Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-inflammatory Role in Recovery from Spinal Cord Injury in Mice
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BACKGROUND: Although macrophages (MPhi) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MPhi subpopulations at the lesion site have further contributed to the controversy and led to the common view of MPhi as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MPhi contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MPhi is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI. METHODS AND FINDINGS: We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MPhi on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MPhi. We followed the infiltration of the monocyte-derived MPhi to the injured site and characterized their spatial distribution and phenotype. Increasing the naïve monocyte pool by either adoptive transfer or CNS-specific vaccination resulted in a higher number of spontaneously recruited cells and improved recovery. Selective ablation of infiltrating monocyte-derived MPhi following SCI while sparing the resident microglia, using either antibody-mediated depletion or conditional ablation by diphtheria toxin, impaired recovery. Reconstitution of the peripheral blood with monocytes resistant to ablation restored the lost motor functions. Importantly, the infiltrating monocyte-derived MPhi displayed a local anti-inflammatory beneficial role, which was critically dependent upon their expression of interleukin 10. CONCLUSIONS: The results of this study attribute a novel anti-inflammatory role to a unique subset of infiltrating monocyte-derived MPhi in SCI recovery, which cannot be provided by the activated resident microglia. According to our results, limited recovery following SCI can be attributed in part to the inadequate, untimely, spontaneous recruitment of monocytes. This process is amenable to boosting either by active vaccination with a myelin-derived altered peptide ligand, which indicates involvement of adaptive immunity in monocyte recruitment, or by augmenting the naïve monocyte pool in the peripheral blood. Thus, our study sheds new light on the long-held debate regarding the contribution of MPhi to recovery from CNS injuries, and has potentially far-reaching therapeutic implications.
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Some studies suggest that infiltrating macrophages possess a greater ability than resident microglia to remove CNS plaques.
“Some studies suggest that infiltrating macrophages possess a greater ability than resident microglia to remove CNS plaques,15–17”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [16]
The Discussion (page unavailable) says infiltrating macrophages and resident microglia have different roles in recovery from spinal cord injury, and notes that macrophages can clear cell debris. It does not compare their ability to remove CNS plaques or report plaque removal. (LLM, conf=0.78)
Experimental — accuracy not yet measuredA small number of blood-derived monocytes participate in default CNS tissue remodeling at late time points even without blood-brain barrier breach.
“A small number of blood-derived monocytes have been observed to participate in the default tissue remodeling response in the CNS at late time points following injury, even in the absence of a breach of the blood–brain barrier [129,130].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [130]
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Protective and pathogenic functions of macrophage subsets
Murray, P. J., & Wynn, T. A. (2011) · Nature Reviews Immunology · doi:10.1038/nri3073 · Cited by 5,269 · see citing works
Development of Monocytes, Macrophages, and Dendritic Cells
Geissmann, F., Manz, M. G., Jung, S., Sieweke, M. H., Merad, M., & Ley, K. (2010) · Science · doi:10.1126/science.1178331 · Cited by 3,049 · see citing works
Self-citationMonocytes and macrophages: developmental pathways and tissue homeostasis
Ginhoux, F., & Jung, S. (2014) · Nature Reviews Immunology · doi:10.1038/nri3671 · Cited by 1,840 · see citing works
Self-citationMicroglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329 · see citing works
Microglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180 · see citing works
Self-citationMicroglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · see citing works
Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., & Badylak, S. F. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.02.034 · Cited by 926 · see citing works
“A small number of blood-derived monocytes have been observed to participate in the default tissue remodeling response in the CNS at late time points following injury, even in the absence of a breach of the bloodebrain barrier [129,130].”
BackgroundInflammation and neuroprotection in traumatic brain injury.
Corps, K. N., Roth, T. L., & McGavern, D. B. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3558 · Cited by 853 · see citing works
Microglia: Scapegoat, saboteur, or something else?
