Programming of Intestinal Epithelial Differentiation by IL-33 Derived from Pericryptal Fibroblasts in Response to Systemic Infection

Abstract

The intestinal epithelium constitutes an efficient barrier against the microbial flora. Here, we demonstrate an unexpected function of IL-33 as a regulator of epithelial barrier functions. Mice lacking IL-33 showed decreased Paneth cell numbers and lethal systemic infection in response to Salmonella typhimurium. IL-33 was produced upon microbial challenge by a distinct population of pericryptal fibroblasts neighboring the intestinal stem cell niche. IL-33 programmed the differentiation of epithelial progenitors toward secretory IEC including Paneth and goblet cells. Finally, IL-33 suppressed Notch signaling in epithelial cells and induced expression of transcription factors governing differentiation into secretory IEC. In summary, we demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial infection into an epithelial response to promote antimicrobial defense.

Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family

“…Although they are less well characterized, non‐immune cells may also constitute important cellular targets of IL‐33 in vivo. These include endothelial cells, epithelial cells, fibroblasts, astrocytes, and neurons …”

IL-33 and the intestine: The good, the bad, and the inflammatory

“…This process is mediated by a well-established pathway in which intestinal stem cells from the crypts mature and differentiate into one of many cell types that make up the mucosal barrier [25]. A recent study by Mahapatro et al demonstrated that intestinal IL-33 expression is localized to the pericryptal fibroblasts during homeostasis and is increased during infection [55]. These authors have also elucidated a role for IL-33/ST2 signaling in the differentiation of stem cells in organoid culture.…”

“…These authors have also elucidated a role for IL-33/ST2 signaling in the differentiation of stem cells in organoid culture. Activation of the IL-33/ST2 pathway in epithelial progenitor cells leads to inhibition of Notch signaling and results in the differentiation of stem cells towards a secretory intestinal cell lineage [55]. These secretory cells include Paneth cells, goblet cells, and enteroendocrine cells.…”

Role of the intestinal mucosa in acute gastrointestinal GVHD

“…[69][70][71] In contrast to Paneth cell deficiency, the cytokine IL-33 was recently reported to promote Paneth cell differentiation. 72 IL-33 and its receptor ST2 appear to both play important roles in several aspects of GVHD pathophysiology that are highly context-dependent.…”