Inhibitory effect of PPARγ on NLRP3 inflammasome activation

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 gamma, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-kappa B activation and additionally attenuates NLRP3-dependent IL-1 beta and IL-18 production. Therefore, we hypothesized that PPAR gamma serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPAR gamma agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPAR gamma on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPAR gamma and the NLRP3 inflammasome. Results: Exposure to the PPAR gamma agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1 beta maturation. Moreover, PPAR gamma 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 gamma DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPAR gamma was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPAR gamma 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 gamma in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPAR gamma agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases.