Itaconate: an emerging determinant of inflammation in activated macrophages

Abstract

Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

“…Itaconate is a metabolite produced by immune‐responsive gene 1 (Irg1) and has been found in lipopolysaccharide (LPS)‐treated macrophages and dendritic cells . Itaconate is involved in regulating immunity and limiting inflammation . Similarly, the membrane‐permeable derivatives of itaconate, including dimethyl itaconate (DI) and 4‐octyl itaconate (OI), exhibit anti‐inflammatory activity and DI has been used in several studies .…”

“…3 Itaconate is involved in regulating immunity and limiting inflammation. [3][4][5] Similarly, the membrane-permeable derivatives of itaconate, including dimethyl itaconate (DI) and 4-octyl itaconate (OI), exhibit anti-inflammatory activity and DI has been used in several studies. 6,7 DI treatment suppresses interleukin-6 (IL-6) and inducible nitric oxide synthase expression in LPS-stimulated bone marrow-derived macrophages and protects against hypoxia-induced cell death and cardiac ischemia-reperfusion injury.…”

Metabolic Reprogramming of Mouse Bone Marrow Derived Macrophages Following Erythrophagocytosis

“…Krebs cycle rewiring has profound implications for macrophage effector function and is intimately involved in the remodeling necessary for supporting biosynthetic and bioenergetic requirements (Ryan and O'Neill, 2017). This pathway is disrupted during macrophage activation by inflammatory stimuli and leads to the accumulation of various metabolites, including succinate and citrate (Jha et al, 2015;Lampropoulou et al, 2016;Ryan and O'Neill, 2017;Williams and O'Neill, 2018;Yu et al, 2019). Although succinate and itaconate levels were not significantly elevated before or after EP, a significant SUCC/ITA ratio (p = 0.0215) was observed in BMDMs following RBC ingestion, suggesting that the balance between these two metabolites is regulated by EP.…”

Target the Host, Kill the Bug; Targeting Host Respiratory Immunosuppressive Responses as a Novel Strategy to Improve Bacterial Clearance During Lung Infection

“…The targeting of metabolic pathways in macrophages could also be potentially used as a therapeutic approach during pulmonary bacterial infection to skew macrophages toward a more protective M1 phenotype. Itaconate promotes macrophage switching from a pro-to an anti-inflammatory state and the metabolite is emerging as a crucial determinant in macrophage activity (190). The inhibition of itaconate may be of benefit in chronic bacterial lung infection where enhanced M1 responses could improve bacterial clearance.…”