Suppression of experimental colitis by intestinal mononuclear phagocytes

The contribution of innate immunity to inflammatory bowel disease (1111)) remains an area of intense interest. Macrophages (M circle divide) 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 circle divide/DC depletion transgenic mouse line-M circle divide Fas-induced apoptosis-to systemically deplete iMNP, DSS colitis histopathology was shown to be more severe in M circle divide/DC-depleted compared with M circle divide/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 circle divide/DC-intact, DSS-treated mice. Histology revealed that iMNP depletion during DSS treatment led to increased neutrophilic inflammation, increased epithetial injury, and enhanced mucin depletion from Goblet cells. iMNP depletion did not further elevate DSS-induced expression of TNF-alpha and IFN-gamma mRNA but significantly increased expression of CXCL1 chemokine mRNA. Myeloperoxidase activity was increased in colons of M circle divide/DC-depleted, DSS-treated mice, compared with DSS alone, coincident with increased neutrophil infiltration in diseased colons. Neutrophil depletion combined with M circle divide/DC depletion prevented the increase in DSS colitis severity compared with M circle divide/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 circle divide/DC-mediated down-regulation of neutrophil infiltration.