Differential roles of microglia and monocytes in the inflamed central nervous system

J Exp Med. 2014 Jul 28;211(8):1533-49. doi: 10.1084/jem.20132477. Epub 2014 Jul 7.

Abstract

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Shape
  • Central Nervous System / pathology*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Homeostasis / genetics
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology*
  • Kinetics
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Microglia / pathology*
  • Microglia / ultrastructure
  • Monocytes / pathology*
  • Monocytes / ultrastructure
  • Ranvier's Nodes / pathology
  • Receptors, CCR2 / metabolism
  • Receptors, Chemokine / metabolism
  • Signal Transduction / genetics
  • Time Factors

Substances

  • CX3C Chemokine Receptor 1
  • Ccr2 protein, mouse
  • Cx3cr1 protein, mouse
  • Receptors, CCR2
  • Receptors, Chemokine