Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus

Immunity. 2013 Mar 21;38(3):555-69. doi: 10.1016/j.immuni.2013.02.012. Epub 2013 Mar 7.

Abstract

Monocyte-derived macrophages are essential for recovery after spinal cord injury, but their homing mechanism is poorly understood. Here, we show that although of common origin, the homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages to traumatized spinal cord (SC) was distinctly regulated, neither being through breached blood-brain barrier. The M1 macrophages (Ly6c(hi)CX3CR1(lo)) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6c(lo)CX3CR1(hi)) derived from monocytes trafficked through a remote blood-cerebrospinal-fluid (CSF) barrier, the brain-ventricular choroid plexus (CP), via VCAM-1-VLA-4 adhesion molecules and epithelial CD73 enzyme for extravasation and epithelial transmigration. Blockage of these determinants, or mechanical CSF flow obstruction, inhibited M2 macrophage recruitment and impaired motor-function recovery. The CP, along with the CSF and the central canal, provided an anti-inflammatory supporting milieu, potentially priming the trafficking monocytes. Overall, our finding demonstrates that the route of monocyte entry to central nervous system provides an instructional environment to shape their function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / antagonists & inhibitors
  • 5'-Nucleotidase / genetics
  • 5'-Nucleotidase / immunology
  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Antigens, Ly / immunology
  • Antigens, Ly / metabolism
  • Blood-Brain Barrier / immunology
  • Blood-Brain Barrier / metabolism
  • CX3C Chemokine Receptor 1
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Choroid Plexus / immunology*
  • Choroid Plexus / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Gene Expression / immunology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Integrin alpha4beta1 / genetics
  • Integrin alpha4beta1 / immunology
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Meninges / immunology
  • Meninges / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / immunology*
  • Spinal Cord / metabolism
  • Spinal Cord Injuries / cerebrospinal fluid
  • Spinal Cord Injuries / genetics
  • Spinal Cord Injuries / immunology*
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / immunology

Substances

  • Antigens, Ly
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Enzyme Inhibitors
  • Integrin alpha4beta1
  • Ly-6C antigen, mouse
  • Receptors, Chemokine
  • Vascular Cell Adhesion Molecule-1
  • alpha,beta-methyleneadenosine 5'-diphosphate
  • Green Fluorescent Proteins
  • Adenosine Diphosphate
  • Leukocyte Common Antigens
  • Ptprc protein, mouse
  • 5'-Nucleotidase