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Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury

Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases — for example, in different forms of crescentic glomerulonephritis — because of their rapid antiinflammatory effects, low cost, and wide availability. Despite their routine use for decades, t...

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Autores principales: Riedel, Jan-Hendrik, Robben, Lennart, Paust, Hans-Joachim, Zhao, Yu, Asada, Nariaki, Song, Ning, Peters, Anett, Kaffke, Anna, Borchers, Alina, Tiegs, Gisa, Seifert, Larissa, Tomas, Nicola M., Hoxha, Elion, Wenzel, Ulrich O., Huber, Tobias B., Wiech, Thorsten, Turner, Jan-Eric, Krebs, Christian F., Panzer, Ulf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870076/
https://www.ncbi.nlm.nih.gov/pubmed/36355429
http://dx.doi.org/10.1172/jci.insight.160251
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author Riedel, Jan-Hendrik
Robben, Lennart
Paust, Hans-Joachim
Zhao, Yu
Asada, Nariaki
Song, Ning
Peters, Anett
Kaffke, Anna
Borchers, Alina
Tiegs, Gisa
Seifert, Larissa
Tomas, Nicola M.
Hoxha, Elion
Wenzel, Ulrich O.
Huber, Tobias B.
Wiech, Thorsten
Turner, Jan-Eric
Krebs, Christian F.
Panzer, Ulf
author_facet Riedel, Jan-Hendrik
Robben, Lennart
Paust, Hans-Joachim
Zhao, Yu
Asada, Nariaki
Song, Ning
Peters, Anett
Kaffke, Anna
Borchers, Alina
Tiegs, Gisa
Seifert, Larissa
Tomas, Nicola M.
Hoxha, Elion
Wenzel, Ulrich O.
Huber, Tobias B.
Wiech, Thorsten
Turner, Jan-Eric
Krebs, Christian F.
Panzer, Ulf
author_sort Riedel, Jan-Hendrik
collection PubMed
description Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases — for example, in different forms of crescentic glomerulonephritis — because of their rapid antiinflammatory effects, low cost, and wide availability. Despite their routine use for decades, the underlying cellular mechanisms by which steroids exert their therapeutic effects need to be fully elucidated. Here, we demonstrate that high-dose steroid treatment rapidly reduced the number of proinflammatory CXCR3(+)CD4(+) T cells in the kidney by combining high-dimensional single-cell and morphological analyses of kidney biopsies from patients with antineutrophil cytoplasmic antibody–associated (ANCA-associated) crescentic glomerulonephritis. Using an experimental model of crescentic glomerulonephritis, we show that the steroid-induced decrease in renal CD4(+) T cells is a consequence of reduced T cell recruitment, which is associated with an ameliorated disease course. Mechanistic in vivo and in vitro studies revealed that steroids act directly on renal tissue cells, such as tubular epithelial cells, but not on T cells, which resulted in an abolished renal expression of CXCL9 and CXCL10 as well as in the prevention of CXCR3(+)CD4(+) T cell recruitment to the inflamed kidneys. Thus, we identified the CXCL9/CXCL10-CXCR3 axis as a previously unrecognized cellular and molecular target of glucocorticoids providing protection from immune-mediated pathology.
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spelling pubmed-98700762023-02-06 Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury Riedel, Jan-Hendrik Robben, Lennart Paust, Hans-Joachim Zhao, Yu Asada, Nariaki Song, Ning Peters, Anett Kaffke, Anna Borchers, Alina Tiegs, Gisa Seifert, Larissa Tomas, Nicola M. Hoxha, Elion Wenzel, Ulrich O. Huber, Tobias B. Wiech, Thorsten Turner, Jan-Eric Krebs, Christian F. Panzer, Ulf JCI Insight Research Article Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases — for example, in different forms of crescentic glomerulonephritis — because of their rapid antiinflammatory effects, low cost, and wide availability. Despite their routine use for decades, the underlying cellular mechanisms by which steroids exert their therapeutic effects need to be fully elucidated. Here, we demonstrate that high-dose steroid treatment rapidly reduced the number of proinflammatory CXCR3(+)CD4(+) T cells in the kidney by combining high-dimensional single-cell and morphological analyses of kidney biopsies from patients with antineutrophil cytoplasmic antibody–associated (ANCA-associated) crescentic glomerulonephritis. Using an experimental model of crescentic glomerulonephritis, we show that the steroid-induced decrease in renal CD4(+) T cells is a consequence of reduced T cell recruitment, which is associated with an ameliorated disease course. Mechanistic in vivo and in vitro studies revealed that steroids act directly on renal tissue cells, such as tubular epithelial cells, but not on T cells, which resulted in an abolished renal expression of CXCL9 and CXCL10 as well as in the prevention of CXCR3(+)CD4(+) T cell recruitment to the inflamed kidneys. Thus, we identified the CXCL9/CXCL10-CXCR3 axis as a previously unrecognized cellular and molecular target of glucocorticoids providing protection from immune-mediated pathology. American Society for Clinical Investigation 2023-01-10 /pmc/articles/PMC9870076/ /pubmed/36355429 http://dx.doi.org/10.1172/jci.insight.160251 Text en © 2023 Riedel et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Riedel, Jan-Hendrik
Robben, Lennart
Paust, Hans-Joachim
Zhao, Yu
Asada, Nariaki
Song, Ning
Peters, Anett
Kaffke, Anna
Borchers, Alina
Tiegs, Gisa
Seifert, Larissa
Tomas, Nicola M.
Hoxha, Elion
Wenzel, Ulrich O.
Huber, Tobias B.
Wiech, Thorsten
Turner, Jan-Eric
Krebs, Christian F.
Panzer, Ulf
Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title_full Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title_fullStr Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title_full_unstemmed Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title_short Glucocorticoids target the CXCL9/CXCL10-CXCR3 axis and confer protection against immune-mediated kidney injury
title_sort glucocorticoids target the cxcl9/cxcl10-cxcr3 axis and confer protection against immune-mediated kidney injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870076/
https://www.ncbi.nlm.nih.gov/pubmed/36355429
http://dx.doi.org/10.1172/jci.insight.160251
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