期刊
CELL
卷 153, 期 2, 页码 362-375出版社
CELL PRESS
DOI: 10.1016/j.cell.2013.03.010
关键词
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资金
- Oliver Bird Rheumatism Programme, Nuffield Foundation, UK
- Medical Research Council, UK [MRCG0900867]
- European Research Council [ERC-2010-StG-261299 MPS2010]
- European Science Foundation (ERC EURYI Award)
- MRC [G0900867] Funding Source: UKRI
- Medical Research Council [G0900867] Funding Source: researchfish
The functions of Nr4a1-dependent Ly6C(low) monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid danger signal, which may signify viral infection or local cell death, triggers Gai-dependent intravascular retention of Ly6C(low) monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C(low) monocyte development, crawling, or retention in Nr4a1(-/-), Itgal(-/-), and Tlr7(host-/-BM+/+) and Cx3cr1(-/-) mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7(host+/+BM-/-) mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C(low) monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.
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