, Pils MC, Guzman CA, Mostafa A, Pleschka S, Falk C, Michelucci A, Pessler F (January 2022). "Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection". PLOS Pathogens. 18 (1): e1010219. doi: 10.1371/journal.ppat.1010219 . PMC   8846506 . PMID   35025971.
  30. ↑ Urso A, Prince A (2022). "Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection". Frontiers in Cellular and Infection Microbiology. 12: 925746. doi: 10.3389/fcimb.2022.925746 . PMC   9240774 . PMID   35782110.
  31. 1 2 3 Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa AS, Higgins M, Hams E, Szpyt J, Runtsch MC, King MS, McGouran JF, Fischer R, Kessler BM, McGettrick AF, Hughes MM, Carroll RG, Booty LM, Knatko EV, Meakin PJ, Ashford ML, Modis LK, Brunori G, Sévin DC, Fallon PG, Caldwell ST, Kunji ER, Chouchani ET, Frezza C, Dinkova-Kostova AT, Hartley RC, Murphy MP, O'Neill LA (April 2018). "Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1". Nature. 556 (7699): 113–117. Bibcode:2018Natur.556..113M. doi:10.1038/nature25986. PMC   6047741 . PMID   29590092.
  32. ↑ Fujie N, Ito M, Kishida M, Hirata Y, Kondo A, Tanaka T (November 2022). "Metabolic engineering of Schizosaccharomyces pombe for itaconic acid production". Journal of Biotechnology. 358: 111–117. doi:10.1016/j.jbiotec.2022.09.006. hdl: 20.500.14094/0100476961 . PMID   36122598.
  33. 1 2 3 4 5 6 Zeng YR, Song JB, Wang D, Huang ZX, Zhang C, Sun YP, Shu G, Xiong Y, Guan KL, Ye D, Wang P (March 2023). "The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response". The Journal of Clinical Investigation. 133 (6). doi:10.1172/JCI160463. PMC   10014103 . PMID   36919698.
  34. 1 2 3 4 Ye D, Wang P, Chen LL, Guan KL, Xiong Y (March 2024). "Itaconate in host inflammation and defense". Trends in Endocrinology and Metabolism. doi:10.1016/j.tem.2024.02.004. PMID   38448252.
  35. ↑ Kanaoka Y, Maekawa A, Austen KF (April 2013). "Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand". The Journal of Biological Chemistry. 288 (16): 10967–72. doi: 10.1074/jbc.C113.453704 . PMC   3630866 . PMID   23504326.
  36. ↑ Sasaki F, Yokomizo T (August 2019). "The leukotriene receptors as therapeutic targets of inflammatory diseases". International Immunology. 31 (9): 607–615. doi:10.1093/intimm/dxz044. PMID   31135881.
  37. 1 2 3 He W, Henne A, Lauterbach M, Geißmar E, Nikolka F, Kho C, Heinz A, Dostert C, Grusdat M, Cordes T, Härm J, Goldmann O, Ewen A, Verschueren C, Blay-Cadanet J, Geffers R, Garritsen H, Kneiling M, Holm CK, Metallo CM, Medina E, Abdullah Z, Latz E, Brenner D, Hiller K (May 2022). "Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages". Nature Metabolism. 4 (5): 524–533. doi:10.1038/s42255-022-00565-1. PMC   9744384 . PMID   35655024.
  38. 1 2 3 Swain A, Bambouskova M, Kim H, Andhey PS, Duncan D, Auclair K, Chubukov V, Simons DM, Roddy TP, Stewart KM, Artyomov MN (July 2020). "Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages". Nature Metabolism. 2 (7): 594–602. doi:10.1038/s42255-020-0210-0. PMC   7378276 . PMID   32694786.
  39. 1 2 Gruenwald M, Chen F, Bähre H, Pessler F (July 2022). "Itaconate Isomers in Bread". Antioxidants (Basel, Switzerland). 11 (7): 1382. doi: 10.3390/antiox11071382 . PMC   9312323 . PMID   35883873.
