Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal

Carlin, L. M. , Stamatiades, E. G., Auffray, C., Hanna, R. N., Glover, L., Vizcay-Barrena, G., Hedrick, C. C., Cook, H. T., Diebold, S. and Geissmann, F. (2013) Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell, 153(2), pp. 362-375. (doi: 10.1016/j.cell.2013.03.010) (PMID:23582326) (PMCID:PMC3898614)

Abstract

The functions of Nr4a1-dependent Ly6Clow 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 Gαi-dependent intravascular retention of Ly6Clow 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 Ly6Clow monocyte development, crawling, or retention in Nr4a1−/−, Itgal−/−, and Tlr7host−/−BM+/+ and Cx3cr1−/− mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7host+/+BM−/− mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6Clow 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.

• Item Type: Articles
• Additional Information: E.G.S. is supported by a PhDfellowship from the Oliver Bird Rheumatism Programme, Nuffield Foundation, UK. Work was supported by grants to F.G. from the Medical Research Council, UK (MRCG0900867), the European Research Council (ERC-2010-StG-261299 MPS2010), and the European Science Foundation (ERC EURYI Award).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carlin, Dr Leo
• Authors: Carlin, L. M., Stamatiades, E. G., Auffray, C., Hanna, R. N., Glover, L., Vizcay-Barrena, G., Hedrick, C. C., Cook, H. T., Diebold, S., and Geissmann, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell
• Publisher: Elsevier
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Copyright Holders: Copyright © 2013 Elsevier Inc.
• First Published: First published in Cell 153(2):362-375
• Publisher Policy: Reproduced under a Creative Commons license