The epithelium of the small intestine is tasked with balancing its role of absorbing nutrients with providing a physical barrier to protect against commensal microbes as well as pathogenic microbes. The barrier function of this surface is supported by the interplay of intestinal stem cells (ISCs) and immune cells associated with the intestinal mucosa. Therefore, crosstalk between these cells is important for intestinal homeostasis and host defense. In this issue of Nature Immunology, Zhu et al. show that the circular RNA (circRNA) circPan3 regulates such epithelial cell–immune cell crosstalk by controlling expression of the gene encoding the cytokine receptor subunit IL-13Rα (Il13Ra1) in the ISCs1 (Fig. 1). The authors identify a novel role for circPan3 in regulating signaling via the type 2 cytokine IL-13 that is critical for the maintenance of ISCs. This detailed study combines extensive biochemical analysis and mouse genetics to provide novel insights into how circRNA promotes the self-renewal of ISCs and thereby contributes to intestinal homeostasis, with potential broad applicability to other mucosal tissues.
