| First Author | Billon C | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 1 | Pages | 10-19 |
| PubMed ID | 30455347 | Mgi Jnum | J:274726 |
| Mgi Id | MGI:6294202 | Doi | 10.1074/jbc.AC118.002127 |
| Citation | Billon C, et al. (2019) RORgamma regulates the NLRP3 inflammasome. J Biol Chem 294(1):10-19 |
| abstractText | RAR-related orphan receptor gamma (RORgamma) 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)-1beta 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 RORgamma-null mice displayed reduced capacity to secrete IL-1beta, 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 RORgamma. RORgamma inverse agonists were effective inhibitors of the inflammasome. RORgamma inverse agonists suppressed lipopolysaccharide (LPS)/ATP-stimulated IL-1beta secretion and expression of Il1b and Nlrp3 in BMDMs. Additionally, the ability of the RORgamma inverse agonists to suppress IL-1beta secretion was lost in Nlrp3-null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using RORgamma inverse agonists was examined in two models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of RORgamma activity reduced plasma IL-1beta as well as IL-1beta production by peritoneal macrophages in a model of LPS-induced sepsis. Additionally, RORgamma inverse agonists reduced mortality in an LPS/d-galactosamine-induced fulminant hepatitis mouse model. These results illustrate a major role for RORgamma in regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with RORgamma inverse agonists may be an effective method to treat NLRP3-associated diseases. |
