Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal

Cell. 2013 Apr 11;153(2):362-75. doi: 10.1016/j.cell.2013.03.010.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / metabolism
  • Cell-Derived Microparticles
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / immunology
  • Humans
  • Inflammation
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kidney / blood supply
  • Kidney / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Monitoring, Immunologic*
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Neutrophils / immunology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Receptors, Chemokine / metabolism


  • Cell Adhesion Molecules
  • Lipopolysaccharide Receptors
  • Lymphocyte Function-Associated Antigen-1
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Chemokine
  • Intercellular Adhesion Molecule-1