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IL-17 Receptor C Signaling Controls CD4 + T H 17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases.

Authors :
Schmidt T
Luebbe J
Kilian C
Riedel JH
Hiekmann S
Asada N
Ginsberg P
Robben L
Song N
Kaffke A
Peters A
Borchers A
Flavell RA
Gagliani N
Pelzcar P
Huber S
Huber TB
Turner JE
Paust HJ
Krebs CF
Panzer U
Source :
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2021 Dec; Vol. 32 (12), pp. 3081-3098.
Publication Year :
2021

Abstract

Background: IL-17A-producing CD4 <superscript>+</superscript> T helper (T <subscript>H</subscript> 17) 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 <superscript>+</superscript> T cell subsets, remains to be elucidated.<br />Methods: Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFN γ , and Foxp3 triple-reporter mice for sorting of renal CD4 <superscript>+</superscript> T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T <subscript>H</subscript> 17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in T <subscript>H</subscript> 17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4 <superscript>+</superscript> CD45RB <superscript>high</superscript> T cell transfer colitis model.<br />Results: We identified a specific expression of the IL-17 receptor A/C complex on CD4 <superscript>+</superscript> T <subscript>H</subscript> 17 cells. Single-cell RNA sequencing of T <subscript>H</subscript> 17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4 <superscript>+</superscript> T cells and, most importantly, specifically in CD4 <superscript>+</superscript> T <subscript>H</subscript> 17 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.<br />Conclusions: Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4 <superscript>+</superscript> T <subscript>H</subscript> 17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T <subscript>H</subscript> 17 treatment strategies.<br /> (Copyright © 2021 by the American Society of Nephrology.)

Details

Language :
English
ISSN :
1533-3450
Volume :
32
Issue :
12
Database :
MEDLINE
Journal :
Journal of the American Society of Nephrology : JASN
Publication Type :
Academic Journal
Accession number :
35167487
Full Text :
https://doi.org/10.1681/ASN.2021030426