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

Antje Kroner; Andrew D Greenhalgh; Juan G Zarruk; Rosmarini Passos Dos Santos; Matthias Gaestel; Samuel David

doi:10.1016/j.neuron.2014.07.027

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.

Authors

Antje Kroner¹, Andrew D Greenhalgh¹, Juan G Zarruk¹, Rosmarini Passos Dos Santos¹, Matthias Gaestel², Samuel David³

Affiliations

¹ Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.
² Institute of Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
³ Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada. Electronic address: sam.david@mcgill.ca.

PMID: 25132469
DOI: 10.1016/j.neuron.2014.07.027

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

Grants and funding

MOP-14828/Canadian Institutes of Health Research/Canada