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Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

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Abstract

Hedgehog (Hh) signaling is essential for intestinal homeostasis and has been associated with inflammation and tissue repair. We hypothesized that Hh signaling could affect the inflammatory process in inflammatory bowel disease (IBD). For this purpose, colon specimens from the inflamed and non-inflamed mucosa of 15 patients with Crohn’s disease (CD), 15 with ulcerative colitis, and 15 controls were analyzed by immunohistochemistry and real-time PCR. The production and modulation of cytokines were measured by ELISA from culture explants. Apoptosis was assessed by TUNEL and caspase-3 activity assays. Chemotaxis was evaluated using a transwell system. Primary human intestinal and skin fibroblasts were used for analyzing migration and BrdU incorporation. Hh proteins were generally expressed at the superficial epithelium, and a marked reduction was observed in CD. In the lamina propria, Gli-1 predominantly co-localized with vimentin- and alpha-smooth muscle actin-positive cells, with lower levels observed in CD. In colon explants, Hh stimulation resulted in reduction, while blockade increased, TNF α, IL-17, and TGF β levels. Apoptotic rates were higher in inflamed samples, and they increased after Hh blockade. Levels of Gli-1 mRNA were negatively correlated with caspase-3 activity. Hh blockade increased chemoattraction of monocytes. Primary fibroblasts incorporated more BrdU, but migrated less after Hh blockade. These results suggest that Hh signaling provides a negative feedback to the lamina propria, down-regulating inflammatory cytokines, and inhibiting leukocyte migration and fibroblast proliferation, while favoring fibroblast migration. Therefore, Hh signaling is strongly implicated in the pathogenesis of intestinal inflammation, and it may represent a novel therapeutic target for IBD.

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Abbreviations

Hh:

Hedgehog

IBD:

Inflammatory bowel disease

CD:

Crohn’s disease

UC:

Ulcerative colitis

IL:

Interleukin

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Acknowledgments

We thank Alyson do Rosario Jr and Jose Nazioberto D. de Farias for the technical assistance with tissue processing; Grasiella M. Ventura for help with confocal microscopy; and all staff of the Division of Gastroenterology (University Hospital, Federal University of Rio de Janeiro) for help with the collection of intestinal mucosal specimens. This work was supported by grants from the Brazilian Research Council (CNPq) and the FAPERJ (Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro).

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Buongusto, F., Bernardazzi, C., Yoshimoto, A.N. et al. Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation. Clin Exp Med 17, 351–369 (2017). https://doi.org/10.1007/s10238-016-0434-1

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