The innate immune system comprises several classes of pattern recognition receptors, including Toll- like receptors (TLRs), NOD-like receptors (NLRs), and RIG-1-like receptors (RLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs and RLRs detect microbial components in the cytosol. In some autoinflammatory conditions, abnormalities in NLR signaling pathways are involved in pathogenesis, as exemplified by cryopyrin mutations associated with three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease. Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the ASC and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-12 into an active form, the secretion of which leads to a potent inflammatory response. Recent studies have demonstrated that cryopyrin mutations found in patients with autoinflammatory disease function as activating mutations resulting in enhanced IL-12 secretion. In addition, pyrin, the product of familial fever (FMF), negatively regulates the cryopyrin inflammasome signaling. Results from our laboratory and others show that cryopyrin and ASC play a critical role in the response of macrophages to microbial components, bacteria and viruses. Altogether, the central hypothesis on which this proposal is based is that dysregulated cryopyrin inflammasome signaling is a primary contributor to the spectrum of autoinflammatory diseases. To address our hypotheses and to understand the role of innate immune responses in inflammatory and infectious diseases, we propose to study the role of cryopyrin/ASC signaling pathway in inflammatory disease, host defense and regulation of cytokine/chemokine secretion. The proposed studies will help development of new molecular insights into the molecular and cellular mechanisms regulating infection and autoinflammation, thus leading to novel therapeutic targets for inflammatory and infectious diseases.
The studies proposed will provide novel insights into the physiological role of the innate immune system/cryopyrin signaling in inflammation, host defense and into the pathogenesis of autoinflammatory syndromes thus leading to novel therapeutic targets for inflammatory and infectious diseases.
|Lukens, John R; Gross, Jordan M; Calabrese, Christopher et al. (2014) Critical role for inflammasome-independent IL-1? production in osteomyelitis. Proc Natl Acad Sci U S A 111:1066-71|
|Vande Walle, Lieselotte; Van Opdenbosch, Nina; Jacques, Peggy et al. (2014) Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 512:69-73|
|Lupfer, Christopher; Thomas, Paul G; Kanneganti, Thirumala-Devi (2014) Nucleotide oligomerization and binding domain 2-dependent dendritic cell activation is necessary for innate immunity and optimal CD8+ T Cell responses to influenza A virus infection. J Virol 88:8946-55|
|Demon, D; Kuchmiy, A; Fossoul, A et al. (2014) Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis. Mucosal Immunol 7:1480-91|
|Wagener, Jeanette; Malireddi, R K Subbarao; Lenardon, Megan D et al. (2014) Fungal chitin dampens inflammation through IL-10 induction mediated by NOD2 and TLR9 activation. PLoS Pathog 10:e1004050|
|Zhu, Qifan; Man, Si Ming; Gurung, Prajwal et al. (2014) Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol 193:4779-82|
|Lupfer, Christopher R; Anand, Paras K; Liu, Zhiping et al. (2014) Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection. PLoS Pathog 10:e1004410|
|Zaki, Md Hasan; Man, Si Ming; Vogel, Peter et al. (2014) Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci U S A 111:385-90|
|Gurung, Prajwal; Anand, Paras K; Malireddi, R K Subbarao et al. (2014) FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol 192:1835-46|
|Lukens, John R; Kanneganti, Thirumala-Devi (2014) Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease. Semin Immunopathol 36:595-609|
Showing the most recent 10 out of 51 publications