The innate immune system is the first line of defense against invading microorganisms. The focus of our lab is a recently described family of molecules called NLRs (nucleotide-binding domain leucine-rich repeat containing 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, 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. The NLRP3 inflammasome can be activated by a number of diverse stimuli including bacterial toxins, endogenous danger signals and environmental pollutants. NLRC4, another NLR family member that is capable of forming an inflammasome, has been shown to play a crucial role in response to infection with a number of Gram-negative bacteria including Pseudomonas aeruginosa.
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 infection and identifying mechanisms pathogens use to evade these innate immune defenses. 3) Characterizing the role of NLRs in murine models of autoimmune and autoinflammatory disease and correlating this to disease pathogenesis in humans.
1. Cassel, S.L., S.C. Eisenbarth, S.S. Iyer, J.J. Sadler, O.R. Colegio, L.A. Tephly, A.B. Carter, P.B. Rothman, R.A. Flavell*, and F.S. Sutterwala*. 2008. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl. Acad. Sci. U.S.A. 105:9035-9040. *equal contribution.
2. S. Joly, N. Ma, J.J. Sadler, D.R. Soll, S.L. Cassel, and F.S. Sutterwala. 2009. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183:3578-81.
3. S.S. Iyer, W.P. Pulskens, J.J. Sadler, L.M. Butter, G.J. Teske, T. Ulland, S.C. Eisenbarth, S. Florquin, R.A. Flavell, J.C. Leemans*, and F.S. Sutterwala*. 2009. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl. Acad. Sci. U S A. 106:20388-93. *equal contribution.
4. Ulland TK, Buchan BW, Ketterer MR, Fernandes-Alnemri T, Meyerholz DK, Apicella MA, Alnemri ES, Jones BD, Nauseef WM* and Sutterwala FS*. 2010. Cutting Edge: Mutation of Francisella tularensis mviN leads to increased macrophage AIM2 inflammasome activation and a loss of virulence. J. Immunol. 185:2670-4 *equal contribution.
5. Joly S, Eisenbarth SC, Olivier AK, Williams A, Kaplan DH, Cassel SL, Flavell RA, Sutterwala FS. 2012. Cutting Edge: Nlrp10 Is Essential for Protective Antifungal Adaptive Immunity against Candida albicans. J. Immunol. 189:4713-7.
6. Ulland T, Janowski A, Buchan B, Faron M, Cassel S, Jones B, Sutterwala FS. 2013. Francisella tularensis LVS folate metabolism and pseudouridine synthase gene mutants modulate macrophage caspase-1 activation. Infect Immun. 81:201-8.
7. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L. 2013. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun. 4:1611.
8. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier A, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, Eisenbarth SC, Nauseef WM, Cassel SL*, Sutterwala FS*. 2013. Mitochondrial cardiolipin regulates Nlrp3 inflammasome activation. Immunity. 39:311-323. *equal contribution.
9. Cassel SL*, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, Iwakura Y, Shayakhmetov DM, Bassuk AG, Abu-Amer Y, Brogden KA, Burns TL, Sutterwala FS*, Ferguson PJ*. 2014. Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A. 111:1072-7. *equal contribution.