IL-17F Promotes Tissue Injury in Autoimmune Kidney Diseases

TY - JOUR

T1 - IL-17F Promotes Tissue Injury in Autoimmune Kidney Diseases

AU - Riedel, Jan-Hendrik

AU - Paust, Hans-Joachim

AU - Krohn, Sonja

AU - Turner, Jan-Eric

AU - Kluger, Malte A

AU - Steinmetz, Oliver M

AU - Krebs, Christian F

AU - Stahl, Rolf A K

AU - Panzer, Ulf

N1 - Copyright © 2016 by the American Society of Nephrology.

PY - 2016/12

Y1 - 2016/12

N2 - The TH17 immune response has 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 GN. However, the relative importance of additional TH17 effector cytokines, including IL-17F, in immune-mediated tissue injury remains to be fully elucidated. Here, using a mouse model of acute crescentic GN (nephrotoxic nephritis), we identified CD4(+)T cells andγδT cells as the major cellular source of IL-17F in the inflamed kidney. Interventional studies using IL-17F gene-deficient mice, IL-17F-neutralizing antibodies, and adoptive transfer experiments into Rag1(-/-)mice demonstrated that CD4(+)T cell-derived IL-17F drives renal tissue injury in acute crescentic GN. Notably, IL-17F-deficient nephritic mice had fewer renal infiltrating neutrophils than wild-type nephritic mice, and neutrophil depletion did not affect the course of GN in IL-17F-deficient mice. Moreover, in the chronic model of pristane-induced SLE, IL-17F-deficient mice developed less severe disease than wild-type mice, with respect to survival and renal injury. Finally, we show that IL-17F induced expression of the neutrophil-attracting chemokines CXCL1 and CXCL5 in kidney cells. The finding that IL-17F has a nonredundant function in the development of renal tissue injury in experimental GN might be of great importance for the development of anti-IL-17 cytokine therapies in TH17-mediated human autoimmune diseases.

AB - The TH17 immune response has 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 GN. However, the relative importance of additional TH17 effector cytokines, including IL-17F, in immune-mediated tissue injury remains to be fully elucidated. Here, using a mouse model of acute crescentic GN (nephrotoxic nephritis), we identified CD4(+)T cells andγδT cells as the major cellular source of IL-17F in the inflamed kidney. Interventional studies using IL-17F gene-deficient mice, IL-17F-neutralizing antibodies, and adoptive transfer experiments into Rag1(-/-)mice demonstrated that CD4(+)T cell-derived IL-17F drives renal tissue injury in acute crescentic GN. Notably, IL-17F-deficient nephritic mice had fewer renal infiltrating neutrophils than wild-type nephritic mice, and neutrophil depletion did not affect the course of GN in IL-17F-deficient mice. Moreover, in the chronic model of pristane-induced SLE, IL-17F-deficient mice developed less severe disease than wild-type mice, with respect to survival and renal injury. Finally, we show that IL-17F induced expression of the neutrophil-attracting chemokines CXCL1 and CXCL5 in kidney cells. The finding that IL-17F has a nonredundant function in the development of renal tissue injury in experimental GN might be of great importance for the development of anti-IL-17 cytokine therapies in TH17-mediated human autoimmune diseases.

U2 - 10.1681/ASN.2015101077

DO - 10.1681/ASN.2015101077

M3 - SCORING: Journal article

C2 - 27030744

VL - 27

SP - 3666

EP - 3677

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 12

ER -