Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Hooftman, A; Angiari, S; Hester, S; Corcoran, SE; Runtsch, MC; Ling, C; Ruzek, MC; Slivka, PF; McGettrick, AF; Banahan, K; Hughes, MM; Irvine, AD; Fischer, R; O'Neill, LAJ.
The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation.
Cell Metab. 2020; 32(3): 468-478.
Doi: 10.1016/j.cmet.2020.07.016
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- Co-Autor*innen der Med Uni Graz
- Angiari Stefano
- Runtsch Marah
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- 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. Copyright © 2020 Elsevier Inc. All rights reserved.