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.
|Valente, Anthony J; Irimpen, Anand M; Siebenlist, Ulrich et al. (2014) OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med 70:117-28|
|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|
|Lee, Yu-Jin; Zhang, Xiaozhen; Vazquez, Estefania et al. (2014) Impaired HCV clearance in HIV/HCV coinfected subjects treated with PegIFN and RBV due to interference of IFN signaling by IFN*R2a. J Interferon Cytokine Res 34:28-34|
|Ferreira, Maria Carolina; Whibley, Natasha; Mamo, Anna J et al. (2014) Interleukin-17-induced protein lipocalin 2 is dispensable for immunity to oral candidiasis. Infect Immun 82:1030-5|
|Valente, Anthony J; Sakamuri, Siva S V P; Siddesha, Jalahalli M et al. (2013) TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cell Signal 25:2176-84|
|Claudio, Estefania; Sonder, Soren Ulrik; Saret, Sun et al. (2009) The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol 182:1617-30|