Data from animal models and human inflammatory bowel diseases have implicated the ER (endoplasmic reticulum) stress pathway in intestinal inflammation. We have characterized the development of inflammation in Winnie mice in which ER stress arises due to a single missense mutation in the MUC2 mucin produced by intestinal goblet cells. This model has allowed us to explore the genesis of inflammation ensuing from a single gene polymorphism affecting secretory cells. In these mice, a proportion of MUC2 misfolds during biosynthesis, leading to ER stress and activation of the unfolded protein response. Winnie mice develop spontaneous complex progressive inflammation that is most severe in the distal colon. Inflammation involves TH1, TH2 and TH17 T-cells, with a progressive development of a TH17-dominated response, but also involves innate immunity, in a pattern not dissimilar to human colitis. Experimental inhibition of tolerance in this model severely exacerbates colitis, demonstrating active effective suppression of inflammation. Even though the misfolding of MUC2 is a consequence of an inherited mutation, as inflammation develops, the molecular markers of ER stress increase further and goblet cell pathology becomes worse, suggesting that inflammation itself exacerbates ER stress.
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August 2011
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Conference Article|
July 20 2011
Intestinal secretory cell ER stress and inflammation
Michael A. McGuckin;
Michael A. McGuckin
1
*Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia
1To whom correspondence should be addressed (email mmcguckin@mmri.mater.org.au).
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Rajaraman D. Eri;
Rajaraman D. Eri
*Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia
†School of Human Life Sciences, University of Tasmania, Launceston, TAS 7250, Australia
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Indrajit Das;
Indrajit Das
*Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia
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Rohan Lourie;
Rohan Lourie
*Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia
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Timothy H. Florin
Timothy H. Florin
*Immunity, Infection and Inflammation Program, Mater Medical Research Institute and the University of Queensland, Mater Health Services, South Brisbane, QLD 4101, Australia
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Publisher: Portland Press Ltd
Received:
March 28 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem Soc Trans (2011) 39 (4): 1081–1085.
Article history
Received:
March 28 2011
Citation
Michael A. McGuckin, Rajaraman D. Eri, Indrajit Das, Rohan Lourie, Timothy H. Florin; Intestinal secretory cell ER stress and inflammation. Biochem Soc Trans 1 August 2011; 39 (4): 1081–1085. doi: https://doi.org/10.1042/BST0391081
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