Many of the signaling pathways that lead to innate immune responses during infection are also involved in the regulation of auto inflammatory and autoimmune diseases. The early recognition of pathogens or damage signals by innate immune pattern-recognition receptors (PRRs) initiates signaling pathways that promote the induction of proinflammatory responses. Cytosolic PRRs of the Nod-like receptor (NLR) family mediating these pathways form the core of an early recognition and response system that both precedes and initiates the development of T- and B-cell mediated immunity. Although these mechanisms evolved to protect the host, it is clear that differences in virulence, morbidity and mortality dueto pathogens are dependent on host innate immune responses. Furthermore, the occurrence of autoimmune or auto inflammatory diseases is linked to deregulation of many of the same pathways. Indeed our studies suggest that the Nlrp3 inflammasome can modulate both protective and pathologic immune responses. The appropriate activation of Nlrp3 triggers the innate immune response to invading pathogens including influenza A virus and Citrobacter rodentium, and its excessive response underlies auto inflammatory CAPS (cryopyrin associated periodic syndromes). The Nlrp3 inflammasome is also triggered by abnormal metabolic conditions that lead to the development of common debilitating disorders such as gout and type II diabetes mellitus. Intriguingly, our studies suggest that another NLR family member, Nlrc2, and its adaptor, Ripk2, affect inflammasome activation and downstream production of IL-1??and IL-18. We hypothesize that Nlrc2 and Ripk2 dampen inflammation by negatively regulating inflammasome activation by clearing damaged mitochondria via autophagy. Thus, the major goals of this proposal are to define the cellular and molecular basis underlying the regulation of inflammation and innate immune responses by NLRs.
The studies proposed will provide novel insights into the physiological role of the innate immune system/inflammasome signaling in inflammation, host defense and into the pathogenesis of autoinflammatory syndromes thus leading to novel therapeutic targets for inflammatory and infectious diseases.
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