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| Biology of the NOD-like receptor family in infection and inflammation. | |||||||
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The innate immune system is the first line of defense against invading microorganisms. The focus of our studies is a recently described family of molecules called NLRs (NOD-like receptors) that are involved in the regulation of innate immune responses and cell death pathways. Some NLR family members promote the activation of pro-inflammatory caspases within multiprotein complexes called inflammasomes. Mutations within NLRP3 (also known as NALP3), a member of the NLR family, have been linked to a group of autoinflammatory disorders in humans collectively known as the Cryopyrin-associated periodic syndromes. NLRC4 (also known as IPAF), another NLR family member, plays a crucial role in response to infection with a number of Gram-negative bacteria. To understand the role of NLRs in coordinating the immune response we have used a gene-targeting approach utilizing mice deficient in specific inflammasome components.
We are interested in three major areas of study. 1. Characterizing the signaling events involved in activation of the NLRP3- and NLRC4-inflammasomes. This entails determining the specific ligand for NLRP3 and NLRC4 and identifying downstream events mediated by their activation. 2. Determining the role of NLRP3 and NLRC4 in the host response to bacterial and fungal infections and identifying mechanisms pathogens use to evade these innate immune defenses. 3. Characterizing the role of NLRs in murine models of malignancy and autoinflammatory disease and correlating this to disease pathogenesis in humans. |
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| Selected Publications | |||||||
| Click Here for a Complete List of Articles | |||||||
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Sutterwala F.S., Mijares, L.A., Li, L., Ogura, Y., Kazmierczak, B.I. and R.A. Flavell. Immune recognition of Pseudomonas aeruginosa is mediated by the IPAF inflammasome. J. Exp. Med. 204:3235-3245, 2007.
Eisenbarth, S.C., Colegio, O.R., O’Connor, W., Sutterwala F.S. and Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminum adjuvants. Nature. 453:1122-1126, 2008. Cassel, S.L., Eisenbarth, S.C., Iyer, S.S., Sadler, J.J., Colegio, O.R., Tephly, L.A., Carter, A.B., Rothman, P.B., Flavell, R.A. and Sutterwala F.S. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl. Acad. Sci. U.S.A. 105:9035-9040, 2008. Imaeda, A., Watanabe, A., Mahmood, S., Sohail, M., Sutterwala F.S., Flavell, R.A. and Mehal, W. Acetaminophen Induced Hepatotoxicity is Dependent on TLR9 and the NALP3 Inflammasome. J. Clin. Invest. 119:305-14, 2009. Joly, S., Ma, N., Sadler, J.J., Soll, D.R., Cassel, S.L. and Sutterwala F.S. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. In press, 2009. |
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| Department/Program Affiliations |
| Internal Medicine |
| Biosciences |
| Immunology |
| Molecular and Cellular Biology |