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Abstract
SUMMARYItaconate 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.
Highlights
Aconitate decarboxylase 1 is the enzyme solely responsible for itaconate production by activated macrophages (Michelucci et al, 2013)
Irg1 establishes LPS-mediated tolerance to signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation We previously demonstrated that itaconate inhibits NLRP3 inflammasome activation in macrophages (Lampropoulou et al, 2016; Swain et al, 2020)
Using a caspase recruitment domain (ASC)-mCitrine-expressing bone marrow-derived macrophages (BMDMs) (Tzeng et al, 2016), we found that itaconate pre-treatment did not affect ASC speck formation upon NLRP3 inflammasome triggering, whereas a known NLRP3 inhibitor, MCC950 (Coll et al, 2015), blocked ASC speck formation (Figures S1A–S1D)
Summary
Aconitate decarboxylase 1 (encoded by Acod or Immuneresponsive gene 1; Irg1) is the enzyme solely responsible for itaconate production by activated macrophages (Michelucci et al, 2013). Itaconate reaches high intracellular concentrations in activated macrophages, its regulatory effect on IL-1b secretion appears to be relatively modest based on studies with itaconate-deficient Irg1À/À macrophages after LPS treatment (Lampropoulou et al, 2016; Swain et al, 2020). This raises the more general question of why macrophages undergo such a substantial metabolic commitment to itaconate production, even though its regulatory impact appears to be disproportionately small. One consideration that reconciles these observations is the possibility that LPS activation or conventional NLRP3 inflammasome activation by itself might not be the optimal context to reveal the key functional aspects of itaconate’s immunoregulatory potential
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