Aguzzi, A., Barres, B. A., & Bennett, M. L. (2013) · Science · doi:10.1126/science.1227901 · Cited by 836 · see citing works
Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Macrophages, Foreign Body Giant Cells and Their Response to Implantable Biomaterials
Sheikh, Z., Brooks, P., Barzilay, O., Fine, N., & Glogauer, M. (2015) · Materials · doi:10.3390/ma8095269 · Cited by 701 · see citing works
Revisiting the Mechanisms of CNS Immune Privilege
Louveau, A., Harris, T. H., & Kipnis, J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.006 · Cited by 682 · see citing works
Rejuvenation of Regeneration in the Aging Central Nervous System
Ruckh, J. M., Zhao, J.-W., Shadrach, J. L., van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.11.019 · Cited by 649 · see citing works
Hanna, R. N., Carlin, L. M., Hubbeling, H. G., Nackiewicz, D., Green, A. M., Punt, J. A., Geissmann, F., & Hedrick, C. C. (2011) · Nature Immunology · doi:10.1038/ni.2063 · Cited by 639 · see citing works
Wild-type microglia arrest pathology in a mouse model of Rett syndrome
Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B. G., Guyenet, P. G., & Kipnis, J. (2012) · Nature · doi:10.1038/nature10907 · Cited by 607 · see citing works
Inefficient clearance of myelin debris by microglia impairs remyelinating processes
Lampron, A., Larochelle, A., Laflamme, N., Préfontaine, P., Plante, M.-M., Sánchez, M. G., Yong, V. W., Stys, P. K., Tremblay, M.-È., & Rivest, S. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141656 · Cited by 595 · see citing works
Cronk, J. C., Filiano, A. J., Louveau, A., Marin, I., Marsh, R., Ji, E., Goldman, D. H., Smirnov, I., Geraci, N., Acton, S., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180247 · Cited by 412 · see citing works
Plasticity of myeloid-derived suppressor cells in cancer
Tcyganov, E., Mastio, J., Chen, E., & Gabrilovich, D. I. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.03.009 · Cited by 398 · see citing works
Therapeutic options for targeting inflammatory osteoarthritis pain
Conaghan, P. G., Cook, A. D., Hamilton, J. A., & Tak, P. P. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0221-y · Cited by 405 · see citing works
Dealing with danger in the CNS: the response of the immune system to injury
Gadani, S. P., Walsh, J. T., Lukens, J. R., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.019 · Cited by 342 · see citing works
Varvel, N. H., Neher, J. J., Bosch, A., Wang, W., Ransohoff, R. M., Miller, R. J., & Dingledine, R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604263113 · Cited by 357 · see citing works
Gadani, S. P., Walsh, J. T., Smirnov, I., Zheng, J., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.01.013 · Cited by 359 · see citing works
“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses, respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”
BackgroundSchwartz, M., & Baruch, K. (2014) · The EMBO Journal · doi:10.1002/embj.201386609 · Cited by 349 · see citing works
Self-citationEffect of modulating macrophage phenotype on peripheral nerve repair
Mokarram, N., Merchant, A., Mukhatyar, V., Patel, G., & Bellamkonda, R. V. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.08.050 · Cited by 334 · see citing works
IFN-γ-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair
Kunis, G., Baruch, K., Rosenzweig, N., Kertser, A., Miller, O., Berkutzki, T., & Schwartz, M. (2013) · Brain · doi:10.1093/brain/awt259 · Cited by 321 · see citing works
Self-citationMicroglia, seen from the CX3CR1 angle
Wolf, Y., Yona, S., Kim, K.-W., & Jung, S. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00026 · Cited by 316 · see citing works
Macrophages prevent hemorrhagic infarct transformation in murine stroke models
Gliem, M., Mausberg, A. K., Lee, J., Simiantonakis, I., van Rooijen, N., Hartung, H., & Jander, S. (2012) · Annals of Neurology · doi:10.1002/ana.23529 · Cited by 284 · see citing works
Pro-cognitive properties of T cells
Kipnis, J., Gadani, S., & Derecki, N. C. (2012) · Nature Reviews Immunology · doi:10.1038/nri3280 · Cited by 246 · see citing works
Systemic inflammatory cells fight off neurodegenerative disease
Schwartz, M., & Shechter, R. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.71 · Cited by 240 · see citing works
Self-citationDonnelly, D. J., Longbrake, E. E., Shawler, T. M., Kigerl, K. A., Lai, W., Tovar, C. A., Ransohoff, R. M., & Popovich, P. G. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2114-11.2011 · Cited by 219 · see citing works
The benefits and detriments of macrophages/microglia in models of multiple sclerosis
Rawji, K. S., & Yong, V. W. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/948976 · Cited by 217 · see citing works
Fenn, A. M., Hall, J. C. E., Gensel, J. C., Popovich, P. G., & Godbout, J. P. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1146-14.2014 · Cited by 207 · see citing works
