Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK.
Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria.
Nat Commun. 2022 Jul 14;13(1):4075. doi: 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 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.
Th17 细胞是自身免疫性疾病的关键驱动因素。然而，调节 Th17 极化的信号通路还知之甚少。Hedgehog 信号在胚胎发生和成人组织模式形成过程中调节细胞命运决定。在这里，我们发现细胞自主 Hedgehog 信号，独立于外源性配体，选择性地驱动 Th17 细胞的极化，但不驱动其他 T 辅助细胞亚群的极化。我们表明，内源性 Hedgehog 配体 Ihh 通过 Gli3 和 AMPK 信号转导，激活经典和非经典 Hedgehog 途径。我们证明，用临床批准的小分子抑制剂 vismodegib 或在 CD4T 细胞中遗传敲除 Ihh 抑制 Hedgehog 途径，可大大降低两种肠道炎症的小鼠模型的疾病严重程度。我们证实 Hedgehog 途径的表达在溃疡性结肠炎患者的组织中上调，并与 Th17 标志物的表达相关。这项工作表明 Hedgehog 信号在 Th17 极化和肠道免疫病理学中起作用，并表明 Hedgehog 抑制剂在治疗炎症性肠病方面具有潜在的治疗用途。
