Control of inflammation by stromal Hedgehog pathway activation restrains colitis
Control of inflammation by stromal Hedgehog pathway activation restrains colitis
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DOI：
10.1073/pnas.1616447113
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发表时间：
2016-11-22
影响因子：
11.1
通讯作者：
Beachy, Philip A.
中科院分区：
文献类型：
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作者：
Lee, John J.;Rothenberg, Michael E.;Beachy, Philip A.
炎症破坏组织结构和功能，从而促成多种疾病的发病机制;因此，促进或限制组织炎症的信号代表了治疗干预的潜在靶点。在这里，我们报告说，遗传或药理学刺猬途径抑制加剧结肠炎（结肠炎）小鼠。相反，Hedgehog反应的遗传增强和全身性小分子Hedgehog通路激活有效地改善结肠炎并抑制结肠炎诱导的腺癌的发生和进展。在结肠内，Hedgehog蛋白信号不直接作用于上皮本身，而是作用于下层基质细胞以诱导IL-10的表达，IL-10是一种长期已知抑制炎性肠损伤的免疫调节细胞因子。IL-10功能是结肠炎中小分子Hedgehog通路激活的完全保护作用所必需的; Hedgehog通路活性和基质IL-10表达的药理学增强与CD 4（+）Foxp 3（+）调节性T细胞的存在增加相关。因此，我们确定基质细胞作为结肠炎症的细胞协调者，并建议将其药理学操作作为治疗结肠炎的潜在手段。
Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+) Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.