Indian Hedgehog Suppresses a Stromal Cell-Driven Intestinal Immune Response.

Autor:	Westendorp BF; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Büller NVJA; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Karpus ON; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., van Dop WA; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Koster J; Department of Oncogenomics and Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands., Versteeg R; Department of Oncogenomics and Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands., Koelink PJ; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Snel CY; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Meisner S; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Roelofs JJTH; Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands., Uhmann A; Institute of Human Genetics, Georg August University of Göttingen, Göttingen, Germany., Ver Loren van Themaat E; Max Planck Institute for Plant Breeding Research, Cologne, Germany., Heijmans J; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Hahn H; Institute of Human Genetics, Georg August University of Göttingen, Göttingen, Germany., Muncan V; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Wildenberg ME; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., van den Brink GR; Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.; GlaxoSmithKline, Medicines Research Center, Stevenage, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2017 Sep 05; Vol. 5 (1), pp. 67-82.e1. Date of Electronic Publication: 2017 Sep 05 (Print Publication: 2018).
DOI:	10.1016/j.jcmgh.2017.08.004
Abstrakt:	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.
Databáze:	MEDLINE
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