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An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity

Eri, RD; Adams, RJ; Tran, TV; Tong, H; Das, I; Roche, DK; Oancea, I; Png, Chin Wen; Jeffery, PL; Radford-Smith, Graham L; Cook, Matthew; Florin, Timothy H.J.; McGuckin, Michael A.

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We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c+ major histocompatibility complex (MHC) class II hi) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor...[Show more]

dc.contributor.authorEri, RD
dc.contributor.authorAdams, RJ
dc.contributor.authorTran, TV
dc.contributor.authorTong, H
dc.contributor.authorDas, I
dc.contributor.authorRoche, DK
dc.contributor.authorOancea, I
dc.contributor.authorPng, Chin Wen
dc.contributor.authorJeffery, PL
dc.contributor.authorRadford-Smith, Graham L
dc.contributor.authorCook, Matthew
dc.contributor.authorFlorin, Timothy H.J.
dc.contributor.authorMcGuckin, Michael A.
dc.date.accessioned2015-12-10T22:18:43Z
dc.identifier.issn1933-0219
dc.identifier.urihttp://hdl.handle.net/1885/51534
dc.description.abstractWe recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c+ major histocompatibility complex (MHC) class II hi) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal TH17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple TH1, TH2, and TH17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4+ T lymphocytes. Loss of T and B lymphocytes in Rag1-/- × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1-/-, indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/TH17 response, similar to that of human ulcerative colitis.
dc.publisherNature Publishing Group
dc.sourceMucosal Immunology
dc.subjectKeywords: chemokine receptor CCR6; glycoprotein p 15095; interleukin 12p40; interleukin 12p70; interleukin 17; interleukin 17F; interleukin 3; interleukin 5; interleukin 9; messenger RNA; thymic stromal lymphopoietin; transforming growth factor beta; tumor necrosis
dc.titleAn intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolumeOnline 24 Nov 2010
dc.date.issued2010
local.identifier.absfor110704 - Cellular Immunology
local.identifier.absfor110307 - Gastroenterology and Hepatology
local.identifier.ariespublicationu4201517xPUB226
local.type.statusPublished Version
local.contributor.affiliationEri, RD, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationAdams, RJ, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationTran, TV, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationTong, H, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationDas, I, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationRoche, DK, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationOancea, I, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationPng, Chin Wen, University of Queensland
local.contributor.affiliationJeffery, PL, Mater Medical Research Institute and the University of Queensland
local.contributor.affiliationRadford-Smith, Graham L, Royal Brisbane and Women's Research Foundation
local.contributor.affiliationCook, Matthew, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationFlorin, Timothy H.J., Mater Medical Research Institute
local.contributor.affiliationMcGuckin, Michael A., Mater Medical Research Institute
local.description.embargo2037-12-31
local.bibliographicCitation.startpage11
local.identifier.doi10.1038/mi.2010.74
dc.date.updated2016-02-24T10:41:36Z
local.identifier.scopusID2-s2.0-79955106916
local.identifier.thomsonID000289616800013
CollectionsANU Research Publications

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