Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity
de la Roche, Marc
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Hanna, J., Beke, F., O'Brien, L., Kapeni, C., Chen, H., Carbonaro, V., Kim, A., et al. (2022). Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity. Nature Communications https://doi.org/10.1038/s41467-022-31722-5
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.
This work was supported by Cancer Research UK (MdlR (A22257), FB, LMOB, CK, H-CC, VC); Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (MdlR (WT107609); LMOB); Gates Cambridge Trust (AK); JH is undertaking a PhD funded by the Cambridge School of Clinical Medicine, Frank Edward Elmore Fund and the Medical Research Council’s Doctoral Training Partnership (award reference: 1954837). TA is grateful for the support from the Austrian Science Fund (FWF P33070) and the European Research Council (ERC – STG: 101039320).
Wellcome Trust (107609/Z/15/Z)
Cancer Research UK (C14303/A17197)
Cancer Research UK (22257)
External DOI: https://doi.org/10.1038/s41467-022-31722-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/339801
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/