  40. 1 2 3 4 5 McGettrick AF, O'Neill LA (February 2023). "Two for the price of one: itaconate and its derivatives as an anti-infective and anti-inflammatory immunometabolite". Current Opinion in Immunology. 80: 102268. doi:10.1016/j.coi.2022.102268. PMID   36446152.
  41. ↑ Krause BM, Bauer B, Neudörfl JM, Wieder T, Schmalz HG (December 2021). "ItaCORMs: conjugation with a CO-releasing unit greatly enhances the anti-inflammatory activity of itaconates". RSC Medicinal Chemistry. 12 (12): 2053–2059. doi:10.1039/d1md00163a. PMC   8672850 . PMID   35024614.
  42. 1 2 3 Xiao F, Du W, Zhu X, Tang Y, Liu L, Huang E, Deng C, Luo C, Han M, Chen P, Ding L, Hong X, Wu L, Jiang Q, Zou H, Liu D, Lu L (2021). "IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjögren's syndrome". Clinical & Translational Immunology. 10 (4): e1277. doi:10.1002/cti2.1277. PMC   8082715 . PMID   33968407.
  43. 1 2 3 4 Feng Y, Chen Z, Xu Y, Han Y, Jia X, Wang Z, Zhang N, Lv W (2023). "The central inflammatory regulator IκBζ: induction, regulation and physiological functions". Frontiers in Immunology. 14: 1188253. doi: 10.3389/fimmu.2023.1188253 . PMC   10291074 . PMID   37377955.
  44. 1 2 Willems M, Dubois N, Musumeci L, Bours V, Robe PA (October 2016). "IκBζ: an emerging player in cancer". Oncotarget. 7 (40): 66310–66322. doi:10.18632/oncotarget.11624. PMC   5323236 . PMID   27579619.
  45. ↑ Feijoo-Siota L, Rama JL, Sánchez-Pérez A, Villa TG (July 2017). "Considerations on bacterial nucleoids". Applied Microbiology and Biotechnology. 101 (14): 5591–5602. doi:10.1007/s00253-017-8381-7. PMID   28664324.
  46. ↑ McNeil MB, Clulow JS, Wilf NM, Salmond GP, Fineran PC (May 2012). "SdhE is a conserved protein required for flavinylation of succinate dehydrogenase in bacteria". The Journal of Biological Chemistry. 287 (22): 18418–28. doi: 10.1074/jbc.M111.293803 . PMC   3365757 . PMID   22474332.
  47. ↑ Cordes T, Metallo CM (February 2021). "Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex II and Methylmalonyl-CoA Mutase". Metabolites. 11 (2): 117. doi: 10.3390/metabo11020117 . PMC   7922098 . PMID   33670656.
  48. 1 2 Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, Cervantes-Barragan L, Ma X, Huang SC, Griss T, Weinheimer CJ, Khader S, Randolph GJ, Pearce EJ, Jones RG, Diwan A, Diamond MS, Artyomov MN (July 2016). "Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation". Cell Metabolism. 24 (1): 158–66. doi:10.1016/j.cmet.2016.06.004. PMC   5108454 . PMID   27374498.
  49. 1 2 Fu J, Wu H (April 2023). "Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation". Annual Review of Immunology. 41: 301–316. doi: 10.1146/annurev-immunol-081022-021207 . PMC   10159982 . PMID   36750315.
  50. 1 2 Pyrillou K, Burzynski LC, Clarke MC (2020). "Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease". Frontiers in Immunology. 11: 613170. doi: 10.3389/fimmu.2020.613170 . PMC   7775495 . PMID   33391283.
  51. ↑ McGettrick AF, O'Neill LA (October 2020). "The Role of HIF in Immunity and Inflammation". Cell Metabolism. 32 (4): 524–536. doi: 10.1016/j.cmet.2020.08.002 . PMID   32853548.
