IL-17 receptor c signaling controls CD4+TH17 immune responses and tissue injury in immune-mediated kidney diseases
Beteiligte Einrichtungen
Abstract
BACKGROUND: IL-17A-producing CD4+ T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD4+ T cell subsets, remains to be elucidated.
METHODS: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4+CD45RBhigh T cell transfer colitis model.
RESULTS: We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4+ T cells and, most importantly, specifically in CD4+ TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis.
CONCLUSIONS: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4+ TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.
Bibliografische Daten
Originalsprache | Englisch |
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ISSN | 1046-6673 |
DOIs | |
Status | Veröffentlicht - 12.2021 |
Anmerkungen des Dekanats
Funding Information:
This study was supported by Deutsche Forschungsgemeinschaft grant SFB 1192 (to U. Panzer and C.F. Krebs).
Funding Information:
R.A. Flavell reports serving as an advisor to GlaxoSmithKline and Zai Lab. N. Gagliani reports receiving honoraria from Novartis and research funding from Roche. S. Huber reports having consultancy agreements with Abbvie, Falk, Ferring, and Janssen Cilag; and having other interests in/relationships with American Association of Immunology, DACED, Deutsche Gesellschaft fu€r Innere Medizin, and Deutsche Gesellschaft fu€r Verdauungs-und Stoffwechselkrankheiten. T.B. Huber reports receiving research funding from Amicus Therapeutics and Fresenius Medical Care; having consultancy agreements with, and receiving honoraria from, Astra-Zeneca, Bayer, Boehringer-Ingelheim, DaVita, Deerfield, Fresenius Medical Care, Goldfinch Bio, Mantrabio, Novartis, and Retrophin; and serving as a scientific advisor for, or member of, Kidney International (on the journal editorial board) and Nature Reviews Nephrology (on the journal advisory board). All remaining authors have nothing to disclose.
Publisher Copyright:
© 2021 American Society of Nephrology. All rights reserved.