Interleukin-22 receptor signaling in Paneth cells is critical for their maturation and antimicrobial function

Abstract

Interleukin-22 (IL-22) acts in the intestine to promote critical tissue protective functions. However, since a diverse array of intestinal cell types (absorptive, secretory, and 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 mucosal host defense. To address this question, we used entire gut epithelium, intestinal stem cell (ISC)-specific, and Paneth cell-specific IL-22Ra1 knockout mice. Entire epithelium-specific IL-22Ra1 knockout (Il22Ra1fl/fl;Villin-cre) mice displayed defects in Paneth cell function. Using ISC-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Lgr5-EGFP-creERT2) and lineage tracing mice, we ruled out the involvement of Lgr5+ 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-22Ra1 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector functions, gene expression of specific WNTs (Wnt6 and Wnt9b), and enteroid 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 Paneth cell-specific IL-22Ra1 signaling helps provide immunity against Salmonella typhimurium. Collectively, our findings provide a unique and novel role of IL-22 in Paneth cell-mediated small intestinal host defense.

Metabolic Modulation of Cellular Function

“…When NEC and other inflammatory reactions occur, the amount of IL-22 (secreted by CD4+T cells) decreases, which can affect the differentiation and maturation of PCs (Lindemans et al, 2015). The secretion of Wnt and Notch signals in PCs is inhibited, which prevent the differentiation and maturation of ISC (Zha et al, 2019;Gaudino et al, 2021). These studies highlight the critical link between ISC function, PC-secreted ISC ligands, and intestinal barrier disruption in NEC.…”

Paneth cell development in the neonatal gut: pathway regulation, development, and relevance to necrotizing enterocolitis

“…When NEC and other inflammatory reactions occur, the amount of IL-22 (secreted by CD4+T cells) decreases, which can affect the differentiation and maturation of PCs (Lindemans et al, 2015). The secretion of Wnt and Notch signals in PCs is inhibited, which prevent the differentiation and maturation of ISC (Zha et al, 2019;Gaudino et al, 2021). These studies highlight the critical link between ISC function, PC-secreted ISC ligands, and intestinal barrier disruption in NEC.…”