  52. ↑ Ryan DG, Murphy MP, Frezza C, Prag HA, Chouchani ET, O'Neill LA, Mills EL (January 2019). "Coupling Krebs cycle metabolites to signaling in immunity and cancer". Nature Metabolism. 1: 16–33. doi:10.1038/s42255-018-0014-7. PMC   6485344 . PMID   31032474.
  53. ↑ Coll RC, Schroder K, Pelegrín P (August 2022). "NLRP3 and pyroptosis blockers for treating inflammatory diseases". Trends in Pharmacological Sciences. 43 (8): 653–668. doi:10.1016/j.tips.2022.04.003. PMID   35513901.
  54. ↑ Nigar S, Shimosato T (2019). "Cooperation of Oligodeoxynucleotides and Synthetic Molecules as Enhanced Immune Modulators". Frontiers in Nutrition. 6: 140. doi: 10.3389/fnut.2019.00140 . PMC   6718720 . PMID   31508424.
  55. 1 2 Hooftman A, Angiari S, Hester S, Corcoran SE, Runtsch MC, Ling C, Ruzek MC, Slivka PF, McGettrick AF, Banahan K, Hughes MM, Irvine AD, Fischer R, O'Neill LA (September 2020). "The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation". Cell Metabolism. 32 (3): 468–478.e7. doi:10.1016/j.cmet.2020.07.016. PMC   7422798 . PMID   32791101.
  56. 1 2 3 4 Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, Duncan D, Bregman H, Keskin A, Santeford A, Apte RS, Sehgal R, Johnson B, Amarasinghe GK, Soares MP, Satoh T, Akira S, Hai T, de Guzman Strong C, Auclair K, Roddy TP, Biller SA, Jovanovic M, Klechevsky E, Stewart KM, Randolph GJ, Artyomov MN (April 2018). "Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis". Nature. 556 (7702): 501–504. Bibcode:2018Natur.556..501B. doi:10.1038/s41586-018-0052-z. PMC   6037913 . PMID   29670287.
  57. ↑ Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC, Kennedy K, Hai T, Bolouri H, Aderem A (May 2006). "Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4". Nature. 441 (7090): 173–8. Bibcode:2006Natur.441..173G. doi:10.1038/nature04768. PMID   16688168.
  58. ↑ Duan X, Hu M, Yang L, Zhang S, Wang B, Li T, Tan Y, Li Y, Liu X, Zhan Z (July 2023). "IRG1 prevents excessive inflammatory responses and cardiac dysfunction after myocardial injury". Biochemical Pharmacology. 213: 115614. doi:10.1016/j.bcp.2023.115614. PMID   37209857.
  59. 1 2 3 4 5 Gautam P, Maenner S, Cailotto F, Reboul P, Labialle S, Jouzeau JY, Bourgaud F, Moulin D (October 2022). "Emerging role of IκBζ in inflammation: Emphasis on psoriasis". Clinical and Translational Medicine. 12 (10): e1032. doi:10.1002/ctm2.1032. PMC   9574490 . PMID   36245291.
  60. 1 2 Cong B, Zhang Q, Cao X (March 2021). "The function and regulation of TET2 in innate immunity and inflammation". Protein & Cell. 12 (3): 165–173. doi:10.1007/s13238-020-00796-6. PMC   7895883 . PMID   33085059.
  61. ↑ Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X, Su X, Liu J, Ge W, Levine RL, Li N, Cao X (September 2015). "Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6". Nature. 525 (7569): 389–393. Bibcode:2015Natur.525..389Z. doi:10.1038/nature15252. PMC   4697747 . PMID   26287468.
  62. ↑ Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ (November 2017). "Tet2 restrains inflammatory gene expression in macrophages". Experimental Hematology. 55: 56–70.e13. doi: 10.1016/j.exphem.2017.08.001 . PMID   28826859.
