Human inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, constitutes a major health problem in developed countries. Ulcerative colitis exhibits a characteristic profile of chronic inflammation involving the distal colon and rectum, and is generally recognized as an immune-mediated disorder resulting from abnormal interaction between colonic microflora and mucosal immune cells. Excessive inflammatory and immune responses in the intestine are thought to be due to a breach in the epithelial barrier in the gut that segregates commensal microflora from the host's systemic organs. Indeed, deterioration of the mucus layer of the colon is prominent in patients with ulcerative colitis. In addition, studies in rodents have linked tissue damage and disruption of the epithelial barrier in the gut to cytokine imbalances. The production of these inflammatory mediators has been implicated in the pathogenesis of experimental colitis, IBD and colorectal cancer in humans. The gastrointestinal tract is constantly exposed to bacteria and microbial products that are recognized by innate immune receptors such as the Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Thus, defects in the innate immune system are associated with the development of colonic inflammation. Recent studies indeed, revealed that mutations in two of the NLR family members NOD2 and cryopyrin/NLRP3 are associated with a high risk for developing Crohn's disease. The focus of this proposal is to study the role of NLRs and their adaptor proteins in the development of intestinal inflammation and related diseases. Results from our laboratory and others demonstrated that the NLRs are pivotal to the activation of the innate immune response to enteroinvasive pathogens such as Salmonella, Shigella and Listeria and drive the activation of NF-:B, MAPK and caspase-1 signaling pathways. Our preliminary data also show that a subgroup of NLR family members mediate the induction and release of proinflammatory mediators and protect against colits. Altogether, the goal of this proposal is to define the precise role of NLR signaling in intestinal inflammation and colon carcinogenesis. The proposed project will provide novel and important information that will help to elucidate the role of NLRs in inflammation, the pathogenesis of IBD and host-commensal interactions.

Public Health Relevance

Innate immune system has been suggested to mediate the development of intestinal inflammation and gastroinstestinal carconogenesis (GIC). Nonetheless, the role of distinct innate immune signaling pathways in the development of inflammation and GIC is yet to be unraveled. The proposed studies will contribute to our insight into the molecular mechanisms by which the innate immune system participates in colitis/carcinogenesis and might create new therapeutic options for inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI088177-02
Application #
8074102
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2010-06-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$207,900
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi (2012) Regulation of immune pathways by the NOD-like receptor NLRC5. Immunobiology 217:13-6
Anand, Paras K; Tait, Stephen W G; Lamkanfi, Mohamed et al. (2011) TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation. J Biol Chem 286:42981-91
Shaw, Patrick J; Barr, Maggie J; Lukens, John R et al. (2011) Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. Immunity 34:75-84
Zaki, Md Hasan; Vogel, Peter; Malireddi, R K Subbarao et al. (2011) The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20:649-60
Stienstra, Rinke; van Diepen, Janna A; Tack, Cees J et al. (2011) Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A 108:15324-9
Ippagunta, Sirish K; Malireddi, R K Subbarao; Shaw, Patrick J et al. (2011) The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nat Immunol 12:1010-6
Zaki, Md Hasan; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi (2011) The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends Immunol 32:171-9
Zaki, Md Hasan; Lamkanfi, Mohamed; Kanneganti, Thirumala-Devi (2011) Inflammasomes and Intestinal Tumorigenesis. Drug Discov Today Dis Mech 8:e71-e78
Lukens, John R; Dixit, Vishwa Deep; Kanneganti, Thirumala-Devi (2011) Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov Med 12:65-74
Lamkanfi, Mohamed; Vande Walle, Lieselotte; Kanneganti, Thirumala-Devi (2011) Deregulated inflammasome signaling in disease. Immunol Rev 243:163-73

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