P40 IL-17F PROMOTES TISSUE INJURY IN AUTOIMMUNE KIDNEY DISEASES

The TH17 immune response plays a central role in the pathogenesis of autoimmune diseases, implicating the TH17 “master cytokine” IL-17A as the critical mediator of diseases such as human and experimental crescentic glomerulonephritis (GN). However, the relative importance of additional TH17 effector cytokines, including IL-17F, in immune-mediated tissue injury remains to be fully elucidated. Methods: Here, we used a mouse model of acute crescentic GN (nephrotoxic Nephritis) including interventional studies using IL17F-gene-deficient mice, IL-17F-neutralizing antibodies, as well as adoptive cell transfer experiments into Rag1-/mice. Moreover, also in the chronic model of pristane induced systemic lupus, IL-17Fdeficient mice were analyzed. Results: In a mouse model of acute crescentic GN, we identified CD4+ T cells and T cells as the major cellular source of IL-17F in the inflamed kidney. In our studies using IL-17F-gene-deficient mice as well as IL-17F-neutralizing antibodies, and adoptive cell transfer experiments into Rag1-/mice we demonstrated that CD4+ T cellderived IL-17F drives renal tissue injury in acute crescentic GN. Moreover, also in the chronic model of pristane induced systemic lupus, IL-17F-deficient mice developed less severe disease with respect to survival and renal injury. Finally, we show that IL-17F induced expression of the chemokines CXCL1 and CXCL5 in kidney cells, which recruited destructive neutrophils. Conclusions: In conclusion, using gene-deficient mice, neutralizing antibodies and adoptive cell transfer experiments, we demonstrate for the first time that IL-17F promotes kidney injury in acute and chronic experimental glomerulonephritis. Our data, which challenge the paradigm of IL-17A as being the unique TH17 master cytokine, might be of direct importance for future antiTH17/IL-17 treatment strategies in human autoimmune diseases.