Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration

Abstract

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch, and epidermal growth factor (EGF) signals supporting Lgr5+ crypt base columnar ISCs for normal epithelial maintenance1,2. However, little is known about the regulation of the ISC compartment after tissue damage. Utilizing ex vivo organoid cultures, we provide evidence that innate lymphoid cells (ILCs), potent producers of Interleukin-22 (IL-22) after intestinal injury3,4, increased the growth of murine small intestine (SI) organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both murine and human intestinal organoids, increasing proliferation, and promoting ISC expansion. IL-22 induced Stat3 phosphorylation in Lgr5+ ISCs, and Stat3 was critical for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after murine allogeneic bone marrow transplantation (BMT) enhanced recovery of ISCs, increased epithelial regeneration, and reduced intestinal pathology and mortality from graft vs. host disease (GVHD). Atoh1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independent of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support intestinal epithelium, activating ISCs to promote regeneration.

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

“…Chronic stimulation of Nod2 in human monocyte-derived macrophages has been associated with a downregulation of TNF-a secretion (45), indicating that expression of Nod2 is important for both the induction and the regulation of this response. These results suggest that deletion of Nod2 in Lyz2-expressing cells can trigger higher levels of TNF-a, thus inducing a stronger IEC apoptosis and the increased expression of IL-22, a cytokine involved in gut barrier integrity and epithelial regeneration (46,47).…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Cryptopatches predominantly contain LTi‐like ILC3 and dendritic cells organized around stromal cell populations, and are situated close to the bottom of intestinal crypt structures. Cryptopatch‐resident ILC3 maintain the local crypt stem cell pool and regulate tissue repair following inflammation, chemotherapy or transplantation 37, 38, 39. In addition, cryptopatches act as a site for B‐cell recruitment to form mature tertiary lymphoid structures known as isolated lymphoid follicules (ILFs) 36, 40, 41.…”

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…A second scenario could be that the activity of a single stem cell population is adaptively controlled upon injury. Indeed, inflammation increases the activity of intestinal stem cells (ISCs) in a cell-autonomous manner (Lindemans et al, 2015). Similarly, calorie restriction can impinge on stem cell activity, for example by augmenting the function of Paneth cells, which indirectly increases the number of CBCs (Richmond et al, 2015;Yilmaz et al, 2012).…”