In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 12 ( 2021-12), p. 3081-3098
Abstract:
CD4 + IL-17A–producing CD4 + T helper (T H 17) cells play a unique role in autoimmune and chronic inflammatory diseases of the kidney, skin, and gut. Their proinflammatory functions are mediated through the release of IL-17A and -F, which activate the IL-17 receptor A (IL-17RA) and IL-17RC signaling pathways in epithelial and endothelial cells. We report that the IL-17RA/IL-17RC complex is highly expressed in CD4 + T H 17 cells. Disruption of the IL-17R signaling pathway in these cells potentiates T H 17 cell pathogenicity and accelerates experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. These findings indicate that IL-17 receptor signaling controls the T H 17 response via the IL-17RA/IL-17RC complex through a self-inhibitory loop in immune-mediated diseases and might provide new insights into the development of more efficient anti-T H 17 treatment strategies. Background IL-17A–producing CD4 + T helper (T H 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 + T cell subsets, remains to be elucidated. Methods Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFN γ , and Foxp3 triple-reporter mice for sorting of renal CD4 + T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T H 17 cell–specific IL-17RA and IL-17RC gene–deficient mice and studied the functional role of IL-17 signaling in T H 17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4 + CD45RB high T cell transfer colitis model. Results We identified a specific expression of the IL-17 receptor A/C complex on CD4 + T H 17 cells. Single-cell RNA sequencing of T H 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 + T cells and, most importantly, specifically in CD4 + T H 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. Conclusions Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4 + T H 17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T H 17 treatment strategies.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2021030426
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
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