  63. 1 2 Chen LL, Morcelle C, Cheng ZL, Chen X, Xu Y, Gao Y, Song J, Li Z, Smith MD, Shi M, Zhu Y, Zhou N, Cheng M, He C, Liu KY, Lu G, Zhang L, Zhang C, Zhang J, Sun Y, Qi T, Lyu Y, Ren ZZ, Tan XM, Yin J, Lan F, Liu Y, Yang H, Qian M, Duan C, Chang X, Zhou Y, Shen L, Baldwin AS, Guan KL, Xiong Y, Ye D (March 2022). "Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses". Nature Cell Biology. 24 (3): 353–363. doi:10.1038/s41556-022-00853-8. PMC   9305987 . PMID   35256775.
  64. ↑ Ohgakiuchi Y, Saino Y, Muromoto R, Komori Y, Sato A, Hirashima K, Kitai Y, Kashiwakura JI, Oritani K, Matsuda T (January 2020). "Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17-induced IκB-ζ expression". Biochemical and Biophysical Research Communications. 521 (4): 957–963. doi:10.1016/j.bbrc.2019.11.036. hdl: 2115/82065 . PMID   31718798.
  65. ↑ Furue M, Furue K, Tsuji G, Nakahara T (February 2020). "Interleukin-17A and Keratinocytes in Psoriasis". International Journal of Molecular Sciences. 21 (4): 1275. doi: 10.3390/ijms21041275 . PMC   7072868 . PMID   32070069.
  66. ↑ Schinocca C, Rizzo C, Fasano S, Grasso G, La Barbera L, Ciccia F, Guggino G (2021). "Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview". Frontiers in Immunology. 12: 637829. doi: 10.3389/fimmu.2021.637829 . PMC   7937623 . PMID   33692806.
  67. 1 2 Fragoulis GE, Siebert S, McInnes IB (2016). "Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases". Annual Review of Medicine. 67: 337–53. doi:10.1146/annurev-med-051914-021944. PMID   26565676.
  68. ↑ Tsukazaki H, Kaito T (September 2020). "The Role of the IL-23/IL-17 Pathway in the Pathogenesis of Spondyloarthritis". International Journal of Molecular Sciences. 21 (17): 6401. doi: 10.3390/ijms21176401 . PMC   7504446 . PMID   32899140.
  69. ↑ Noviello D, Mager R, Roda G, Borroni RG, Fiorino G, Vetrano S (2021). "The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges". Frontiers in Immunology. 12: 611256. doi: 10.3389/fimmu.2021.611256 . PMC   8165319 . PMID   34079536.
  70. ↑ El-Mansi M (January 2023). "Control of central metabolism's architecture in Escherichia coli: An overview". Microbiological Research. 266: 127224. doi: 10.1016/j.micres.2022.127224 . PMID   36327660.
  71. ↑ Naujoks J, Tabeling C, Dill BD, Hoffmann C, Brown AS, Kunze M, Kempa S, Peter A, Mollenkopf HJ, Dorhoi A, Kershaw O, Gruber AD, Sander LE, Witzenrath M, Herold S, Nerlich A, Hocke AC, van Driel I, Suttorp N, Bedoui S, Hilbi H, Trost M, Opitz B (February 2016). "IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid". PLOS Pathogens. 12 (2): e1005408. doi: 10.1371/journal.ppat.1005408 . PMC   4734697 . PMID   26829557.
  72. ↑ Ruetz M, Campanello GC, Purchal M, Shen H, McDevitt L, Gouda H, Wakabayashi S, Zhu J, Rubin EJ, Warncke K, Mootha VK, Koutmos M, Banerjee R (November 2019). "Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair". Science. 366 (6465): 589–593. Bibcode:2019Sci...366..589R. doi:10.1126/science.aay0934. PMC   7070230 . PMID   31672889.
  73. ↑ Riquelme SA, Liimatta K, Wong Fok Lung T, Fields B, Ahn D, Chen D, Lozano C, Sáenz Y, Uhlemann AC, Kahl BC, Britto CJ, DiMango E, Prince A (June 2020). "Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation". Cell Metabolism. 31 (6): 1091–1106.e6. doi:10.1016/j.cmet.2020.04.017. PMC   7272298 . PMID   32428444.
