期刊
CIRCULATION
卷 125, 期 2, 页码 364-U415出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.111.061986
关键词
atherosclerosis; imaging; immune system; immunology; macrophages
资金
- National Institutes of Health [1R01 HL095612, U01 HL080731, P50 CA86355, U24 CA092782, P01-A154904, 2R01 HL069948]
- American Heart Association
- Massachusetts General Hospital ECOR
- Boehringer Ingelheim Fonds
- German Research Foundation
Background-Atherosclerotic lesions are believed to grow via the recruitment of bone marrow-derived monocytes. Among the known murine monocyte subsets, Ly-6C(high) monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here, we hypothesized that the bone marrow outsources the production of Ly-6C(high) monocytes during atherosclerosis. Methods and Results-Using murine models of atherosclerosis and fate-mapping approaches, we show that hematopoietic stem and progenitor cells progressively relocate from the bone marrow to the splenic red pulp, where they encounter granulocyte macrophage colony-stimulating factor and interleukin-3, clonally expand, and differentiate to Ly-6C(high) monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atheromata. On lesional infiltration, Ly-6C(high) monocytes secrete inflammatory cytokines, reactive oxygen species, and proteases. Eventually, they ingest lipids and become foam cells. Conclusions-Our findings indicate that extramedullary sites supplement the hematopoietic function of the bone marrow by producing circulating inflammatory cells that infiltrate atherosclerotic lesions. (Circulation. 2012; 125: 364-374.)
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