IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity

Abstract

Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

Effects of Lactococcus lactis on the Intestinal Functions in Weaning Piglets

“…Our study also found that L.lactis increased the jejunal gene expression of IL-18 and IL-22 and reduced the ileal gene expression of IL-22. IL-18 can induce the intestinal epithelium to produce antimicrobial proteins ( 37 ), while, intestinal IL-22 signaling was positively correlated with the differentiation and antimicrobial effect of Paneth cells ( 38 ), and IL-22 has been reported to promote intestinal stem cell-mediated epithelial regeneration ( 39 ). Thus, L.lactis transplantation regulates intestinal immune response, which would help maintain intestinal immune homeostasis.…”

Dynamic, Transient, and Robust Increase in the Innervation of the Inflamed Mucosa in Inflammatory Bowel Diseases

“…Neuroglial identifier gene lists were generated taking advantage of the newly available single-cell RNA sequencing datasets from the enteric nervous system (SCP1038 [ 10 ], SRP135960 [ 12 ]), intestinal epithelial and stromal cells (GSE92332 [ 24 ], SCP259 [ 25 ]), as well as bulk RNA sequencing datasets from isolated intestinal epithelial organoids (GSE148727 [ 26 ], GSE159423 [ 27 ]). Genes with a specific expression in the enteric neuroglial datasets but not the other datasets including epithelial and stromal were chosen to create the list.…”

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

“…Moreover, the localization of paneth cells at the crypt bottom exposes them to an environment that was suggested by computational modeling to be characterized by particularly high ILC3-derived IL-22 levels (95). Together with the recently shown importance of IL-22 signaling for paneth cell differentiation and effector functions (104), this predisposes ILC3s as potential regulators of paneth cells. Future research will help to clarify the biological relevance of these suggested ILC-IEC interactions in IBD.…”