ROR{gamma} regulates the NLRP3 inflammasome [Signal Transduction] (Journal of Biological Chemistry)

RAR-related orphan receptor ? (ROR?) is a nuclear receptor that plays an essential role in the development of T helper 17 (Th17) cells of the adaptive immune system. The NLRP3 inflammasome is a component of the innate immune system that processes interleukin (IL)-1? into a mature cytokine. Elevated activity of the NLRP3 inflammasome contributes to the progression of an array of inflammatory diseases. Bone marrow-derived macrophages (BMDMs) isolated from ROR?-null mice displayed reduced capacity to secrete IL-1?, and they also displayed a reduction in Nlrp3 and Il1b gene expression. Examination of the promoters of the Il1b and Nlrp3 genes revealed multiple putative ROR response elements (ROREs) that were occupied by ROR?. ROR? inverse agonists were effective inhibitors of the inflammasome. ROR? inverse agonists suppressed lipopolysaccharide (LPS)/ATP-stimulated IL-1? secretion and expression of Il1b and Nlrp3 in BMDMs. Additionally, the ability of the ROR? inverse agonists to suppress IL-1? secretion was lost in Nlrp3-null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using ROR? inverse agonists was examined in two models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of ROR? activity reduced plasma IL-1? as well as IL-1? production by peritoneal macrophages in a model of LPS-induced sepsis. Additionally, ROR? inverse agonists reduced mortality in an LPS/d-galactosamine-induced fulminant hepatitis mouse model. These results illustrate a major role for ROR? in regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with ROR? inverse agonists may be an effective method to treat NLRP3-associated diseases.