Loss of SLC26A3 Results in Colonic Mucosal Immune Dysregulation via Epithelial-Immune Cell Crosstalk
Background & Aims: Down-regulation of chloride transporter SLC26A3 or down-regulated in adenoma (DRA) in colonocytes has recently been linked to the pathogenesis of ulcerative colitis (UC). Because exaggerated immune responses are one of the hallmarks of UC, these current studies were undertaken to define the mechanisms by which loss of DRA relays signals to immune cells to increase susceptibility to inflammation. Methods: NanoString Immunology Panel, fluorescence assisted cell sorting, immunoblotting, immunofluorescence, and quantitative real-time polymerase chain reaction assays were used in wild-type and DRA knockout (KO) mice. Interleukin (IL)-33 blocking was used to determine specific changes in immune cells and co-housing/broad spectrum antibiotics administration, and ex vivo studies in colonoids were conducted to rule out the involvement of microbiota. Colonoid-derived monolayers from healthy and UC patient biopsies were analyzed for translatability. Results: There was a marked induction of Th2 (<2-fold), CD4+ Th2 cells (∼8-fold), RORγt+ Th17, and FOXP3+ regulatory T cells (Tregs). DRA KO colons also exhibited a robust induction of IL-33 (<8-fold). In vivo studies using blocking of IL-33 established that T2 immune dysregulation (alterations in ILC2, Th2, and GATA3+ iTregs) in response to loss of DRA was due to altered epithelial-immune cell crosstalk via IL-33. Conclusions: Loss of DRA in colonocytes triggers the release of IL-33 to drive a type 2 immune response. These observations emphasize the critical importance of DRA in mucosal immune homeostasis and its implications in the pathogenesis of UC..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Cellular and Molecular Gastroenterology and Hepatology - 15(2023), 4, Seite 903-919 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Dulari Jayawardena [VerfasserIn] |
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| Links: |
doi.org [kostenfrei] |
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| Themen: |
Diseases of the digestive system. Gastroenterology |
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| doi: |
10.1016/j.jcmgh.2022.12.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
DOAJ079926231 |
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| 520 | |a Background & Aims: Down-regulation of chloride transporter SLC26A3 or down-regulated in adenoma (DRA) in colonocytes has recently been linked to the pathogenesis of ulcerative colitis (UC). Because exaggerated immune responses are one of the hallmarks of UC, these current studies were undertaken to define the mechanisms by which loss of DRA relays signals to immune cells to increase susceptibility to inflammation. Methods: NanoString Immunology Panel, fluorescence assisted cell sorting, immunoblotting, immunofluorescence, and quantitative real-time polymerase chain reaction assays were used in wild-type and DRA knockout (KO) mice. Interleukin (IL)-33 blocking was used to determine specific changes in immune cells and co-housing/broad spectrum antibiotics administration, and ex vivo studies in colonoids were conducted to rule out the involvement of microbiota. Colonoid-derived monolayers from healthy and UC patient biopsies were analyzed for translatability. Results: There was a marked induction of Th2 (<2-fold), CD4+ Th2 cells (∼8-fold), RORγt+ Th17, and FOXP3+ regulatory T cells (Tregs). DRA KO colons also exhibited a robust induction of IL-33 (<8-fold). In vivo studies using blocking of IL-33 established that T2 immune dysregulation (alterations in ILC2, Th2, and GATA3+ iTregs) in response to loss of DRA was due to altered epithelial-immune cell crosstalk via IL-33. Conclusions: Loss of DRA in colonocytes triggers the release of IL-33 to drive a type 2 immune response. These observations emphasize the critical importance of DRA in mucosal immune homeostasis and its implications in the pathogenesis of UC. | ||
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| 700 | 0 | |a Ramsha Akram |e verfasserin |4 aut | |
| 700 | 0 | |a Arivarasu N. Anbazhagan |e verfasserin |4 aut | |
| 700 | 0 | |a Teruyuki Sano |e verfasserin |4 aut | |
| 700 | 0 | |a Pradeep K. Dudeja |e verfasserin |4 aut | |
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