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

The IL -1 Family member IL -38 has been characterized primarily as an antiinflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL -38 in the murine 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- deficientmice develop more slowly. This reduction in size is likely due to the downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, and Olfm4) expression compared with wild -type organoids. The IL -38 binding to IL -1R6 and IL -1R9 is still a matter of debate. 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 -1(3 which contribute to organoid growth. However, high concentrations of IL -1(3 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 antiinflammatory molecule in the SI, maintaining homeostasis.SignificanceThe IL -1 family member IL -38 has been characterized primarily as an antiinflammatory cytokine for systemic diseases. Here, we describe a central role of IL -38 in driving intestinal stem cell differentiation through the upregulation of WNT3a and IL -1(3. Our findings reveal a dual role of IL -38 in regulating intestinal functions; a) in resting conditions, IL -38 maintains intestinal homeostasis, driving WNT3a production and organoid budding, whereas b) in highly inflamed conditions, IL -38 contributes to proper recovery, by exerting antiinflammatory activities. Thus, we demonstrate a pivotal role of IL -38 in driving tissue turnover and maintenance of homeostasis in intestinal health.