Inhibitory effect of PPARγ on NLRP3 inflammasome activation
Autor: | Yi Ning Cheng, Chih Hsing Wu, Kuo Ting Lee, Ching Chun Yang, Pei Jane Tsai, Yau Sheng Tsai, Ta Chun Lin, Chin Sung Chang |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Inflammasomes Regulator Medicine (miscellaneous) Stimulation Peripheral blood mononuclear cell Rosiglitazone Mice 03 medical and health sciences 0302 clinical medicine In vivo NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Hypoglycemic Agents Obesity Pharmacology Toxicology and Pharmaceutics (miscellaneous) Inflammation integumentary system Chemistry HEK 293 cells NF-kappa B NLRP3 inflammasome/ macrophages/ obesity/ PPARγ/ rosiglitazone Inflammasome Cell biology Mice Inbred C57BL PPAR gamma 030104 developmental biology 030220 oncology & carcinogenesis Leukocytes Mononuclear Macrophages Peritoneal NLRP3 inflammasome activation Research Paper medicine.drug |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | 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. PPARγ, a known regulator of energy metabolism, plays an anti-inflammatory role through the inhibition of NF-κB activation and additionally attenuates NLRP3-dependent IL-1β and IL-18 production. Therefore, we hypothesized that PPARγ serves as an endogenous modulator that attenuates NLRP3 inflammasome activation in macrophages. Methods: Mouse peritoneal macrophages with exposure to a PPARγ agonist at different stages and the NLRP3 inflammasome-reconstituted system in HEK293T cells were used to investigate the additional anti-inflammatory effect of PPARγ on NLRP3 inflammasome regulation. Circulating mononuclear cells of obese patients with weight-loss surgery were used to identify the in vivo correlation between PPARγ and the NLRP3 inflammasome. Results: Exposure to the PPARγ agonist, rosiglitazone, during the second signal of NLRP3 inflammasome activation attenuated caspase-1 and IL-1β maturation. Moreover, PPARγ 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 PPARγ DNA-binding domain and the nucleotide-binding and leucine-rich repeat domains of NLRP3. Furthermore, PPARγ was required to limit metabolic damage-associated molecular pattern-induced NLRP3 inflammasome activation in mouse macrophages. Finally, the mature caspase-1/PPARγ 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 PPARγ in suppressing NLRP3 inflammasome activation through interaction with NLRP3. Thus, our study highlights that PPARγ agonism may be a therapeutic option for targeting NLRP3-related metabolic diseases. |
Databáze: | OpenAIRE |
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