Immune-responsive gene 1 (IRG1) and dimethyl itaconate are involved in the mussel immune response

Sendra, Marta; Saco, Amaro; Rey-Campos, Magalí; Novoa, Beatriz; Figueras, António

doi:10.1016/j.fsi.2020.07.034

Cited by 14 publications

(8 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our experimental studies of Irg1 in oysters and amphioxus, the most distantly diverged metazoan species that are known to contain Irg1, revealed itaconate biosynthesis is enriched in the innate immune cells (in oysters) and is induced upon innate immune stimulus (in oysters and amphioxus), suggesting an ancient and yet already specialized role of itaconate in innate immunity at the base of the metazoan lineage. The induction of oyster pIrg1 is consistent with the increased itaconate level reported in oysters upon marine herpesvirus infection 55 and is also supported by the induced expression of pIrg1 56 and increased itaconate 57,58 in another marine bivalve (mussels; Perna canaliculus) upon infection with a gram-negative Vibrio strain. In these contexts, itaconate might play an antimicrobial function, as itaconate inhibits a pathogenic marine Vibrio strain growth in vitro and disruption of central carbon metabolism 59 .…”

Section: Discussionsupporting

confidence: 80%

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense

Szeligowski

Miros

Sáez

et al. 2022

Preprint

View full text Add to dashboard Cite

Itaconate is an innate immune metabolite specifically produced in stimulated immune cells via the decarboxylation of the TCA cycle intermediate cis-aconitate. Due to its inhibition of succinate-related metabolic processes, itaconate exhibits antimicrobial properties at the expense of potentially disrupting the hosts own central energy metabolism, a double-edged dilemma of immunometabolism. To understand the evolutionary logic of itaconate biosynthesis, we investigate the evolutionary trajectory of the Irg1 gene, which codes for the itaconate-producing enzyme cis-aconitate decarboxylase (CAD). Phylogenetic analysis reveals a putative independent acquisition of metazoan and fungal Irg1 from prokaryotic sources. The metazoan Irg1 underwent duplication in vertebrates and a subsequent loss of one paralog in mammals, a process that removes the mitochondrial targeting sequences (MTS) and relocates CAD outside of the mitochondrial matrix thus preventing a direct inhibition of energy metabolism. Experiments in the most diverged metazoan species that are known to contain Irg1, oysters and amphioxus, reveal that the expression of primitive Irg1 genes is induced by innate immune stimulants in invertebrates and basal chordates, suggesting an already specialized role of itaconate production for innate immune defense in early bilaterians. Our combined in silico and experimental analysis of Irg1 highlights that a trend of tightened transcriptional regulation and sequence-level change optimizes itaconate biosynthesis for innate immunity, a mechanism that may be broadly utilized to resolve other types of double-edged dilemmas in immunometabolism.

show abstract

Section: Discussionsupporting

confidence: 80%

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense

Szeligowski

Miros

Sáez

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“… 33 Recent studies have revealed the unique function of the IRG1/itaconate axis in modulating inflammation and demonstrated the anti-inflammatory effects of itaconate on suppressing succinate dehydrogenase (SDH) activity, activating the Nrf2/HO-1 pathway and ameliorating disease severity in several animal disease models. 8 , 9 , 22 , 34–36 Presently, the immunomodulatory effects of the IRG1/itaconate axis were mainly studied in the peripheral inflammatory immune responses. Recently, our group showed that DMI, an itaconate derivative, suppressed neuroinflammation and ameliorated disease severity in experimental autoimmune encephalomyelitis, a chronic CNS disease.…”

Section: Discussionmentioning

confidence: 99%

“… 32 The induction of IRG1 has been shown to increase endogenous itaconate production that subsequently activates Nrf2/HO-1 pathway in several disease models. 29 , 34–36 Interestingly, a previous study reported that IRG1 could be induced by HO-1 inducers in combination with carbon monoxide to inhibit LPS-induced sepsis and pro-inflammatory cytokine production. 41 These results suggest that the reciprocal effects may exist between IRG1 and HO-1 gene induction.…”

Section: Discussionmentioning

confidence: 99%

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia

Kuo

Weng

Scofield

et al. 2021

Brain Communications

View full text Add to dashboard Cite

Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood–brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1−/− stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke.

show abstract

“…Itaconate is ubiquitous in nature, as revealed by its production in fungi, 1 mussels, 134 shrimp, 135 mammals, [10][11] and even some bacteria (e.g. Bacillus subtilis).…”

Section: Unanswered Questionsmentioning

confidence: 99%

Itaconate: an antimicrobial metabolite of macrophages

Duncan

Auclair

2022

Can. J. Chem.

View full text Add to dashboard Cite

Itaconate is a conjugated 1,4-dicarboxylate produced by macrophages. This small molecule has recently received increasing attention due to its role in modulating the immune response of macrophages upon exposure to pathogens. Itaconate has also been proposed to play an antimicrobial function; however, this has not been explored as intensively. Consistent with the latter, itaconate is known to show antibacterial activity in vitro and was reported to inhibit isocitrate lyase, an enzyme required for survival of bacterial pathogens in mammalian systems. Recent studies have revealed bacterial growth inhibition under biologically relevant conditions. In addition, an antimicrobial role for itaconate is substantiated by the high concentration of itaconate found in bacteria-containing vacuoles, and by the production of itaconate-degrading enzymes in pathogens such as Salmonella enterica ser. Typhimurium, Pseudomonas aeruginosa, and Yersinia pestis. This review describes the current state of literature in understanding the role of itaconate as an antimicrobial agent in host-pathogen interactions.

show abstract

Immune-responsive gene 1 (IRG1) and dimethyl itaconate are involved in the mussel immune response

Cited by 14 publications

References 40 publications

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense

Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia

Itaconate: an antimicrobial metabolite of macrophages

Contact Info

Product

Resources

About