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.
Highlights
A growing number of reports have shown that the metabolism is widely associated with immune response and many pathologies, such as inflammatory diseases and cancer
This study demonstrated that the anti-inflammatory effect of itaconate was irrelevant to the nuclear factor-κB (NF-κB) pathway as the LPS-induced production of tumor necrosis factors-α (TNF-α) was not affected in the aconitate decarboxylase 1 (Acod1) knockout or dimethyl itaconate (DI)-treated macrophages [28]
Since its pivotal immunoregulatory roles were revealed in macrophages, we began to realize the complex interaction between the metabolism and immune response, and this gave us a novel perspective on inflammatory diseases
Summary
A growing number of reports have shown that the metabolism is widely associated with immune response and many pathologies, such as inflammatory diseases and cancer. Itaconate can be induced by a wide range of factors, such as LPS, type I and type II interferons, and agonists of Toll-like receptor (TLR) [5, 6]. All of these factors mentioned above can increase the level of enzyme aconitate decarboxylase 1 (Acod1), which is encoded by the immune responsive gene 1 (Acod, known as Irg1), enhancing the probability that cis-aconitate will be diverted away from the TCA cycle and promoting the production of itaconate [5]. We describe the metabolic change of itaconate in macrophages and summarize its potential and therapeutic roles in the treatment of inflammatory diseases
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