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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mancini, Marie
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Hirano, Yoshio; Yasuma, Tetsuhiro; Mizutani, Takeshi et al. (2014) IL-18 is not therapeutic for neovascular age-related macular degeneration. Nat Med 20:1372-5
Tarallo, Valeria; Hirano, Yoshio; Gelfand, Bradley D et al. (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149:847-59
Embry, Chelsea A; Franchi, Luigi; Nuñez, Gabriel et al. (2011) Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci Signal 4:ra28
Shaw, Michael H; Kamada, Nobuhiko; Warner, Neil et al. (2011) The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation. Trends Immunol 32:73-9
Reimer, Thornik; Shaw, Michael H; Franchi, Luigi et al. (2010) Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur J Immunol 40:764-9
Muñoz-Planillo, Raúl; Franchi, Luigi; Miller, Lloyd S et al. (2009) A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J Immunol 183:3942-8
Franchi, Luigi; Eigenbrod, Tatjana; Núñez, Gabriel (2009) Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 183:792-6
Franchi, Luigi; Warner, Neil; Viani, Kyle et al. (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227:106-28
Franchi, Luigi; Eigenbrod, Tatjana; Muñoz-Planillo, Raúl et al. (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10:241-7
Harder, Jürgen; Franchi, Luigi; Muñoz-Planillo, Raúl et al. (2009) Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 183:5823-9

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