IL-17 receptor c signaling controls CD4+TH17 immune responses and tissue injury in immune-mediated kidney diseases
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IL-17 receptor c signaling controls CD4+TH17 immune responses and tissue injury in immune-mediated kidney diseases. / Schmidt, Tilman; Luebbe, Jonas; Kilian, Christoph; Riedel, Jan Hendrik; Hiekmann, Sonja; Asada, Nariaki; Ginsberg, Pauline; Robben, Lennart; Song, Ning; Kaffke, Anna; Peters, Anett; Borchers, Alina; Flavell, Richard A.; Gagliani, Nicola; Pelzcar, Penelope; Huber, Samuel; Huber, Tobias B.; Turner, Jan Eric; Paust, Hans Joachim; Krebs, Christian F.; Panzer, Ulf.
in: J AM SOC NEPHROL, Jahrgang 32, Nr. 12, 12.2021, S. 3081-3098.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - IL-17 receptor c signaling controls CD4+TH17 immune responses and tissue injury in immune-mediated kidney diseases
AU - Schmidt, Tilman
AU - Luebbe, Jonas
AU - Kilian, Christoph
AU - Riedel, Jan Hendrik
AU - Hiekmann, Sonja
AU - Asada, Nariaki
AU - Ginsberg, Pauline
AU - Robben, Lennart
AU - Song, Ning
AU - Kaffke, Anna
AU - Peters, Anett
AU - Borchers, Alina
AU - Flavell, Richard A.
AU - Gagliani, Nicola
AU - Pelzcar, Penelope
AU - Huber, Samuel
AU - Huber, Tobias B.
AU - Turner, Jan Eric
AU - Paust, Hans Joachim
AU - Krebs, Christian F.
AU - Panzer, Ulf
N1 - Publisher Copyright: © 2021 American Society of Nephrology. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120655819&partnerID=8YFLogxK
U2 - 10.1681/ASN.2021030426
DO - 10.1681/ASN.2021030426
M3 - SCORING: Journal article
AN - SCOPUS:85120655819
VL - 32
SP - 3081
EP - 3098
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 12
ER -
