Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity.
Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity.
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DOI：
10.1038/s41467-022-31722-5
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发表时间：
2022-07-14
影响因子：
16.6
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Th17细胞是自身免疫性疾病的关键驱动力。然而，调节Th17极化的信号通路却知之甚少。Hedgehog信号调节胚胎发育和成体组织构型过程中细胞命运的决定。在这里，我们发现细胞自主的Hedgehog信号，不依赖于外源配体，选择性地驱动Th17细胞的极化，而不是其他T辅助细胞亚群。我们发现内源性Hedgehog配体IHH通过Gli3和AMPK信号激活规范和非规范的Hedgehog通路。我们证明，无论是用临床批准的小分子抑制剂vismodegib抑制Hedgehog通路，还是遗传切除CD4+T细胞中的IHH，都可以极大地降低两种肠道炎症模型的疾病严重程度。我们证实Hedgehog通路在人类溃疡性结肠炎患者的组织中表达上调，并与Th17标志物的表达相关。这项工作涉及Hedgehog信号在Th17极化和肠道免疫病理中的作用，并表明Hedgehog抑制剂在炎症性肠病治疗中的潜在治疗用途。Th17细胞在一系列自身免疫性疾病的免疫病理中起着关键作用。在这里，作者将Hedgehog信号与Th17极化和小鼠肠道炎症的免疫病理机制联系起来，并建议在炎症性肠病的背景下Hedgehog信号具有治疗靶点。
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. Th17 cells are critical players in the immunopathology of a range of autoimmune diseases. Here the authors implicate Hedgehog signaling in Th17 polarization and in the immunopathology of intestinal inflammation in murine models and suggest therapeutic targeting of Hedgehog signaling in the context of inflammatory bowel disease.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Esplugues, Enric;Huber, Samuel;Gagliani, Nicola;Hauser, Anja E.;Town, Terrence;Wan, Yisong Y.;O'Connor, William, Jr.;Rongvaux, Anthony;Van Rooijen, Nico;Haberman, Ann M.;Iwakura, Yoichiro;Kuchroo, Vijay K.;Kolls, Jay K.;Bluestone, Jeffrey A.;Herold, Kevan C.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
23.9
作者：
Brownell, Isaac;Guevara, Elizabeth;Bai, C. Brian;Loomis, Cynthia A.;Joyner, Alexandra L.
通讯作者：
Joyner, Alexandra L.
影响因子：
16.6
作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
通讯作者：
Denson, Lee A.
影响因子：
64.8
作者：
通讯作者：
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