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Published online before print August 3, 2006
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*Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, College of Medicine, Lexington; and Vrije Universiteit, VUMC, Department of Molecular Cell Biology, Amsterdam, The Netherlands
@ To whom correspondence should be addressed. E-mail: dcohen{at}uky.edu.
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Abstract |
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The contribution of innate immunity to inflammatory bowel disease (IBD) remains an area of intense interest. Macrophages (M
) and dendritic cells (DC) are considered important factors in regulating the onset of IBD. The goal of this study was to determine if intestinal mononuclear phagocytes (iMNP) serve a pathological or protective role in dextran sulfate sodium (DSS)-induced colitis in mice. Using a conditional M/DC depletion transgenic mouse line--M Fas-induced apoptosis--to systemically deplete iMNP, DSS colitis histopathology was shown to be more severe in M/DC-depleted compared with M/DC-intact mice. Similarly, localized iMNP depletion by clodronate-encapsulated liposomes into C57BL/6, BALB/c, and CB.17/SCID mice also increased DSS colitis severity, as indicated by increased histopathology, weight loss, rectal bleeding, decreased stool consistency, and colon length compared with M/DC-intact, DSS-treated mice. Histology revealed that iMNP depletion during DSS treatment led to increased neutrophilic inflammation, increased epithelial injury, and enhanced mucin depletion from Goblet cells. iMNP depletion did not further elevate DSS-induced expression of TNF-
and IFN-
mRNA but significantly increased expression of CXCL1 chemokine mRNA. Myeloperoxidase activity was increased in colons of M/DC-depleted, DSS-treated mice, compared with DSS alone, coincident with increased neutrophil infiltration in diseased colons. Neutrophil depletion combined with M/DC depletion prevented the increase in DSS colitis severity compared with M/DC depletion alone. This study demonstrates that iMNP can serve a protective role during development of acute colitis and that protection is associated with M/DC-mediated down-regulation of neutrophil infiltration.
Key Words: dextran sodium sulfate • dendritic cells • monocytes/macrophages • mice
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