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[200904 저널발표] The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation

한지희 │ 2020-09-03

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Cell Metabolism
Volume 32, Issue 3, 1 September 2020, Pages 468-478.e7
Journal home page for Cell Metabolism

Short Article
The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation

Highlights

Itaconate and its derivative 4-OI (which generates itaconate) block NLRP3 activation

Itaconate-depleted Irg1−/− BMDMs exhibit increased NLRP3 inflammasome activation

4-OI “dicarboxypropylates” C548 on NLRP3 and blocks the NLRP3-NEK7 interaction

4-OI reduces peritonitis in vivo and blocks IL-1β release from CAPS patient PBMCs

Summary

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-1β, 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-1β 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.

Keywords

inflammasome
NLRP3
NEK7
pyroptosis
itaconate
metabolite
macrophage
IL-1β
immunometabolism
cysteine modification



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