Hyperactivation of the NLRP3 Inflammasome in Myeloid Cells Leads to Severe Organ Damage in Experimental Lupus.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune syndrome associated with severe organ damage resulting from the activation of immune cells. Recently, a role for caspase-1 in murine lupus was described, indicating an involvement of inflammasomes in the development of SLE. Among multiple inflammasomes identified, the NLRP3 inflammasome was connected to diverse diseases, including autoimmune encephalomyelitis. However, the function of NLRP3 in SLE development remains elusive. In this study, we explored the role of NLRP3 in the development of SLE using the pristane-induced experimental lupus model. It was discovered that more severe lupus-like syndrome developed in Nlrp3-R258W mice carrying the gain-of-function mutation. Nlrp3-R258W mutant mice exhibited significantly higher mortality upon pristane challenge. Moreover, prominent hypercellularity and interstitial nephritis were evident in the glomeruli of Nlrp3-R258W mice. In addition, hyperactivation of the NLRP3 inflammasome in this mouse line resulted in proteinuria and mesangial destruction. Importantly, all of these phenotypes were largely attributed to the Nlrp3-R258W mutation expressed in myeloid cells, because Cre recombinase-mediated depletion of this mutant from such cells rescued mice from experimental lupus. Taken together, our study demonstrates a critical role for NLRP3 in the development of SLE and suggests that modulating the inflammasome signal may help to control the inflammatory damage in autoimmune diseases, including lupus.