IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β 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-deficient mice 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-1β which contribute to organoid growth. However, high concentrations of IL-1β 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.

Citation

Alberto Dinarello, Makenna May, Jesus Amo-Aparicio, Tania Azam, Joseph M Gaballa, Carlo Marchetti, Annachiara Tesoriere, Rachele Ghirardo, Jasmina S Redzic, William S Webber, Shaikh M Atif, Suzhao Li, Elan Z Eisenmesser, Dennis M de Graaf, Charles A Dinarello. IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1β secretion. Proceedings of the National Academy of Sciences of the United States of America. 2023 Nov 07;120(45):e2306476120

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PMID: 37906644

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