TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord
Open accessAbstract
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.
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Additional studies support the idea that excess iron predisposes macrophages towards a pro-inflammatory phenotype.
“Additional studies support the idea that excess iron predispose macrophages towards a pro-inflammatory phenotype [79,80], thereby linking macrophage iron handling to their role in inflammatory disease.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [79]
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- Authors
- Kroner, A., Greenhalgh, A. D., Zarruk, J. G., Passos dos Santos, R., Gaestel, M., & David, S.
- Affiliations
- McGill University Health Centre (CA)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- David, Samuel
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 83
- Issue
- 5
- Pages
- 1098-1116
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2093230923
- Cited by
- 655
- References
- 83
- Citations by year
- 2026: 39 · 2025: 63 · 2024: 59 · 2023: 62 · 2022: 65 · 2021: 76 · 2020: 46 · 2019: 46 · 2018: 53 · 2017: 53 · 2016: 44 · 2015: 46 · 2014: 2
- FWCI
- 35.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-06-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft
- Canadian Institutes of Health Research (MOP14828)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- spinal cord injury, macrophage polarization, M1/M2 macrophages, TNF-α, intracellular iron, microglia, phagocytosis, myelin phagocytosis, neuroinflammation, macrophage transplantation
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Animals, Disease Models, Animal, Gene Expression Regulation, Intracellular Fluid, Iron, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Phenotype, Spinal Cord Injuries, Time Factors, Tumor Necrosis Factor-alpha, Cytokines, Apoptosis, Protein Serine-Threonine Kinases, Microglia, Cytoprotection, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Mice
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