title: Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal.
abstract: 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 Gαi-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.
authors.affiliation: Centre for Molecular and Cellular Biology of Inflammation, King's College London, London SE1 1UL, UK.
authors.forename: Leo M
authors.initials: LM
authors.lastname: Carlin
authors.forename: Efstathios G
authors.initials: EG
authors.lastname: Stamatiades
authors.forename: Cedric
authors.initials: C
authors.lastname: Auffray
authors.forename: Richard N
authors.initials: RN
authors.lastname: Hanna
authors.forename: Leanne
authors.initials: L
authors.lastname: Glover
authors.forename: Gema
authors.initials: G
authors.lastname: Vizcay-Barrena
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Sandra
authors.initials: S
authors.lastname: Diebold
authors.forename: Frederic
authors.initials: F
authors.lastname: Geissmann
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D055252:Cell-Derived Microparticles; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D015166:Monitoring, Immunologic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D018950:Lipopolysaccharide Receptors; D016169:Lymphocyte Function-Associated Antigen-1; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1