Many of the signaling pathways that lead to innate immune responses during infection are also involved in the regulation of auto inflammatory and autoimmune diseases. The early recognition of pathogens or damage signals by innate immune pattern-recognition receptors (PRRs) initiates signaling pathways that promote the induction of proinflammatory responses. Cytosolic PRRs of the Nod-like receptor (NLR) family mediating these pathways form the core of an early recognition and response system that both precedes and initiates the development of T- and B-cell mediated immunity. Although these mechanisms evolved to protect the host, it is clear that differences in virulence, morbidity and mortality dueto pathogens are dependent on host innate immune responses. Furthermore, the occurrence of autoimmune or auto inflammatory diseases is linked to deregulation of many of the same pathways. Indeed our studies suggest that the Nlrp3 inflammasome can modulate both protective and pathologic immune responses. The appropriate activation of Nlrp3 triggers the innate immune response to invading pathogens including influenza A virus and Citrobacter rodentium, and its excessive response underlies auto inflammatory CAPS (cryopyrin associated periodic syndromes). The Nlrp3 inflammasome is also triggered by abnormal metabolic conditions that lead to the development of common debilitating disorders such as gout and type II diabetes mellitus. Intriguingly, our studies suggest that another NLR family member, Nlrc2, and its adaptor, Ripk2, affect inflammasome activation and downstream production of IL-1??and IL-18. We hypothesize that Nlrc2 and Ripk2 dampen inflammation by negatively regulating inflammasome activation by clearing damaged mitochondria via autophagy. Thus, the major goals of this proposal are to define the cellular and molecular basis underlying the regulation of inflammation and innate immune responses by NLRs.

Public Health Relevance

The studies proposed will provide novel insights into the physiological role of the innate immune system/inflammasome signaling in inflammation, host defense and into the pathogenesis of autoinflammatory syndromes thus leading to novel therapeutic targets for inflammatory and infectious diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Mao, Su-Yau
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St. Jude Children's Research Hospital
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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

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