TY - JOUR
T1 - Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal
AU - Carlin, Leo M.
AU - Stamatiades, Efstathios G.
AU - Auffray, Cedric
AU - Hanna, Richard N.
AU - Glover, Leanne
AU - Vizcay-Barrena, Gema
AU - Hedrick, Catherine C.
AU - Cook, H. Terence
AU - Diebold, Sandra
AU - Geissmann, Frederic
N1 - Funding Information:
I. Charo, B. Engelhardt and J.V. Stein, and R. Alon kindly provided Ccr2 −/− , Icam1 −/− and Icam2 −/− , and Igal −/− mice, respectively. The authors are also indebted to G. Burn and A. Fischer for helpful discussions, to C. Trouillet for the management of the Geissmann lab, and to A. McGuigan and her colleagues from the Biological Service Unit at King’s College London, Guy’s Campus, for support with mouse husbandry. E.G.S. is supported by a PhD fellowship 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).
PY - 2013/4/11
Y1 - 2013/4/11
N2 - 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, 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.
AB - 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, 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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U2 - 10.1016/j.cell.2013.03.010
DO - 10.1016/j.cell.2013.03.010
M3 - Article
C2 - 23582326
AN - SCOPUS:84876207357
SN - 0092-8674
VL - 153
SP - 362
EP - 375
JO - Cell
JF - Cell
IS - 2
ER -