title: TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord.
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.
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Greenhalgh
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.
authors.forename: Juan G
authors.initials: JG
authors.lastname: Zarruk
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada.
authors.forename: Rosmarini
authors.initials: R
authors.lastname: Passos Dos Santos
authors.affiliation: Institute of Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: 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.
authors.forename: Samuel
authors.initials: S
authors.lastname: David
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D016207:Cytokines; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2