| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所 === 101 === NLRP3 inflammasome, a multiprotein complex consisting of NLRP3, ASC and caspase-1, is expressed in immune cells and is a component for the innate immune system. Activators from microbe, stress and damage signals trigger inflammsome assembly to direct cleavage of caspase-1 for maturation and secretion of IL-1β and cell death. Thus, aberrant IL-1β production and inflammasome activation are important in diseases associated with dysregulated inflammatory responses. PPARγ, a nuclear hormone receptor, plays an important role in adipocyte differentiation and glucose homeostasis. PPARγ is also expressed in macrophages, and inhibits the expression of inflammatory cytokines, including IL-1β, by inhibition of NF-κB activation. Several studies showed an inverse correlation between PPARγ activation and IL-1β production. Thus we hypothesized that PPARγ attenuates inflammasome activation in macrophages. First, we found that expression of inflammasome components, IL-1β, caspase-1 and NLRP3, was increased in PPARγ-defective macrophages in response to LPS. Treatment of PPARγ agonist rosiglitazone attenuated cleavages of caspase-1 and IL-1β in LPS-primed nigericin-stimulated macrophages. Consistently, cleavages of caspase-1 and IL-1β were higher in macrophages from PPARγ-defective mice (PpargC/- and PpargL/+) than wild-type mice. Moreover, PPARγ activation during nigericin stimulation effectively attenuated inflammasome activation. In addition to nigericin, PPARγ activation also attenuated crystal-mediated NLRP3 inflammasome activation. We further set up an artificial NLRP3 inflammasome reconstituted system in HEK293T cells. We found that PPARγ also reduced IL-1β maturation and blocked inflammasome complex formation in reconstituted HEK293T cells. Interestingly, immunofluorescence staining and immunoprecipitaion showed that PPARγ was associated with NLRP3 in both basal and inflammasome activated states. Finally, we found that PPARγ was downregulated during inflammasome activation. Inhibition of NF-κB or proteasome, but not caspase-1, effectively attenuated PPARγ degradation. Prevention of PPARγ from degradation was associated with reduction of inflammasome activation. In conclusion, PPARγ attenuates NLRP3 inflammasome activation in macrophages, partly through its interaction with NLRP3. Upon inflammasome stimulation, PPARγ is then degraded to allow a full inflammasome activation. Our study demonstrates a novel function of PPARγ in attenuation of inflammatory response and provides a candidate for PPARγ agonist in the treatment of inflammasome-associated diseases.
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