IRG1

Official Full Name

aconitate decarboxylase 1

Organism

Homo sapiens

GeneID

730249

Background

Enables aconitate decarboxylase activity and protein homodimerization activity. Involved in defense response; positive regulation of antimicrobial humoral response; and tolerance induction to lipopolysaccharide. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

ACOD1; CAD; IRG1;

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Detailed Information

The IRG1 gene, officially designated as ACOD1 (Aconitate Decarboxylase 1), is highly induced in macrophages in response to pathogen-associated molecular patterns (PAMPs). ACOD1 encodes a mitochondria-localized enzyme that catalyzes the decarboxylation of cis-aconitate, an intermediate of the tricarboxylic acid (TCA) cycle, to produce itaconate. This reaction is biochemically distinctive, providing mammalian cells with a metabolic branch independent of classical oxidative phosphorylation. ACOD1 expression is nearly undetectable in resting immune cells but is dramatically upregulated upon stimulation with pro-inflammatory signals such as lipopolysaccharide (LPS) or interferon-γ, making itaconate one of the most abundant metabolites in activated macrophages. This expression pattern places ACOD1 at the heart of the emerging field of immunometabolism, exemplifying how metabolic reprogramming directly shapes immune cell effector functions.

Biological Significance

ACOD1 and its product itaconate serve as a crucial bridge linking core cellular metabolism with innate immune defense. Far from being a mere metabolic byproduct, itaconate has been redefined as a multifunctional immunoregulatory molecule. First, it acts as a potent antimicrobial agent by inhibiting bacterial isocitrate lyase, thereby disrupting the glyoxylate cycle essential for certain pathogens and limiting intracellular bacterial replication. More importantly, itaconate functions as a robust intracellular anti-inflammatory and antioxidant signal. It alkylates and inhibits succinate dehydrogenase, reducing mitochondrial reactive oxygen species (ROS) production and succinate accumulation, which attenuates inflammatory responses. Additionally, itaconate activates the transcription factor Nrf2, upregulating a suite of genes involved in antioxidant defense and cytoprotection.

Figure 1. Various stimuli, including live pathogens, PAMPs, and DAMPs, activate innate immune cells and induce mitochondrial ACOD1 expression. (Wu R, et al.2022)

Itaconate can also modulate multiple key signaling proteins and metabolic enzymes through alkylation, a process termed "itaconation." For example, it modifies glycolytic enzymes such as GAPDH and ALD-A, shifting cellular energy metabolism from efficient oxidative phosphorylation to relatively less efficient glycolysis during peak inflammation. This metabolic switch is thought to limit excessive proliferation while supporting antimicrobial function. Moreover, the ACOD1/itaconate pathway is critical for establishing "endotoxin tolerance," an adaptive hyporesponsive state that prevents excessive tissue damage during sustained inflammatory stimuli. Recent studies also indicate that itaconate possesses antiviral activity in neurons, suggesting that its immunometabolic functions extend beyond myeloid cells. In sum, the induced expression of ACOD1 and the abundant production of itaconate constitute a core program that allows immune cells to coordinate energy demand, biosynthesis, and effector function, effectively "weaponizing" a metabolite to directly combat pathogens while fine-tuning inflammatory responses.

Clinical Relevance

The ACOD1/itaconate pathway holds broad therapeutic potential across infectious diseases, autoimmune disorders, neurodegenerative diseases, and cancer. In hyperinflammatory syndromes such as sepsis, exogenous administration of itaconate or derivatives is considered a potential therapeutic strategy to leverage its intrinsic anti-inflammatory and cytoprotective properties, mitigating uncontrolled cytokine storms. Preclinical studies demonstrate that derivatives like 4-octyl itaconate significantly improve survival and reduce organ damage in mouse models of sepsis. Conversely, in persistent intracellular infections such as Mycobacterium tuberculosis, enhancing ACOD1 function or administering itaconate may strengthen macrophage antimicrobial capacity, complementing traditional antibiotics against resistant strains.

In autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, dysregulation of the ACOD1/itaconate pathway is frequently observed in patient immune cells. Supplementation with itaconate analogs may offer a novel intervention to modulate hyperactive immune cells and alleviate pathological inflammation. In neurodegenerative conditions such as Alzheimer's disease, chronic microglial neuroinflammation drives disease progression; ACOD1 activation and itaconate accumulation have been shown to promote an anti-inflammatory, neuroprotective microglial phenotype, providing a new therapeutic avenue. In oncology, tumor-associated macrophages (TAMs) are key components of the tumor microenvironment, influencing antitumor immunity. ACOD1 is highly expressed in M1-like (pro-inflammatory, antitumor) macrophages, and its itaconate production can suppress M2-like (anti-inflammatory, protumor) gene programs and potentially enhance T cell–mediated antitumor responses, positioning the pathway as a promising target for modulating the tumor immune microenvironment.

Clinical translation of this pathway faces challenges, including developing suitable drug delivery systems to ensure effective tissue and cellular targeting of itaconate or its derivatives, and precisely defining its context-specific effects to avoid unintended immunosuppression.

References

Michelucci A, Cordes T, Ghelfi J, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A. 2013;110(19):7820–7825.
Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556(7699):113–117.
O'Neill LAJ, Artyomov MN. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol. 2019;19(5):273–281.
Wu R, Kang R, Tang D. Mitochondrial ACOD1/IRG1 in infection and sterile inflammation. J Intensive Med. 2022 Feb 12;2(2):78-88.

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