Inhibitory effect of PPAR? on NLRP3 inflammasome activation.

ABSTRACT: Rationale: Stimulation of the NLRP3 inflammasome by metabolic byproducts is known to result in inflammatory responses and metabolic diseases. However, how the host controls aberrant NLRP3 inflammasome activation remains unclear. PPAR?, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-?B activation and additionally attenuates NLRP3-dependent IL-1? and IL-18 production. Therefore, we hypothesized that PPAR? serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPAR? agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPAR? on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPAR? and the NLRP3 inflammasome. Results: Exposure to the PPAR? agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1? maturation. Moreover, PPAR? interfered with NLRP3 inflammasome formation by decreasing NLRP3-ASC and NLRP3-NLRP3 interactions as well as NLRP3-dependent ASC oligomerization, which is mediated through interaction between the PPAR? DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPAR? was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPAR? ratio was reduced in circulating mononuclear cells of obese patients after weight-loss surgery, which we define as an "NLRP3 accelerating index". Conclusions: These results revealed an additional anti-inflammatory role for PPAR? in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPAR? agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.

SUBMITTER: Yang CC 

PROVIDER: S-EPMC7797672 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature