The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation

Alexander Hooftman1, Stefano Angiari1, Svenja Hester2, Sarah E Corcoran1, Marah C Runtsch1, Chris Ling3, Melanie C Ruzek4, Peter F Slivka4, Anne F McGettrick1, Kathy Banahan1, Mark M Hughes1, Alan D Irvine5, Roman Fischer2, Luke A J O'Neill6

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  2. Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  3. Mass Spectrometry, Analytical Research Technologies, Abbvie, North Chicago, IL 60064, USA.
  4. Immunology Discovery, Abbvie, Worcester, MA 01605, USA.
  5. Pediatric Dermatology, Children's Health Ireland, Crumlin, Dublin 12, Ireland; Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
  6. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.

Abstract

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.

Presented By Alexander Hooftman

Immunology & MicrobiologyNicholas Liao2020-09 (Sep)