Itaconate confers tolerance to late NLRP3 inflammasome activation

Abstract

Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage.

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Cited by papers we hold 7

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• Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation · 2025
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• Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors · 2023
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• Gasdermin D-mediated pyroptosis: mechanisms, diseases, and inhibitors · 2023
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• The role of itaconate in host defense and inflammation · 2022
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• How location and cellular signaling combine to activate the NLRP3 inflammasome · 2022
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• Impact of intracellular innate immune receptors on immunometabolism · 2021
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