1. IL-17C/IL-17 Receptor E Signaling in CD4 + T Cells Promotes T H 17 Cell-Driven Glomerular Inflammation.
- Author
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Krohn S, Nies JF, Kapffer S, Schmidt T, Riedel JH, Kaffke A, Peters A, Borchers A, Steinmetz OM, Krebs CF, Turner JE, Brix SR, Paust HJ, Stahl RAK, and Panzer U
- Subjects
- Animals, Antibodies, Antineutrophil Cytoplasmic immunology, Autoimmune Diseases blood, Autoimmune Diseases pathology, Autoimmune Diseases prevention & control, Glomerulonephritis blood, Glomerulonephritis pathology, Glomerulonephritis prevention & control, Humans, Interleukin-17 biosynthesis, Interleukin-17 deficiency, Interleukin-17 genetics, Kidney immunology, Kidney pathology, Lupus Nephritis chemically induced, Lupus Nephritis immunology, Lupus Nephritis pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy, RNA, Messenger biosynthesis, Radiation Chimera, Receptors, Interleukin-17 biosynthesis, Receptors, Interleukin-17 deficiency, Receptors, Interleukin-17 genetics, Terpenes toxicity, Up-Regulation, Autoimmune Diseases immunology, CD4-Positive T-Lymphocytes immunology, Glomerulonephritis immunology, Interleukin-17 blood, Interleukin-17 physiology, Receptors, Interleukin-17 physiology, Th17 Cells immunology
- Abstract
The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced T
H 17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH 17 cells, and loss of this expression prevented the TH 17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH 17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH 17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH 17-induced autoimmune disorders., (Copyright © 2018 by the American Society of Nephrology.)- Published
- 2018
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