  74. ↑ Puccioni-Sohler M, Nascimento Soares C, Christo PP, Almeida SM (December 2023). "Review of dengue, zika and chikungunya infections in nervous system in endemic areas". Arquivos de Neuro-psiquiatria. 81 (12): 1112–1124. doi:10.1055/s-0043-1777104. PMC   10756841 . PMID   38157877.
  75. 1 2 3 4 Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, Hait A, Hernaez B, Knudsen A, Iversen MB, Schilling M, Jørgensen SE, Thomsen M, Reinert LS, Lappe M, Hoang HD, Gilchrist VH, Hansen AL, Ottosen R, Nielsen CG, Møller C, van der Horst D, Peri S, Balachandran S, Huang J, Jakobsen M, Svenningsen EB, Poulsen TB, Bartsch L, Thielke AL, Luo Y, Alain T, Rehwinkel J, Alcamí A, Hiscott J, Mogensen TH, Paludan SR, Holm CK (October 2020). "SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate". Nature Communications. 11 (1): 4938. Bibcode:2020NatCo..11.4938O. doi:10.1038/s41467-020-18764-3. PMC   7532469 . PMID   33009401.
  76. ↑ Daniels BP, Kofman SB, Smith JR, Norris GT, Snyder AG, Kolb JP, Gao X, Locasale JW, Martinez J, Gale M, Loo YM, Oberst A (January 2019). "The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons". Immunity. 50 (1): 64–76.e4. doi:10.1016/j.immuni.2018.11.017. PMC   6342485 . PMID   30635240.
  77. ↑ Piovani D, Hassan C, Repici A, Rimassa L, Carlo-Stella C, Nikolopoulos GK, Riboli E, Bonovas S (September 2022). "Risk of Cancer in Inflammatory Bowel Diseases: Umbrella Review and Reanalysis of Meta-analyses". Gastroenterology. 163 (3): 671–684. doi:10.1053/j.gastro.2022.05.038. PMID   35643170.
  78. ↑ Wang Q, Li XL, Mei Y, Ye JC, Fan W, Cheng GH, Zeng MS, Feng GK (October 2020). "The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer". Journal of Molecular Medicine (Berlin, Germany). 98 (10): 1457–1466. doi:10.1007/s00109-020-01963-2. PMID   32840638.
  79. 1 2 Rathore S, Verma A, Ratna R, Marwa N, Ghiya Y, Honavar SG, Tiwari A, Das S, Varshney A (July 2023). "Retinoblastoma: A review of the molecular basis of tumor development and its clinical correlation in shaping future targeted treatment strategies". Indian Journal of Ophthalmology. 71 (7): 2662–2676. doi: 10.4103/IJO.IJO_3172_22 . PMC   10491038 . PMID   37417104.
  80. 1 2 Liu K, Huang J, Liu J, Klionsky DJ, Kang R, Tang D (June 2022). "Induction of autophagy-dependent ferroptosis to eliminate drug-tolerant human retinoblastoma cells". Cell Death & Disease. 13 (6): 521. doi:10.1038/s41419-022-04974-8. PMC   9163041 . PMID   35654783.
  81. ↑ Noma T, Yoon YS, Yamashiro Y, Fujisawa K, Nakazawa A (September 1999). "Regulation of NeuroD expression by activation of the protein kinase-C pathway in Y79 human retinoblastoma cells". Neuroscience Letters. 272 (1): 45–8. doi:10.1016/s0304-3940(99)00569-8. PMID   10507539.
  82. 1 2 Hayashi K, Nakazato Y, Ouchi M, Fujita T, Endou H, Chida M (October 2021). "Antitumor effect of dimethyl itaconate on thymic carcinoma by targeting LDHA-mTOR axis". Life Sciences. 282: 119847. doi:10.1016/j.lfs.2021.119847. PMID   34293399.
  83. ↑ Conforti F, Pala L, Giaccone G, De Pas T (June 2020). "Thymic epithelial tumors: From biology to treatment". Cancer Treatment Reviews. 86: 102014. doi:10.1016/j.ctrv.2020.102014. PMID   32272379.
