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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.

Original publication

DOI

10.1084/jem.20150318

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

10/2015

Volume

212

Pages

1783 - 1791

Addresses

Department of Hematology and Department of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, 3015 CN Rotterdam, Netherlands.

Keywords

Intestinal Mucosa, Lymphocytes, Stem Cells, Animals, Mice, Inbred C57BL, Mice, Methotrexate, Interleukins, Immunity, Innate