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Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity

Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent o...

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Autores principales: Hanna, Joachim, Beke, Flavio, O’Brien, Louise M., Kapeni, Chrysa, Chen, Hung-Chang, Carbonaro, Valentina, Kim, Alexander B., Kishore, Kamal, Adolph, Timon E., Skjoedt, Mikkel-Ole, Skjoedt, Karsten, de la Roche, Marc, de la Roche, Maike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281293/
https://www.ncbi.nlm.nih.gov/pubmed/35835905
http://dx.doi.org/10.1038/s41467-022-31722-5
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author Hanna, Joachim
Beke, Flavio
O’Brien, Louise M.
Kapeni, Chrysa
Chen, Hung-Chang
Carbonaro, Valentina
Kim, Alexander B.
Kishore, Kamal
Adolph, Timon E.
Skjoedt, Mikkel-Ole
Skjoedt, Karsten
de la Roche, Marc
de la Roche, Maike
author_facet Hanna, Joachim
Beke, Flavio
O’Brien, Louise M.
Kapeni, Chrysa
Chen, Hung-Chang
Carbonaro, Valentina
Kim, Alexander B.
Kishore, Kamal
Adolph, Timon E.
Skjoedt, Mikkel-Ole
Skjoedt, Karsten
de la Roche, Marc
de la Roche, Maike
author_sort Hanna, Joachim
collection PubMed
description Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4(+ )T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.
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spelling pubmed-92812932022-07-14 Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity Hanna, Joachim Beke, Flavio O’Brien, Louise M. Kapeni, Chrysa Chen, Hung-Chang Carbonaro, Valentina Kim, Alexander B. Kishore, Kamal Adolph, Timon E. Skjoedt, Mikkel-Ole Skjoedt, Karsten de la Roche, Marc de la Roche, Maike Nat Commun Article Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4(+ )T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease. Nature Publishing Group UK 2022-07-14 /pmc/articles/PMC9281293/ /pubmed/35835905 http://dx.doi.org/10.1038/s41467-022-31722-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hanna, Joachim
Beke, Flavio
O’Brien, Louise M.
Kapeni, Chrysa
Chen, Hung-Chang
Carbonaro, Valentina
Kim, Alexander B.
Kishore, Kamal
Adolph, Timon E.
Skjoedt, Mikkel-Ole
Skjoedt, Karsten
de la Roche, Marc
de la Roche, Maike
Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title_full Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title_fullStr Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title_full_unstemmed Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title_short Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
title_sort cell-autonomous hedgehog signaling controls th17 polarization and pathogenicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9281293/
https://www.ncbi.nlm.nih.gov/pubmed/35835905
http://dx.doi.org/10.1038/s41467-022-31722-5
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