  84. ↑ Glaviano A, Foo AS, Lam HY, Yap KC, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, Kulke MH, Baird RD, Prabhu JS, Carbone D, Pecoraro C, Teh DB, Sethi G, Cavalieri V, Lin KH, Javidi-Sharifi NR, Toska E, Davids MS, Brown JR, Diana P, Stebbing J, Fruman DA, Kumar AP (August 2023). "PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer". Molecular Cancer. 22 (1): 138. doi: 10.1186/s12943-023-01827-6 . PMC   10436543 . PMID   37596643.
  85. ↑ R. L. Shriner; S. G. Ford; l. J. Roll (1931). "Itaconic anhydride and itaconic acid". Org. Synth. 11: 70. doi:10.15227/orgsyn.011.0070.
  86. ↑ Blumhoff ML, Steiger MG, Mattanovich D, Sauer M (September 2013). "Targeting enzymes to the right compartment: metabolic engineering for itaconic acid production by Aspergillus niger". Metabolic Engineering. 19: 26–32. doi:10.1016/j.ymben.2013.05.003. PMID   23727192.
  87. ↑ Roger A. Sheldon (2014). "Green and sustainable manufacture of chemicals from biomass: state of the art". Green Chem. 16 (3): 950–963. doi:10.1039/C3GC41935E.
  88. ↑ Steiger, Matthias Georg; Blumhoff, Marzena Lidia; Mattanovich, Diethard; Sauer, Michael (2013-01-01). "Biochemistry of microbial itaconic acid production". Frontiers in Microbiology. 4: 23. doi: 10.3389/fmicb.2013.00023 . PMC   3572532 . PMID   23420787.
  89. ↑ Geiser E, Przybilla SK, Friedrich A, Buckel W, Wierckx N, Blank LM, Bölker M (January 2016). "Ustilago maydis produces itaconic acid via the unusual intermediate trans-aconitate". Microbial Biotechnology. 9 (1): 116–26. doi:10.1111/1751-7915.12329. PMC   4720413 . PMID   26639528.
  90. ↑ Geiser, Elena; Przybilla, Sandra K; Friedrich, Alexandra; Buckel, Wolfgang; Wierckx, Nick; Blank, Lars M; Bölker, Michael (2016-01-01). "Ustilago maydis produces itaconic acid via the unusual intermediate trans-aconitate". Microbial Biotechnology. 9 (1): 116–126. doi:10.1111/1751-7915.12329. ISSN   1751-7915. PMC   4720413 . PMID   26639528.
  91. 1 2 Teleky BE, Vodnar DC (June 2019). "Biomass-Derived Production of Itaconic Acid as a Building Block in Specialty Polymers". Polymers. 11 (6): 1035. doi: 10.3390/polym11061035 . PMC   6630286 . PMID   31212656.
  92. ↑ Wierckx N, Agrimi G, Lübeck PS, Steiger MG, Mira NP, Punt PJ (April 2020). "Metabolic specialization in itaconic acid production: a tale of two fungi". Current Opinion in Biotechnology. 62: 153–159. doi:10.1016/j.copbio.2019.09.014. hdl: 1887/84256 . PMID   31689647.
  93. ↑ Sun L, Gong M, Lv X, Huang Z, Gu Y, Li J, Du G, Liu L (November 2020). "Current advance in biological production of short-chain organic acid". Applied Microbiology and Biotechnology. 104 (21): 9109–9124. doi:10.1007/s00253-020-10917-0. PMID   32974742.
  94. 1 2 Geiser E, Hosseinpour Tehrani H, Meyer S, Blank LM, Wierckx N (2018). "Evolutionary freedom in the regulation of the conserved itaconate cluster by Ria1 in related Ustilaginaceae". Fungal Biology and Biotechnology. 5: 14. doi: 10.1186/s40694-018-0058-1 . PMC   6064134 . PMID   30065845.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.