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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR056296-06A1
Application #
8577795
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Mao, Su-Yau
Project Start
2008-07-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$371,875
Indirect Cost
$159,375
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Qi, Xiaopeng; Man, Si Ming; Malireddi, R K Subbarao et al. (2016) Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection. J Exp Med 213:2081-97
Man, Si Ming; Karki, Rajendra; Kanneganti, Thirumala-Devi (2016) DNA-sensing inflammasomes: regulation of bacterial host defense and the gut microbiota. Pathog Dis 74:ftw028
Liu, Zhiping; Man, Si Ming; Zhu, Qifan et al. (2016) DOCK2 confers immunity and intestinal colonization resistance to Citrobacter rodentium infection. Sci Rep 6:27814
Qi, X; Gurung, P; Malireddi, R K S et al. (2016) Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis. Mucosal Immunol :
Man, Si Ming; Karki, Rajendra; Kanneganti, Thirumala-Devi (2016) AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur J Immunol 46:269-80
Man, Si Ming; Kanneganti, Thirumala-Devi (2016) Type I Interferon Keeps IL-1β in Check. Cell Host Microbe 19:272-4
Gurung, Prajwal; Kanneganti, Thirumala-Devi (2016) Autoinflammatory Skin Disorders: The Inflammasomme in Focus. Trends Mol Med 22:545-64
Malik, Ankit; Sharma, Deepika; Zhu, Qifan et al. (2016) IL-33 regulates the IgA-microbiota axis to restrain IL-1α-dependent colitis and tumorigenesis. J Clin Invest 126:4469-4481
Gurung, Prajwal; Burton, Amanda; Kanneganti, Thirumala-Devi (2016) NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1β-mediated osteomyelitis. Proc Natl Acad Sci U S A 113:4452-7
Gurung, Prajwal; Sharma, Bhesh Raj; Kanneganti, Thirumala-Devi (2016) Distinct role of IL-1β in instigating disease in Sharpin(cpdm) mice. Sci Rep 6:36634

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