ABSTRACT
The interleukin (IL)-22 cytokine can be protective or inflammatory in the intestine. It is unclear if IL-22 receptor (IL-22Ra1)-mediated protection involves a specific type of intestinal epithelial cell (IEC). By using a range of IEC type-specific Il22Ra1 conditional knockout mice and a dextran sulfate sodium (DSS) colitis model, we demonstrate that IL-22Ra1 signaling in MATH1+ cells (goblet and progenitor cells) is essential for maintaining the mucosal barrier and intestinal tissue regeneration. The IL-22Ra1 signaling in IECs promotes mucin core-2 O-glycan extension and induces beta-1,3-galactosyltransferase 5 (B3GALT5) expression in the colon. Adenovirus-mediated expression of B3galt5 is sufficient to rescue Il22Ra1IEC mice from DSS colitis. Additionally, we observe a reduction in the expression of B3GALT5 and the Tn antigen, which indicates defective mucin O-glycan, in the colon tissue of patients with ulcerative colitis. Lastly, IL-22Ra1 signaling in MATH1+ progenitor cells promotes organoid regeneration after DSS injury. Our findings suggest that IL-22-dependent protective responses involve O-glycan modification, proliferation, and differentiation in MATH1+ progenitor cells.
Subject(s)
Colitis , Dextran Sulfate , Interleukin-22 , Interleukins , Receptors, Interleukin , Animals , Interleukins/metabolism , Mice , Glycosylation , Colitis/metabolism , Colitis/pathology , Colitis/chemically induced , Receptors, Interleukin/metabolism , Mucins/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Humans , Signal Transduction , Mice, Inbred C57BL , Inflammation/pathology , Inflammation/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Mice, Knockout , Galactosyltransferases/metabolism , Galactosyltransferases/genetics , Stem Cells/metabolismABSTRACT
IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.
Subject(s)
Liver , Metabolic Diseases , Animals , Mice , Liver/metabolism , Inflammation/metabolism , Obesity/metabolism , Lipid Metabolism , Glucose/metabolism , Metabolic Diseases/metabolism , Lipids , Diet, High-Fat/adverse effects , Mice, Inbred C57BLABSTRACT
The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Intestinal Mucosa/cytology , Receptors, G-Protein-Coupled/metabolism , Receptors, Interleukin-17/metabolism , Stem Cells/metabolism , Animals , Cell Communication , Cell Differentiation/drug effects , Cell Lineage/drug effects , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Dextran Sulfate/adverse effects , Humans , Interleukin-17/metabolism , Interleukin-17/pharmacology , Intestinal Mucosa/metabolism , Intestines/drug effects , Intestines/metabolism , Intestines/pathology , Mice , Mice, Knockout , NF-kappa B/metabolism , Receptors, Interleukin-17/deficiency , SOX9 Transcription Factor/metabolism , Signal Transduction , Stem Cells/cytologyABSTRACT
Previous studies indicate that IL-17A plays an important role in mediating the intestinal microbiota and systemic metabolic functions. However, it is not known where IL-17RA signaling occurs to mediate these effects. To investigate this question, we used intestinal epithelial-specific (Il17ra ΔIEC ) and liver-specific (Il17raΔLiver ) IL-17RA knockout mice as well as littermate control mice. Our results indicate that intestinal IL-17RA signaling helps mediate systemic metabolic functions upon exposure to prolonged high-fat diet. Il17ra ΔIEC mice display impaired glucose metabolism, altered hormone and adipokine levels, increased visceral adiposity, and greater hepatic lipid deposition when compared with their littermate controls. We show that IL-17RA-driven changes in microbiota composition are responsible for regulating systemic glucose metabolism. Altogether, our data elucidate the importance of intestinal IL-17RA signaling in regulating high-fat diet-mediated systemic glucose and lipid metabolism.
Subject(s)
Interleukin-17/metabolism , Intestinal Mucosa/physiology , Liver/physiology , Metabolic Diseases/immunology , Microbiota/immunology , Receptors, Interleukin-17/metabolism , Adipokines/metabolism , Animals , Diet, High-Fat , Disease Models, Animal , Glucose/metabolism , Hormones/metabolism , Humans , Lipid Metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal TransductionABSTRACT
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.
Subject(s)
Interleukins/metabolism , Microbiota/physiology , Paneth Cells/metabolism , Receptors, Interleukin/metabolism , Salmonella typhi/physiology , Th17 Cells/immunology , Typhoid Fever/immunology , Animals , Cell Differentiation , Immunity, Mucosal , Interleukins/genetics , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Paneth Cells/pathology , Receptors, Interleukin/genetics , Signal Transduction , Interleukin-22ABSTRACT
Innate immunity is maintained in part by antigen presenting cells (APCs) including dendritic cells, macrophages, and B cells. APCs interact with T cells to link innate and adaptive immune responses. By displaying bacterial and tumorigenic antigens on their surface via major histocompatibility complexes, APCs can directly influence the differentiation of T cells. Likewise, T cell activation, differentiation, and effector functions are modulated by APCs utilizing multiple mechanisms. The objective of this review is to describe how APCs interact with and influence the activation of T cells to maintain innate immunity during exposure to microbial infection and malignant cells. How bacteria and cancer cells take advantage of some of these interactions for their own benefit will also be discussed. While this review will cover a broad range of topics, a general focus will be held around pathogens, cancers, and interactions that typically occur within the gastrointestinal tract.