Zhu, Y., Soderblom, C., Krishnan, V., Ashbaugh, J., Bethea, J. R., & Lee, J. K. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.10.024 · Cited by 199 · see citing works
Microglial immune checkpoint mechanisms
Deczkowska, A., Amit, I., & Schwartz, M. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0145-x · Cited by 185 · see citing works
Self-citationImmune Surveillance of the CNS following Infection and Injury
Russo, M. V., & McGavern, D. B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.002 · Cited by 191 · see citing works
A new genetic strategy for targeting microglia in development and disease
McKinsey, G. L., Lizama, C. O., Keown-Lang, A. E., Niu, A., Santander, N., Larpthaveesarp, A., Chee, E., Gonzalez, F. F., & Arnold, T. D. (2020) · eLife · doi:10.7554/elife.54590 · Cited by 176 · see citing works
Koronyo, Y., Salumbides, B. C., Sheyn, J., Pelissier, L., Li, S., Ljubimov, V., Moyseyev, M., Daley, D., Fuchs, D.-T., Pham, M., et al. (2015) · Brain · doi:10.1093/brain/awv150 · Cited by 153 · see citing works
Brain macrophage development, diversity and dysregulation in health and disease
Silvin, A., Qian, J., & Ginhoux, F. (2023) · Cellular & Molecular Immunology · doi:10.1038/s41423-023-01053-6 · Cited by 137 · see citing works
Lim, J. E., Chung, E., & Son, Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-09639-7 · Cited by 136 · see citing works
Microglia: unique and common features with other tissue macrophages
Prinz, M., Tay, T. L., Wolf, Y., & Jung, S. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1267-1 · Cited by 126 · see citing works
Self-citationThe role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?
Doty, K. R., Guillot-Sestier, M.-V., & Town, T. (2015) · Brain Research · doi:10.1016/j.brainres.2014.09.008 · Cited by 104 · see citing works
The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke
Wicks, E. E., Ran, K. R., Kim, J. E., Xu, R., Lee, R. P., & Jackson, C. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.897022 · Cited by 92 · see citing works
Protective features of peripheral monocytes/macrophages in stroke
Gliem, M., Schwaninger, M., & Jander, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.11.004 · Cited by 88 · see citing works
Identification of a critical sulfation in chondroitin that inhibits axonal regeneration
Pearson, C. S., Mencio, C. P., Barber, A. C., Martin, K. R., & Geller, H. M. (2018) · eLife · doi:10.7554/elife.37139 · Cited by 75 · see citing works
Baruch, K., Kertser, A., Porat, Z., & Schwartz, M. (2015) · The EMBO Journal · doi:10.15252/embj.201591468 · Cited by 75 · see citing works
Self-citationKim, S. J., Ko, W.-K., Jo, M.-J., Arai, Y., Choi, H., Kumar, H., Han, I.-B., & Sohn, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-21621-5 · Cited by 59 · see citing works
Kim, J.-S., Trzebanski, S., Shin, S.-H., Schori, L., Frumer Friedman, G. R., Ilani, N. C., Kadam, A., Vicario, R., Aust, O., Bugaeva, P., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115609 · Cited by 33 · see citing works
Self-citationMatatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., et al. (2025) · Cell Stem Cell · doi:10.1016/j.stem.2025.06.006 · Cited by 23 · see citing works
- Authors
- Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., Rolls, A., Mack, M., Pluchino, S., Martino, G., Jung, S., & Schwartz, M.
- Affiliations
- Weizmann Institute of Science (IL)
- IRCCS Ospedale San Raffaele (IT)
- University of Regensburg (DE)
- Corresponding author
- Jung, Steffen
- Schwartz, Michal
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-07-28
- Volume
- 6
- Issue
- 7
- Pages
- e1000113
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC2707628
- OpenAlex
- W2130529018
- Cited by
- 770
- References
- 90
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 32 · 2023: 34 · 2022: 33 · 2021: 45 · 2020: 45 · 2019: 48 · 2018: 49 · 2017: 36 · 2016: 58 · 2015: 70 · 2014: 69 · 2013: 64 · 2012: 65
- FWCI
- 34.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Cure Huntington's Disease Initiative
- Minerva Foundation
- Israel Science Foundation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- spinal cord injury, infiltrating macrophages, monocyte-derived macrophages, anti-inflammatory macrophages, IL-10, monocyte recruitment, adaptive immunity, motor recovery, adoptive transfer, bone marrow chimeras, diphtheria toxin ablation, neuroinflammation
- MeSH terms
- Animals, Glycoproteins, Inflammation, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Monocytes, Ovalbumin, Peptide Fragments, Spinal Cord, Spinal Cord Injuries, Interleukin-10, Adoptive Transfer, Mice, Myelin-Oligodendrocyte Glycoprotein
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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