TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord

Neuron. 2014 Sep 3;83(5):1098-116. doi: 10.1016/j.neuron.2014.07.027. Epub 2014 Aug 14.

Abstract

Macrophages and microglia can be polarized along a continuum toward a detrimental (M1) or a beneficial (M2) state in the injured CNS. Although phagocytosis of myelin in vitro promotes M2 polarization, macrophage/microglia in the injured spinal cord retain a predominantly M1 state that is detrimental to recovery. We have identified two factors that underlie this skewing toward M1 polarization in the injured CNS. We show that TNF prevents phagocytosis-mediated conversion from M1 to M2 cells in vitro and in vivo in spinal cord injury (SCI). Additionally, iron that accumulates in macrophages in SCI increases TNF expression and the appearance of a macrophage population with a proinflammatory mixed M1/M2 phenotype. In addition, transplantation experiments show that increased loading of M2 macrophages with iron induces a rapid switch from M2 to M1 phenotype. The combined effect of this favors predominant and prolonged M1 macrophage polarization that is detrimental to recovery after SCI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytoprotection / drug effects
  • Cytoprotection / genetics
  • Cytoprotection / physiology*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Intracellular Fluid / metabolism*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Iron / metabolism*
  • Iron / pharmacology
  • Macrophages / physiology*
  • Macrophages / transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Myelin Sheath / metabolism
  • Phenotype
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Spinal Cord Injuries / immunology*
  • Spinal Cord Injuries / pathology*
  • Spinal Cord Injuries / surgery
  • Time Factors
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Tumor Necrosis Factor-alpha
  • Green Fluorescent Proteins
  • Iron
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases