The autoinflammatory disorders familial cold autoinflammatory syndrome (FACS), Muckle-Wells syndrome (MWS), and neonatal-onset multiple-system inflammatory disease (NOMID) are inherited dominant diseases characterized by spontaneous and recurrent episodes of systemic inflammation without an apparent infectious or autoimmune etiology. Although most of these diseases are rare, understanding of their pathogenesis may provide insight into the fundamental mechanisms mediating inflammation and innate immunity. Genetic studies have recently revealed that FACS, MWS and NOMID are caused by missense mutations in Cryopyrin, a member of the NOD family of proteins. NOD family members including NOD1, NOD2 and Cryopyrin are intracellular proteins that have been implicated in the recognition of bacterial components and activation of inflammatory pathways against invading pathogens. Recent work from several laboratories including our own suggest that Cryopyrin mediates is involved in apoptosis, NF-KB activation and regulation of IL-1pYIL-18 processing through its interaction with the adaptor molecule ASC. We have obtained evidence that Cryopyrin mutations found in patients with autoinflammatory disease function as activating mutations in that they induce increased NF-KB activity and IL-1P secretion when compared to the wild-type protein. Moreover, our results indicate that ASC plays a critical role in the response of macrophages to intracellular bacteria. Thus, we hypothesize that Cryopyrin-associated autoinflammatory diseases may be caused by dysregulation of the ASC signaling pathway which is normally involved in the host response to bacterial pathogens. To address these hypotheses and to understand the role of ASC in innate immunity and inflammatory disease, we propose four specific Aims: (i) express the disease- associated Cryopyrin D303NS mutant in mice to develop a model of autoinflammatory syndrome; (ii) characterize mutant mice deficient in ASC to determine the role of ASC in vivo; (iii) determine the interaction between TLR4 and ASC signaling in response to intracellular bacteria Salmonella and (iv) determine the role of ASC in experimental models of autoimmune arthritis. The studies proposed may provide novel insight into signaling pathways linking innate immunity and pathogenesis of autoinflammatory disorders. ? ? ?
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