The Immunomodulatory Potential of the Metabolite Itaconate

Itaconate is a metabolite synthesized from cis-aconitate in the tricarboxylic acid (TCA) cycle. It is produced in large quantities in activated murine macrophages. The reason for this induction is that itaconate can moonlight as an immunomodulator with potent anti-inflammatory and antimicrobial effects. In murine macrophages, itaconate can block the release of proinflammatory cytokines, such as IL-1β and IL-6, through a variety of mechanisms. It inhibits succinate dehydrogenase (SDH)-derived reactive oxygen species (ROS) production, activates the master antioxidant regulator NRF2, and induces the anti-inflammatory transcription factor ATF3. Recent studies have expanded on the role of itaconate – it reduces immunopathology in mice resulting from Mycobacterium tuberculosis infection in vivo and, remarkably, restricts Zika virus replication in murine neurons. Derivatives such as dimethyl itaconate and 4-octyl itaconate are most commonly used to deliver itaconate intracellularly, but may exert itaconate-independent effects. Where possible, itaconic acid should be used instead. The field of immunometabolism has demonstrated that metabolites can lead double lives as immunomodulators. Itaconate is perhaps the best example of such a moonlighting molecule, and has been shown to have multiple anti-inflammatory effects in macrophages. Itaconate is significantly upregulated under inflammatory conditions, and can promote an anti-inflammatory phenotype by reducing oxidative stress and blocking transcriptional responses to lipopolysaccharide (LPS) in murine macrophages. Antibacterial and protumor effects have also been described for itaconate and, most recently, reports have surfaced of its possible modulatory roles during Zika virus infection in murine neurons. We posit here that itaconate is a crucial determinant of innate immune responses, and may potentially be harnessed therapeutically to treat inflammatory diseases. The field of immunometabolism has demonstrated that metabolites can lead double lives as immunomodulators. Itaconate is perhaps the best example of such a moonlighting molecule, and has been shown to have multiple anti-inflammatory effects in macrophages. Itaconate is significantly upregulated under inflammatory conditions, and can promote an anti-inflammatory phenotype by reducing oxidative stress and blocking transcriptional responses to lipopolysaccharide (LPS) in murine macrophages. Antibacterial and protumor effects have also been described for itaconate and, most recently, reports have surfaced of its possible modulatory roles during Zika virus infection in murine neurons. We posit here that itaconate is a crucial determinant of innate immune responses, and may potentially be harnessed therapeutically to treat inflammatory diseases. an LPS-inducible transcription factor which negatively regulates NF-κB signaling, type I IFN release, and secondary transcriptional responses to LPS controlled by IκBζ. electron pair acceptors – α,β-unsaturated compounds such as itaconate, are electrophiles susceptible to nucleophilic attack from nucleophiles (electron pair donors), such as glutathione (GSH), in a process termed a Michael reaction. Such electrophiles may be termed Michael acceptors. an experimental murine model of psoriasis – a chronic inflammatory skin disorder. Topical application of the TLR7/8 agonist imiquimod causes IL-23/IL-17-driven inflammation, resulting in epidermal proliferation and histological changes in the skin which may be quantified. a post-septic state in which innate immune cells are less responsive to secondary inflammatory stimuli. a protein complex that acts as a sensor for cellular damage or cellular stress. It converges on the effector protein caspase-1, which cleaves the cytokines pro-IL-1β and pro-IL-18 into their active forms, and gasdermin D into its active subunit, thereby promoting pyroptosis. also known as endotoxin, a Gram-negative bacterial cell wall component which binds the TLR4 complex on the surface of innate immune cells, triggering inflammatory cytokine production. activated macrophages may be arbitrarily categorized into M1 and M2 subsets. M1 macrophages are activated by LPS or IFN-γ and produce proinflammatory cytokines, such as IL-6 and TNF-α, upon activation. see electrophile. the master antioxidant transcription factor that promotes the transcription of a range of antioxidant genes. NRF2 is repressed by KEAP1, which promotes its degradation. RIPK1 and RIPK3 are both components of the necroptotic pathway, a form of programmed inflammatory cell death. This pathway may be engaged following viral infection, and results in the activation of the effector protein mixed-lineage kinase domain-like protein (MLKL). gain-of-function mutations in Tmem173, the gene encoding STING, cause clinical disorders characterized by excessive production of type I IFN, resulting in severe skin inflammation. also known as respiratory complex II, an enzyme complex that contributes to both the electron transport chain and the tricarboxylic acid (TCA) cycle by oxidizing succinate to fumarate. secondary stimulation of macrophages with LPS following an initial stimulus of LPS leads to the generation of tolerized macrophages. Tolerized macrophages are less responsive to secondary LPS stimulation than to primary stimulation. also known as ‘innate immune memory’, this is a process whereby innate immune cells exhibit stronger immune responses to secondary inflammatory stimuli following initial exposure to a primary stimulus.