Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress

Abstract

Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process can be diverted to generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, the immune response gene 1 is activated and promotes the production of itaconate from the tricarboxylic acid cycle by decarboxylating cis-aconitate. Itaconate has been reported to have multiple immunoregulatory and antioxidative effects. In addition, reports have described its antibacterial and protumor effects. The involved mechanism in these effects includes the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, inhibition of aerobic glycolysis by targeting glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, inhibition of succinate dehydrogenase, and blockade of IκBζ translation. All of these discoveries elucidated the transformation of the pro- into anti-inflammatory status in macrophages, which is crucial in innate immunity and set the ground for the emerging therapeutic implications of itaconate. In this review, we point out that itaconate is a novel and pivotal metabolic determinant of the immunoregulatory response in macrophages and highlight studies that have improved our understanding of the connection between the immune response and metabolism. In addition, we shed light on the therapeutic potential of itaconate and its derivatives to treat inflammatory diseases.

Dimethyl itaconate inhibits LPS‑induced microglia inflammation and inflammasome‑mediated pyroptosis via inducing autophagy and regulating the Nrf‑2/HO‑1 signaling pathway

“…Metabolic products affect crucial biological functions. Itaconate has recently been reported to function as an immunomodulator in macrophages ( 34 ). Following induction of inflammation by a specific stimulus, Irg-1 is activated and promotes the production of itaconate from the TCA cycle by decarboxylating cis-aconitase ( 35 ).…”

Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis

“…Transporters of itaconate have been identified in certain fungal species that are utilised for industrial synthesis of itaconate ( 139 ), however the mechanism by which mammalian cells may excrete or take up itaconate is not known. As a dicarboxylic acid salt, itaconate is unable to freely cross the plasma membrane, and this has resulted in the use of various modified membrane-permeable forms of the metabolite to investigate its role in immune regulation ( 140 ). Puchalska et al.…”

Protective Role of 4‐Octyl Itaconate in Murine LPS/D‐GalN‐Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis

“…Inflammatory stimuli alter the status of respiration and tricarboxylic acid (TCA) cycle, which leads to the accumulation of endogenous metabolites. Itaconate is one of these metabolites capable of regulating inflammation [ 18 ]. Itaconate is synthesized by cis -aconitate decarboxylase (CAD).…”

“…Itaconate is highly induced in activated macrophages and shows remarkable ability in inhibiting inflammatory response [ 19 ]. Mechanically, itaconate exerts controlling of inflammation and oxidative stress by competitive inhibition of succinate dehydrogenase (SDH) mediated oxidation and degradation of Kelch-like ECH-associated protein 1 (Keap1) to activate the Nrf2 pathway [ 18 , 19 ]. Accordingly, itaconate and its derivates, such as 4-octyl itaconate (OI) and dimethyl-itaconate, showed protective effects in many inflammatory diseases' models [ 12 , 20 ].…”