Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage.
Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage.
复制标题
DOI：
10.1084/jem.20150318
复制
发表时间：
2015-10-19
期刊：
影响因子：
--
通讯作者：
Cupedo T
中科院分区：
文献类型：
--
作者：
Aparicio-Domingo P;Romera-Hernandez M;Karrich JJ;Cornelissen F;Papazian N;Lindenbergh-Kortleve DJ;Butler JA;Boon L;Coles MC;Samsom JN;Cupedo T
3型淋巴样细胞（ILC 3）是上皮细胞活化和增殖所必需的，以响应化疗药物诱导的小肠组织损伤。多个ILC 3亚群在肠损伤后被激活，并且ILC 3或其标志性细胞因子IL-22的缺乏导致肠干细胞的维持严重受损。肠上皮屏障的破坏允许细菌移位并易于发生破坏性炎症。为了确保适当的屏障组成，隐窝驻留干细胞持续增殖并在数天内补充所有肠上皮细胞。由于这种高有丝分裂活性，粘膜表面经常被抗癌疗法靶向，导致剂量限制性副作用。控制组织保护和粘膜愈合以响应肠损伤的细胞机制仍然知之甚少。3型先天性淋巴样细胞（ILC 3）是粘膜表面对感染的稳态和组织反应的调节剂。我们现在证明，ILC 3是必需的上皮细胞活化和增殖，以响应由化疗剂甲氨蝶呤诱导的小肠组织损伤。ILC 3的多个子集在肠组织损伤后被激活，并且在不存在ILC 3的情况下，上皮激活丧失，这与肠隐窝的病理学增加和严重损伤相关。使用ILC 3缺陷型Lgr 5报告小鼠，我们发现在缺乏ILC 3或ILC 3标志性细胞因子IL-22的情况下，损伤后肠道干细胞的维持严重受损。这些数据揭示了ILC 3通过保存组织特异性干细胞来限制组织损伤的新功能。
Type 3 lymphoid cells (ILC3s) are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by chemotherapeutics. Multiple ILC3 subsets are activated after intestinal damage, and the absence of ILC3s or their signature cytokine IL-22 results in severely impaired maintenance of intestinal stem cells. Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.