New data implicate podocyte NLRP3 inflammasomes in the pathogenesis of lupus nephritis (LN). These inflammasomes were activated in biopsy samples from patients with LN and in lupus-prone NZM2328 mice. In the mice, NLRP3 inhibition reduced proteinuria, renal histological lesions and podocyte foot-process effacement. Sera from diseased NZM2328 mice activated NLRP3 inflammasomes in cultured podocytes via a mechanism involving production of reactive oxygen species. These findings are consistent with a role of NLRP3 activation in podocyte injury and the development of proteinuria in LN.