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Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response
BACKGROUND & AIMS: Upon intestinal epithelial damage a complex wound healing response is initiated to restore epithelial integrity and defend against pathogenic invasion. Epithelium-derived Indian Hedgehog (Ihh) functions as a critical sensor in this process. Signaling occurs in a paracrine mann...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738458/ https://www.ncbi.nlm.nih.gov/pubmed/29276753 http://dx.doi.org/10.1016/j.jcmgh.2017.08.004 |
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author | Westendorp, B. Florien Büller, Nikè V.J.A. Karpus, Olga N. van Dop, Willemijn A. Koster, Jan Versteeg, Rogier Koelink, Pim J. Snel, Clinton Y. Meisner, Sander Roelofs, Joris J.T.H. Uhmann, Anja Ver Loren van Themaat, Emiel Heijmans, Jarom Hahn, Heidi Muncan, Vanesa Wildenberg, Manon E. van den Brink, Gijs R. |
author_facet | Westendorp, B. Florien Büller, Nikè V.J.A. Karpus, Olga N. van Dop, Willemijn A. Koster, Jan Versteeg, Rogier Koelink, Pim J. Snel, Clinton Y. Meisner, Sander Roelofs, Joris J.T.H. Uhmann, Anja Ver Loren van Themaat, Emiel Heijmans, Jarom Hahn, Heidi Muncan, Vanesa Wildenberg, Manon E. van den Brink, Gijs R. |
author_sort | Westendorp, B. Florien |
collection | PubMed |
description | BACKGROUND & AIMS: Upon intestinal epithelial damage a complex wound healing response is initiated to restore epithelial integrity and defend against pathogenic invasion. Epithelium-derived Indian Hedgehog (Ihh) functions as a critical sensor in this process. Signaling occurs in a paracrine manner because the receptor for Ihh is expressed only in the mesenchyme, but the exact Hedgehog target cell has remained elusive. The aim of this study was to elucidate further the nature of this target cell in the context of intestinal inflammation. METHODS: Hedgehog activity was modulated genetically in both cell type–specific and body-wide models and the resulting animals were analyzed for gene expression profiles and sensitivity for dextran sodium sulfate (DSS) colitis. To characterize the Hedgehog target cell, Gli1-CreERT2-Rosa26-ZsGreen animals were generated, which express ZsGreen in all Hedgehog-responsive cells. These cells were characterized using flow cytometry and immunofluorescence. RESULTS: Loss of Indian Hedgehog from the intestinal epithelium resulted in a rapid increase in expression of inflammation-related genes, accompanied by increased influx of immune cells. Animals with epithelium-specific deletion of Ihh or lacking the Hedgehog receptor Smoothened from Hedgehog target cells were more sensitive to DSS colitis. In contrast, specific deletion of Smoothened in the myeloid compartment did not alter the response to DSS. This suggests that Hedgehog signaling does not repress intestinal immunity through an effect on myeloid cells. Indeed, we found that Hedgehog-responsive cells expressed gp38, smooth muscle actin, and desmin, indicating a fibroblastic nature. Ihh signaling inhibited expression of C-X-C motif chemokine ligand 12 (CXCL12) in fibroblasts in vitro and in vivo, thereby impairing the recruitment of immune cells. CONCLUSIONS: We show that epithelium-derived Indian Hedgehog signals exclusively to fibroblasts in the intestine. Loss of Ihh leads to a rapid immune response with up-regulation of fibroblast-derived CXCL12, and migration of immune cells into the lamina propria. |
format | Online Article Text |
id | pubmed-5738458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-57384582017-12-22 Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response Westendorp, B. Florien Büller, Nikè V.J.A. Karpus, Olga N. van Dop, Willemijn A. Koster, Jan Versteeg, Rogier Koelink, Pim J. Snel, Clinton Y. Meisner, Sander Roelofs, Joris J.T.H. Uhmann, Anja Ver Loren van Themaat, Emiel Heijmans, Jarom Hahn, Heidi Muncan, Vanesa Wildenberg, Manon E. van den Brink, Gijs R. Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Upon intestinal epithelial damage a complex wound healing response is initiated to restore epithelial integrity and defend against pathogenic invasion. Epithelium-derived Indian Hedgehog (Ihh) functions as a critical sensor in this process. Signaling occurs in a paracrine manner because the receptor for Ihh is expressed only in the mesenchyme, but the exact Hedgehog target cell has remained elusive. The aim of this study was to elucidate further the nature of this target cell in the context of intestinal inflammation. METHODS: Hedgehog activity was modulated genetically in both cell type–specific and body-wide models and the resulting animals were analyzed for gene expression profiles and sensitivity for dextran sodium sulfate (DSS) colitis. To characterize the Hedgehog target cell, Gli1-CreERT2-Rosa26-ZsGreen animals were generated, which express ZsGreen in all Hedgehog-responsive cells. These cells were characterized using flow cytometry and immunofluorescence. RESULTS: Loss of Indian Hedgehog from the intestinal epithelium resulted in a rapid increase in expression of inflammation-related genes, accompanied by increased influx of immune cells. Animals with epithelium-specific deletion of Ihh or lacking the Hedgehog receptor Smoothened from Hedgehog target cells were more sensitive to DSS colitis. In contrast, specific deletion of Smoothened in the myeloid compartment did not alter the response to DSS. This suggests that Hedgehog signaling does not repress intestinal immunity through an effect on myeloid cells. Indeed, we found that Hedgehog-responsive cells expressed gp38, smooth muscle actin, and desmin, indicating a fibroblastic nature. Ihh signaling inhibited expression of C-X-C motif chemokine ligand 12 (CXCL12) in fibroblasts in vitro and in vivo, thereby impairing the recruitment of immune cells. CONCLUSIONS: We show that epithelium-derived Indian Hedgehog signals exclusively to fibroblasts in the intestine. Loss of Ihh leads to a rapid immune response with up-regulation of fibroblast-derived CXCL12, and migration of immune cells into the lamina propria. Elsevier 2017-09-05 /pmc/articles/PMC5738458/ /pubmed/29276753 http://dx.doi.org/10.1016/j.jcmgh.2017.08.004 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Westendorp, B. Florien Büller, Nikè V.J.A. Karpus, Olga N. van Dop, Willemijn A. Koster, Jan Versteeg, Rogier Koelink, Pim J. Snel, Clinton Y. Meisner, Sander Roelofs, Joris J.T.H. Uhmann, Anja Ver Loren van Themaat, Emiel Heijmans, Jarom Hahn, Heidi Muncan, Vanesa Wildenberg, Manon E. van den Brink, Gijs R. Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title | Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title_full | Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title_fullStr | Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title_full_unstemmed | Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title_short | Indian Hedgehog Suppresses a Stromal Cell–Driven Intestinal Immune Response |
title_sort | indian hedgehog suppresses a stromal cell–driven intestinal immune response |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738458/ https://www.ncbi.nlm.nih.gov/pubmed/29276753 http://dx.doi.org/10.1016/j.jcmgh.2017.08.004 |
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