Abstract
Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3s) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that ILC3-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3s amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3 independent, but it involves activation of Src family kinases. Our findings reveal that ILC3-driven intestinal repair entails distinct transcriptional networks to control stem cell maintenance and epithelial regeneration, which implies that tissue repair and crypt proliferation can be influenced by targeting innate immune cells independent of the well-established effects of IL-22.
Highlights
The intestinal epithelium forms a physical barrier that prevents translocation of commensal microorganisms, and defects in intestinal barrier integrity or maintenance have severe clinical impact (Konig et al, 2016; Peterson and Artis, 2014)
We show that in response to acute small intestinal damage, the stem cell protective cytokine IL-22 is dispensable for crypt cell proliferation and that in contrast, ILC3s modulate
Pathology in IL-22-deficient mice was similar to pathology of IL-22-sufficient littermate controls (Figure 1A)
Summary
The intestinal epithelium forms a physical barrier that prevents translocation of commensal microorganisms, and defects in intestinal barrier integrity or maintenance have severe clinical impact (Konig et al, 2016; Peterson and Artis, 2014). Barrier loss activates deleterious immune responses and can lead to transmural ulcers and the need for parenteral nutrition (Sonis, 2004). Insufficient intestinal barrier repair is a pathological feature underlying inflammatory bowel disease (IBD) (Hollander et al, 1986; Odenwald and Turner, 2013). Coined mucosal healing, has become a sought-after result in experimental and clinical IBD research, yet the cells and signals that enhance epithelial regeneration are still ill defined (Dulai et al, 2015; Florholmen, 2015; Neurath, 2014; Shah et al, 2016)
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