期刊
JOURNAL OF IMMUNOLOGY
卷 184, 期 12, 页码 6843-6854出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903987
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资金
- Wellcome Trust
- Medical Research Council, United Kingdom
- National Health and Medical Research Council of Australia [252924]
Macrophages (M phi s) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeostasis. It is unclear if these reflect separate populations of M phi s or if resident M phi s change during inflammation. In this study, we identify two subsets of colonic M phi s in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80(+) M phi s are TLR- CCR2(-) CX3CR1(hi) and do not produce TNF-alpha in response to stimulation. The lack of TLR expression is stable, affects all TLRs, and is determined both transcriptionally and posttranscriptionally. During experimental colitis, TLR2(+) CCR2(+) CX3CR1(int) Ly6C(hi) Gr-1(+), TNF-alpha-producing M phi s come to dominate, and some of these are also present in the normal colon. The TLR2(+) and TLR2(-) subsets are phenotypically distinct and have different turnover kinetics in vivo, and these properties are not influenced by the presence of inflammation. There is preferential CCR2- dependent recruitment of the proinflammatory population during colitis, suggesting they are derived from independent myeloid precursors. CCR2 knockout mice show reduced susceptibility to colitis and lack the recruitment of TLR2(+) CCR2(+) Gr-1(+), TNF-alpha-producing M phi s. The balance between proinflammatory and resident M phi s in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease. The Journal of Immunology, 2010, 184: 6843-6854.
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