IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion

Abstract

The IL-1 Family member IL-38 has been characterized as an anti-inflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL 38 in the small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL 38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL 38 deficient mice develop more slowly. This reduction in size is likely due to downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, Olfm4) expression compared with wild type organoids. IL-38 binding to IL-1R6 is postulated to recruit the co-receptor IL-1R9. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL 1R9 deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL 38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL 38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild type mice, IL-38 stimulation induced low concentrations of IL-1β which contribute to organoid growth. However, high concentrations of IL 1beta have detrimental effects on the cultures that were prevented by treatment with recombinant IL 38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an anti-inflammatory molecule in the SI, maintaining homeostasis.