Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord
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Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., “classically activated” proinflammatory (M1) or “alternatively activated” anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or “alternatively” activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.
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Multiple sclerosis, ALS, and spinal cord injury are associated with chronic activation of resident immune cells, microglia.
“These disorders (e.g. multiple sclerosis, ALS, spinal cord injury) are associated with chronic activation of resident immune cells, microglia2–4.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [4]
In a spinal cord injury study, a predominantly M1 phenotype was induced immediately and persisted in lesions; M2 macrophages were seen early but not later, suggesting the M1 to M2 shift does not occur in the same way as in other tissues.
“The results of the study showed that a predominantly M1 phenotype was induced immediately following injury and persisted within spinal cord lesions. A small number of M2 macrophages were also seen in the site of injury at early time points; however, these cells were not observed at later time points in the remodeling process, suggesting that the M1 to M2 phenotype shift does not occur in the same”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [128]
In CNS injury, in the absence of blood-brain barrier breach, tissue remodeling largely involves local microglia at early time points, which possess a predominantly pro-inflammatory phenotype that propagates tissue damage and scar deposition.
“These cells have been shown to possess a predominantly pro-inflammatory phenotype following injury, resulting in a microenvironment that is cytotoxic and propagates tissue damage and scar tissue deposition [128].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [128]
In that study, M1 and M2 macrophages had distinct effects on neuron survival and neurite outgrowth: M1-conditioned media decreased viability and neurite length, while M2-conditioned media improved survival and neurite extension.
“Neurons which were exposed to media conditioned by M1 macrophages were shown to exhibit a decrease in viability as well as a decrease in neurite length, while those cells exposed to media conditioned by M2 macrophages showed improved survival and a greater degree of neurite extension.”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [128]
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- Authors
- Kigerl, K. A., Gensel, J. C., Ankeny, D. P., Alexander, J. K., Donnelly, D. J., & Popovich, P. G.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Popovich, Phillip G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-10-28
- Volume
- 29
- Issue
- 43
- Pages
- 13435-13444
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2788152
- OpenAlex
- W2161456562
- Cited by
- 2,130
- References
- 78
- Citations by year
- 2026: 59 · 2025: 78 · 2024: 114 · 2023: 121 · 2022: 160 · 2021: 149 · 2020: 137 · 2019: 133 · 2018: 171 · 2017: 151 · 2016: 151 · 2015: 172 · 2014: 190 · 2013: 131 · 2012: 106
- FWCI
- 49.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Paralysis Project of America
- Craig H. Neilsen Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS037846)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- macrophage polarization, M1 macrophages, M2 macrophages, spinal cord injury, traumatic spinal cord injury, neurotoxicity, axon regeneration, sensory axons, microglia, blood monocytes, CNS repair, neuroinflammation, proteoglycans, myelin
- MeSH terms
- Animals, Axons, Cell Survival, Cells, Cultured, Cerebral Cortex, Ganglia, Spinal, Macrophages, Mice, Inbred C57BL, Monocytes, Myelin Sheath, Nerve Regeneration, Chondroitin Sulfate Proteoglycans, Sensory Receptor Cells, Spinal Cord, Spinal Cord Injuries, Time Factors, Wallerian Degeneration, Microglia, Mice
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