MCP~(-1) targeting inhibits muscularis macrophage recruitment and intestinal smooth muscle dysfunction in colonic inflammation

摘要

First published October 31, 2007; doi:10.1152/ajpcell.00056.2007.-Upregulation of muscularis macrophage numbers and activities plays an important role in the intestinal dysmotility associated with intestinal inflammation. The present study aimed to clarify changes in population dynamics of intestinal muscularis macrophages during colonic inflammation and to test possible inhibitory actions of agents targeting monocyte chemoattractant protein~(-1) (MCP~(-1)) on muscularis macrophage dynamics and motility disorder in the colonic inflammation elicited by 2,4,6-trinitrobenzene sulfonic acid. In the inflamed muscle layer, EDI antibody-positive monocytes and monocyte-derived macrophages were increased, followed by increasing resident macrophages positively staining for ED2 antibody. Initiation of the EDl-positive macrophage dynamic is associated with MCP~(-1) mRNA expression. MCP~(-1) was expressed in both EDI- and ED2-positive macrophages after inflammation. Electromicro-scopic analysis revealed that the cell-division phase of muscularis macrophages was seen only in the early stages of inflammation. In addition, EDI and ED2 double-positive macrophages can be detected during inflammation. Treatment with dominant negative MCP~(-1) or neutralizing MCP~(-1) antibodies markedly inhibited numbers of both EDI- and ED2-positive macrophages. Inflammation-mediated dysmotility was partially recovered by treatment with neutralizing MCP~(-1) antibodies. These results suggest that the inflamed muscle layer is initially infiltrated by monocytes, which then differentiate and develop into muscularis-resident macrophages. These macrophages express MCP~(-1) for further recruitment of monocytes. MCP~(-1) may be one potential therapeutic target for inhibiting intestinal motility disorders in gut inflammation.