The intestinal epithelial barrier performs a contributory role in the mechanical separation of gut microbiota from stromal cells and underlying innate and adaptive immune cells. This barrier is not static; the intestinal stem cells control the epithelial lining’s regeneration along the crypt-villus axis, maintaining a coordinated balance between ISC self-renewal and differentiation transit-amplifying (TA) cells. The sophisticated growth factor pathways regulate the TA and ISC expansion dynamics in the steady-state. However, it is unknown how cytokines are expressed during inflammation and tissue injury that influence this elaborate process.

Interleukin (IL)22 has gained substantial attention due to its pleiotropic effects in the intestine. The expression of IL22 receptor (IL22R) is restricted primarily to epithelial cells. The IL22/IL22R axis has been shown to promote intestinal barrier defense by inducing antimicrobial peptides such as regenerating islet-derived three protein families, S100 calcium-binding protein family (A7, A8, A9), and β-defensin-2. IL22 signaling to intestinal epithelial cells promotes mucin-1 production and glycosylation.

However, the specific impacts of IL22 on the TA and ISCs remain unclear. Zwarycz et al. first screened for the various effects of inflammatory bowel disease-related cytokines, including IL-6, 17, 21, and 22, on the ileal enteroid growth. An apparent increase in the TA zone’s proliferative cells with negligible effects on ISC numbers, using the IL22-transgenic mice. The data presented by Zha et al. and Zwarycz et al. collectively provide a novel structure for understanding how IL22 and other cytokines can play dual roles in neighboring cell types to regulate barrier function and intestinal epithelial repair. Investigation of the cytokine dose, expression site, and function on specific cell types may provide further insight into the highly integrated system.