Rheumatoid arthritis (RA) and Systemic Lupus Erythematosus (SLE) are debilitating autoimmune diseases afflicting millions of Americans;they also cause a significant economic burden. Recently both diseases have been associated with aberrant T helper-17 (Th17) responses. IL-17(A), along with the less potent IL-17F, are the signature cytokines of Th17 cells;they are members of the IL-17 cytokine family. Adaptive Th17 immune responses and the IL-17 cytokines they produce play important roles in defense against many extracellular bacteria and fungi, but they have also been implicated in autoimmune diseases, such as multiple sclerosis, RA and SLE, as well as in inflammatory diseases, including psoriasis. All IL-17 cytokines signal via an adaptor protein we cloned and named CIKS. Previously we reported the functional significance of CIKS in collagen-induced arthritis (CIA), a mouse model of RA. Mice lacking CIKS were effectively protected from disease and more protected than mice lacking only IL-17, indicating contributions from not only IL-17, but also other members of the family to the pathology observed in the CIA model. This provided a proof-of-principle indicating that CIKS is a possible target for therapeutic intervention in RA. Previously we also established a mouse model for SLE with which to explore the role of CIKS and of IL-17 in this disease. Mice lacking the inhibitory FcgammaR2b protein fail to maintain tolerance to self and with time develop a lupus-like disease. In FY 2013 we have demonstrated that CIKS and IL-17 are essential to the development of fatal lupus nephritis in this model. While IL-17 had previously been suggested to play a role in auto-antibody production, we have now shown that IL-17 cytokines produced locally drive kidney inflammation, leading to fatal glomerulonephritis. Mice lacking CIKS were better protected than mice merely lacking IL-17A, and we were able to demonstrate that this was due at least in part to additional contributions by IL-17C. We also demonstrated that IL-17 cytokines are instrumental in the formation of neutrophil extracellular traps (NETs) in kidneys, which are thought to be highly pathogenic. These findings identify IL-17 cytokines and especially their signaling via CIKS as potential targets of therapeutic intervention in lupus nephritis, an often-fatal consequence of lupus. In FY 2013 we have developed the imiguimod-induced model of psoriasis to explore the molecular mechanisms underlying IL-17 cytokines-driven pathology in this disease. In FY2013 we have also developed a chronic house dust mite-induced model of allergic asthma to investigate the potential role of IL-25 in this inflammatory disease.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$697,567
Indirect Cost
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Yariswamy, Manjunath; Yoshida, Tadashi; Valente, Anthony J et al. (2016) Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction. J Biol Chem 291:19425-36
Whibley, Natasha; Tritto, Elaine; Traggiai, Elisabetta et al. (2016) Antibody blockade of IL-17 family cytokines in immunity to acute murine oral mucosal candidiasis. J Leukoc Biol 99:1153-64
Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy et al. (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153-60
Mummidi, Srinivas; Das, Nitin A; Carpenter, Andrea J et al. (2016) Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo. J Mol Cell Cardiol 98:95-102
Sakamuri, Siva S V P; Valente, Anthony J; Siddesha, Jalahalli M et al. (2016) TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis. Mol Cell Endocrinol 429:84-92
Huang, Yuefeng; Guo, Liying; Qiu, Jin et al. (2015) IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential 'inflammatory' type 2 innate lymphoid cells. Nat Immunol 16:161-9
Somma, Domenico; Mastrovito, Paola; Grieco, Marianeve et al. (2015) CIKS/DDX3X interaction controls the stability of the Zc3h12a mRNA induced by IL-17. J Immunol 194:3286-94
Claudio, Estefania; Tassi, Ilaria; Wang, Hongshan et al. (2015) Cutting Edge: IL-25 Targets Dendritic Cells To Attract IL-9-Producing T Cells in Acute Allergic Lung Inflammation. J Immunol 195:3525-9
Somanna, Naveen K; Yariswamy, Manjunath; Garagliano, Joseph M et al. (2015) Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cell Signal 27:1928-38
Ha, Hye-Lin; Wang, Hongshan; Pisitkun, Prapaporn et al. (2014) IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms. Proc Natl Acad Sci U S A 111:E3422-31

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