Journal
CELL METABOLISM
Volume 32, Issue 3, Pages 468-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2020.07.016
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Funding
- European Research Council Metabinate [834370]
- Science Foundation Ireland [12/IA/1531]
- Wellcome Trust [205455]
- European Research Council (ERC) [834370] Funding Source: European Research Council (ERC)
- Science Foundation Ireland (SFI) [12/IA/1531] Funding Source: Science Foundation Ireland (SFI)
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The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1 beta, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1(-/-) macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and dicarboxypropylated'' C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1 beta release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
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