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      Nr4a1-Dependent Ly6C low Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal

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          Summary

          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 Gα i-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.

          Abstract

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          Highlights

          ► Ly6C low monocytes are accessory cells of the endothelium ► Ly6C low monocytes scavenge microparticles and necrotic debris ► Capillaries retain Ly6C low monocytes in response to a TLR7 “danger signal” ► Ly6C low monocytes recruit neutrophils that mediate necrosis of endothelial cells

          Abstract

          Nr4a1-dependent Ly6C low monocytes scavenge microparticles from the lumenal side of the vascular endothelium and phagocytose cellular debris in response to a TLR7 immune signal, suggesting a role in endothelial surveillance.

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          Author and article information

          Contributors
          Journal
          Cell
          Cell
          Cell
          Cell Press
          0092-8674
          1097-4172
          11 April 2013
          11 April 2013
          : 153
          : 2
          : 362-375
          Affiliations
          [1 ]Centre for Molecular and Cellular Biology of Inflammation, King’s College London, London SE1 1UL, UK
          [2 ]Peter Gorer Department of Immunobiology, King’s College London, London SE1 1UL, UK
          [3 ]Centre for Ultrastructural Imaging, King’s College London, London SE1 1UL, UK
          [4 ]Institut National de la Santé et de la Recherche Médicale (INSERM) U838, Institut Necker, Paris Descartes University, 75015 Paris, France
          [5 ]Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
          [6 ]Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK
          Author notes
          []Corresponding author frederic.geissmann@ 123456kcl.ac.uk
          [7]

          These authors contributed equally to this work

          [8]

          Present address: CNRS UMR8104, INSERM U1016, Institut Cochin, Paris Descartes University, 75014 Paris, France

          Article
          S0092-8674(13)00332-2
          10.1016/j.cell.2013.03.010
          3898614
          23582326
          © 2013 ELL & Excerpta Medica.

          This document may be redistributed and reused, subject to certain conditions.

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          Cell biology

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