Cell-autonomous Hedgehog Signaling Controls Th17 Polarization and Pathogenicity

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 14

PMID 35835905

Authors

Joachim Hanna

Flavio Beke

Louise M OBrien

Chrysa Kapeni

Hung-Chang Chen

Valentina Carbonaro

Alexander B Kim

Kamal Kishore

Timon E Adolph

Mikkel-Ole Skjoedt

Karsten Skjoedt

Marc de la Roche

Maike de la Roche

Affiliations

Soon will be listed here.

Abstract

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 CD4T 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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