NOD-like receptors (NLRs) are a family of intracellular sensor molecules involved in the regulation of inflammatory signaling in response to infection and cellular stress. Recent studies have revealed pivotal roles for NLR-mediated inflammation in a spectrum of diverse human autoimmune and inflammatory disorders. The vast majority of NLRs to date have been defined as activators of inflammatory signaling in innate immune cells. For instance, the prototypical NLR members, NOD1 and NOD2, initiate proinflammatory NF-?B and MAPK signaling in response to their direct recognition of bacterial peptidoglycan fragments. Multiple NLRs have also been described to promote the activation and secretion of the proinflammatory cytokines IL-1? and IL-18 by coordinating the assembly of the inflammasome complex. In contrast, some NLRs, such as NLRP6, NLRP12, NLRC3 and NLRX1, negatively regulate inflammatory signaling. However, the cellular and molecular mechanisms that direct the suppression of inflammation by this new class of inhibitory NLRs are not known. Missense mutations in NLRP12 are associated with inflammatory diseases in humans, but the biochemical mechanisms and pathways underlying these pathologies remain unclear. Recent work from our lab demonstrates that NLRP12 functions as a key negative regulator of NF-?B signaling. Importantly, inflammation and immunopathology are not exclusively restricted to inflammatory and autoimmune diseases. The dysregulation of innate and adaptive immunity can also result in striking differences with regard to morbidity and mortality during infectious disease. In this regard, NLRP12's role in viral infection and generation of adaptive immune responses has not been investigated. Therefore, this project is highly significant, as it will lead to the identification of key immune mechanisms involved in host defense and inflammatory control mechanisms dependent on NLRP12 that regulate inflammation. We will examine these mechanisms through the use of influenza A virus.
Missense mutations in Nlrp12 lead to inflammatory diseases in humans. The studies proposed in this application on the signaling pathways involved in innate and acquired host immune responses, regulated by NLRP12 will increase our understanding of key regulators of immunity and host defense that operate in major human diseases. These studies uncover novel signaling pathways that will help in the design of therapeutics to treat infectious and inflammatory diseases.
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