The innate immune system is capable of integrating a number of diverse signals in order to respond to both pathogenic threats and sterile inflammatory injury. The inflammasome is a multi-protein complex that when assembled mediates the activation of caspase-1 with the subsequent secretion of the proinflammatory cytokines IL-1β and IL-18 as well as the induction of the pyroptotic cell death pathway. Members of the NLR (nucleotide-binding domain leucine-rich repeat containing) family, NLRP1, NLRP3, and NLRC4, as well as the PYHIN (pyrin and HIN200 domain-containing) family member AIM2 have all been demonstrated to form functional inflammasomes capable of activating caspase-1. To understand the role of NLRs in coordinating the immune response we have used a gene-targeting approach utilizing mice deficient in specific inflammasome components. We are interested in three major areas of study. 1) Characterizing the signaling events involved in activation of the inflammasome complexes. 2) Determining the role of NLR family members in host the response to bacterial and fungal infections and identifying mechanisms pathogens use to evade these innate immune defenses. 3) Characterizing the role of NLRs in murine models of autoimmune and autoinflammatory disease and correlating this to disease pathogenesis in humans.