Caspase-1, a cysteine protease, is critical for the processing and secretion of IL-1( and IL-18, two pro- inflammatory cytokines that play an important role in host defense, sepsis, and the pathogenesis of several inflammatory diseases. The activation of caspase-1 is controlled by members of the intracellular NOD-like receptor (NLR) family including NLRC4 and NLRP3. Recent work from several laboratories indicate that NLRC4 and NLRP3 regulate caspase-1 activation through the assembly of a molecular platform termed "the inflammasome" that includes the adaptor ASC and caspase-1. We have obtained evidence that NLRC4 senses bacterial flagellin that is introduced into the host cytosol via membrane pores formed by bacterial type III or IV secretion systems. In contrast, NLRP3 responds to bacterial pore-forming toxins, ATP and particulate matter in macrophages stimulated with microbial molecules or endogenous cytokines. Our knowledge about the inflammasome is limited and primarily derived from cellular and animals models of systemic inflammation. We have obtained Preliminary Results supporting an important role for the inflammasome in intestinal inflammation driven by enteric infection. The goal of this proposal is to provide a better understanding of the mechanisms that govern the activation of the inflammasome in intestinal phagocytes and the role of NLRC4 and NLRP3 in the response to clinically relevant intestinal bacteria. Biochemical, genetic, and cellular approaches will be employed to study the function and activation of the inflammasome in intestinal immunity using Salmonella and Crohn's disease-associated invasive-adherent E. coli. Given the important role of IL-1( in immunity and inflammatory disease, understanding of the mechanism involved in caspase-1 activation and IL-1( production in the intestine is expected to have a significant impact in the medical field

Public Health Relevance

The inflammasomes play a critical in host defense and contributes to inflammatory responses through the regulation of caspase-1 activation and IL-1(/IL-18 secretion. We find that the NLRC4 and NLRP3 inflammasomes are important for the detection of intestinal bacteria pathogens and host defense in the intestine. The main goal of this proposal is to understand the regulation, activation and function of the inflammasomes in response to clinically relevant Salmonella and adherent-invasive E. coli, two enteric bacterial pathogens. These studies may lead to better understanding of mechanisms that control host defense against human pathogens and the pathogenesis of inflammatory disease in the intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091191-09
Application #
8529508
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2005-05-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$306,273
Indirect Cost
$108,038
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Suzuki, Shiho; Mimuro, Hitomi; Kim, Minsoo et al. (2014) Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages. Proc Natl Acad Sci U S A 111:E4254-63
De la Fuente, Marjorie; Franchi, Luigi; Araya, Daniela et al. (2014) Escherichia coli isolates from inflammatory bowel diseases patients survive in macrophages and activate NLRP3 inflammasome. Int J Med Microbiol 304:384-92
Franchi, Luigi; Eigenbrod, Tatjana; Muñoz-Planillo, Raúl et al. (2014) Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J Immunol 193:4214-22
Suzuki, Shiho; Franchi, Luigi; He, Yuan et al. (2014) Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkc?. PLoS Pathog 10:e1003926
Kim, Yun-Gi; Udayanga, Kankanam Gamage Sanath; Totsuka, Naoya et al. (2014) Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE?. Cell Host Microbe 15:95-102
He, Yuan; Varadarajan, Saranyaraajan; Munoz-Planillo, Raul et al. (2014) 3,4-methylenedioxy-*-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem 289:1142-50
Kamada, Nobuhiko; Núñez, Gabriel (2014) Regulation of the immune system by the resident intestinal bacteria. Gastroenterology 146:1477-88
Hasegawa, Mizuho; Yada, Shoko; Liu, Meng Zhen et al. (2014) Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage. Immunity 41:620-32
Elftman, Michael D; Gonzalez-Hernandez, Mariam B; Kamada, Nobuhiko et al. (2013) Multiple effects of dendritic cell depletion on murine norovirus infection. J Gen Virol 94:1761-8
Terwagne, Matthieu; Ferooz, Jonathan; Rolán, Hortensia G et al. (2013) Innate immune recognition of flagellin limits systemic persistence of Brucella. Cell Microbiol 15:942-60

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