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IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity
- Source :
- Mucosal Immunology
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Paneth Cells
Cell type
Immunology
Morphogenesis
Biology
Lymphocyte Activation
digestive system
Article
Interleukin 22
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
medicine
Animals
Immunology and Allergy
Typhoid Fever
Immunity, Mucosal
Mice, Knockout
Effector
Interleukins
Microbiota
LGR5
Cell Differentiation
Receptors, Interleukin
Salmonella typhi
Cell biology
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Paneth cell
Th17 Cells
Stem cell
Signal Transduction
Subjects
Details
- ISSN :
- 19330219
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Mucosal Immunology
- Accession number :
- edsair.doi.dedup.....27343370b62a5de94207b3442893996e