MUC1 cell surface mucin is a critical element of the mucosal barrier to infection
Julie L. McAuley, … , Victoria Korolik, Michael A. McGuckin
Julie L. McAuley, … , Victoria Korolik, Michael A. McGuckin
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2313-2324. https://doi.org/10.1172/JCI26705.
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MUC1 cell surface mucin is a critical element of the mucosal barrier to infection

Abstract

Cell surface mucin glycoproteins are highly expressed by all mucosal tissues, yet their physiological role is currently unknown. We hypothesized that cell surface mucins protect mucosal cells from infection. A rapid progressive increase in gastrointestinal expression of mucin 1 (Muc1) cell surface mucin followed infection of mice with the bacterial pathogen Campylobacter jejuni. In the first week following oral infection, C. jejuni was detected in the systemic organs of the vast majority of Muc1–/– mice but never in Muc1+/+ mice. Although C. jejuni entered gastrointestinal epithelial cells of both Muc1–/– and Muc1+/+ mice, small intestinal damage as manifested by increased apoptosis and enucleated and shed villous epithelium was more common in Muc1–/– mice. Using radiation chimeras, we determined that prevention of systemic infection in wild-type mice was due exclusively to epithelial Muc1 rather than Muc1 on hematopoietic cells. Expression of MUC1-enhanced resistance to C. jejuni cytolethal distending toxin (CDT) in vitro and CDT null C. jejuni showed lower gastric colonization in Muc1–/– mice in vivo. We believe this is the first in vivo experimental study to demonstrate that cell surface mucins are a critical component of mucosal defence and that the study provides the foundation for exploration of their contribution to epithelial infectious and inflammatory diseases.

Authors

Julie L. McAuley, Sara K. Linden, Chin Wen Png, Rebecca M. King, Helen L. Pennington, Sandra J. Gendler, Timothy H. Florin, Geoff R. Hill, Victoria Korolik, Michael A. McGuckin

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Figure 7

MUC1 protects epithelial cells from the C. jejuni CDT.

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MUC1 protects epithelial cells from the C. jejuni CDT. (...
(A) HeLa cells were exposed to 200 AU/ml CDT for 0, 6, or 24 hours. MUC1 extracellular domain and nuclei were stained and examined by confocal microscopy. (B) MUC1 expression in HeLa cervical cancer cells stably expressing 2 differing MUC1 shRNAs (M1.3, M1.4, 2 cultures, A and B, for each shRNA) or a control (luciferase) shRNA were determined by flow cytometry (shaded area represents control antibody; lines show MUC1 staining); percentage decrease in median fluorescence in parentheses. Parent cells and the sublines were exposed to 16–100 AU/ml of CDT for 48 hours. The proportion of cells in the S/G2+M phases of the cell cycle and the percentage of cells in apoptosis (annexin V–positive) were determined by flow cytometry. (C) The EM10 MUC1–expressing clone of HCT116 cells was exposed to 200 AU/ml CDT for 0, 6, or 24 hours and stained as in A. (D) Stable clones of HCT116 cells transfected with MUC1 or the pcDNA3 vector (see MUC1 expression in Figure 2D) were exposed to CDT for 96 hours, and cells were counted and expressed as a proportion of control vehicle–only treated cultures. Two distinct experiments are shown. ANOVA, Tukey’s post-hoc test; *P < 0.05 versus HCT116.MUC1.A; #P < 0.05 versus HCT116.MUC1.B; **P < 0.01 versus HCT116.MUC1.A; ##P < 0.01 versus HCT116.MUC1.B; ***P < 0.001 versus HCT116.MUC1.A; ###P < 0.001 versus HCT116.MUC1.B. (E) The EM10 MUC1–expressing clone of HCT116 cells was exposed to 200 AU/ml CDT for 0 or 24 hours. MUC1 cytoplasmic domain, p53, and nuclei were stained and examined by confocal microscopy; arrows highlight colocalization of MUC1 and p53 in cytoplasmic vesicles.