Editors' ChoiceInflammation

Metabolic control of NLRP3 inflammasome by itaconation

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Science Translational Medicine  16 Sep 2020:
Vol. 12, Issue 561, eabe1714
DOI: 10.1126/scitranslmed.abe1714


The Krebs cycle–derived immunometabolite itaconate constrains NLRP3 inflammasome activation and IL-1β release.

Macrophages are innate immune cells that secure a first line of defense against a broad range of pathogens. Yet, aberrant macrophage activation can propagate the progression of chronic inflammatory diseases such as rheumatoid arthritis and atherosclerosis. Therefore, better understanding of how macrophages are regulated will pave the way to reshaping aberrant macrophage activation and developing novel therapeutics. Recent research in the immunometabolism field highlights that immune cells undergo extensive metabolic rewiring upon activation. These metabolic changes serve functions well beyond the generation of energy and biomass. Metabolites are much more than intermediates of metabolism and serve as important regulators of immunity and disease.

Itaconate is a prototypical immunometabolite that is strongly induced in inflammatory macrophages after activation. Itaconate is synthesized as a side product of the Krebs cycle by the enzyme immune-responsive gene 1 (IRG1). Itaconate and one of its cell-permeable derivatives, 4-octyl-itaconate (4-OI), have been demonstrated to alkylate cysteines on different proteins with roles in metabolism and immunity. As such, this posttranslational modification called itaconation can mediate the immunomodulatory effects of itaconate. For example, 4-OI was previously shown to block transcription of the proinflammatory gene IL1b. Subsequent release and function of the IL1b product, interleukin (IL)-1b, requires activation of the nonobese diabetic (NOD)–, leucine-rich repeat (LRR)–, and pyrin domain-containing protein 3 (NLRP3) inflammasome and cleavage of pro–IL-1β into its active subunit. In the present study, Hooftman et al. explored whether itaconate further modulates IL-1β function by modifying the NLRP3 inflammasome directly. The authors initially applied different forms of itaconate to bone marrow–derived macrophages to show that itaconate and its derivatives specifically block NLRP3 activation and IL-1β release. The authors confirmed these findings in the context of endogenous itaconate by measuring IL-1β release in IRG1-deficient macrophages. Next, the authors used tandem mass spectrometry to demonstrate itaconation of cysteine C548 on NLRP3, which might interfere with protein-protein interactions necessary for inflammasome activation and IL-1β release. To test the therapeutic potential of itaconate, 4-OI was coinjected into mice with NLRP3-activating monosodium urate crystals to demonstrate that 4-OI reduced NLRP3-driven peritonitis in vivo. Finally, Hooftman et al. demonstrated that 4-OI suppressed IL-1β release in vitro from white blood cells of patients with cryopyrin-associated periodic syndrome (CAPS), a genetic disorder characterized by hyperactive NLRP3. Further research should clarify whether itaconate could have utility in treating patients with CAPS and other NLRP3-driven diseases.

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