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Signaling and activation pathways of the NOD-like receptors Ipaf, Nlrp1b and Nlrp12

Final Report Summary - SIGNLRACT (Signaling and activation pathways of the NOD-like receptors Ipaf, Nlrp1b and Nlrp12)

NOD-like receptors (NLRs) play important roles in the immune system. They respond to pathogens and danger signals by initiating signaling cascades that lead to inflammatory and host defense responses. Consequently, mutations in several NLRs are linked with autoinflammatory and immune diseases in patients, but the roles and signalling cascades of most NLRs remain unclear. During this project, we showed that
A20/TNFAIP3 regulated expression and activation of NLRP3 inflammasome components, driving autoinflammatory disease through excessive production of inflammasome substrates IL-1beta and IL-18, whereas activation of other inflammasome pathways was not significantly changed. Our studies further showed that IL-1 production by the Nlrp3 inflammasome is critical for arthritis development in this mouse model of autoinflammatory disease. Given that mutations in both Nlrp3 and A20 are associated with arthritis development and autoinflammatory disease in patients, these results provide a mechanistic link that can be therapeutically exploited in arthritis and autoinflammatory syndromes. We also made significant progress in characterizing the upstream mechanisms controlling activation of the Pyrin inflammasome by characterizing the requirements for Pyrin activation and how inflammatory signaling is altered in peripheral blood mononuclear cells of patients suffering from Familial Mediterranean Fever. In the context of the Nlrp1b and Nlrc4 inflammasomes, we characterized the role of ASC in these CARD-based inflammasomes and defined the requirements for Nlrc4 phosphorylation and Naip5 activation by bacterial flagellin. Finally, we established that inflammatory triggers regulated Nlrp12 expression in different immune cell types. Given the importance of NLRs in infection and autoimmunity, further validation of the activation and signaling pathways of Nlrp1b, Nlrc4 and Nlrp12 is likely to have far-reaching implications for our understanding of host defense and autoimmune diseases.