Recruitment of Beneficial M2 Macrophages to Injured Spinal Cord Is Orchestrated by Remote Brain Choroid Plexus
Open accessAbstract
Monocyte-derived macrophages are essential for recovery after spinal cord injury, but their homing mechanism is poorly understood. Here, we show that although of common origin, the homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages to traumatized spinal cord (SC) was distinctly regulated, neither being through breached blood-brain barrier. The M1 macrophages (Ly6c(hi)CX3CR1(lo)) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6c(lo)CX3CR1(hi)) derived from monocytes trafficked through a remote blood-cerebrospinal-fluid (CSF) barrier, the brain-ventricular choroid plexus (CP), via VCAM-1-VLA-4 adhesion molecules and epithelial CD73 enzyme for extravasation and epithelial transmigration. Blockage of these determinants, or mechanical CSF flow obstruction, inhibited M2 macrophage recruitment and impaired motor-function recovery. The CP, along with the CSF and the central canal, provided an anti-inflammatory supporting milieu, potentially priming the trafficking monocytes. Overall, our finding demonstrates that the route of monocyte entry to central nervous system provides an instructional environment to shape their function.
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Following mechanical spinal cord injury, protective pro-resolution monocytes (Ly6CloCX3CR1hi) gain access to CNS from choroid plexus and migrate to injured spinal cord parenchyma through central canal, whereas detrimental pro-inflammatory monocytes (Ly6ChiCCR2+) transmigrate via spinal cord leptomeninges in a CCL2-dependent manner.
“following mechanical spinal cord injury, ‘protective’ pro-resolution monocytes (Ly6CloCX3CR1hi) were thought to gain access to the CNS from the choroid plexus and migrate to the injured spinal cord parenchyma through the central canal, whereas detrimental pro-inflammatory monocytes (Ly6ChiCCR2+) were proposed to transmigrate via the spinal cord leptomeninges in a CCL2-dependent manner [281]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [281]
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Experimental — accuracy not yet measuredProinflammatory macrophages are recruited to injured CNS through adjacent leptomeninges in a CCL2-dependent manner, while resolving macrophages are preferentially recruited through the choroid plexus.
“The proinflammatory macrophages were recruited to the injured region in the CNS through the adjacent leptomeninges in a CCL2 dependent manner, while the resolving macrophages were preferentially recruited to the CNS through CP.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [146]
Homing of proinflammatory and resolving macrophages derived from circulating monocytes to traumatized spinal cord is distinctly regulated.
“Shechter et al. found that the homing of proinflammatory macrophage and resolving macrophages derived from circulating monocytes to traumatized spinal cord was distinctly regulated.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [146]
CNS region-specific signals may shape eventual functions of monocytes, with those trafficking through choroid plexus and CSF encountering stimuli that shape more anti-inflammatory roles.
“CNS region-specific signals may also shape their eventual functions within the CNS, with those trafficking through the choroid plexus and cerebrospinal fluid encountering stimuli that shape more anti-inflammatory roles [281]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [281]
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- Authors
- Shechter, R., Miller, O., Yovel, G., Rosenzweig, N., London, A., Ruckh, J., Kim, K.-W., Klein, E., Kalchenko, V., Bendel, P., Lira, S. A., Jung, S., & Schwartz, M.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Shechter, Ravid
- Schwartz, Michal
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 38
- Issue
- 3
- Pages
- 555-569
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4115271
- OpenAlex
- W2151417786
- Cited by
- 683
- References
- 8
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 42 · 2023: 43 · 2022: 56 · 2021: 65 · 2020: 59 · 2019: 42 · 2018: 34 · 2017: 47 · 2016: 55 · 2015: 74 · 2014: 71 · 2013: 20 · 2012: 2
- FWCI
- 54.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK072201)
- 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, M2 macrophages, M1 macrophages, choroid plexus, monocyte-derived macrophages, CCL2 chemokine, leptomeninges, blood-CSF barrier, CD73, motor recovery, anti-inflammatory microenvironment, monocyte trafficking
- MeSH terms
- CX3C Chemokine Receptor 1, Adenosine Diphosphate, Animals, Antigens, Ly, Blood-Brain Barrier, Cell Movement, Choroid Plexus, Enzyme Inhibitors, Flow Cytometry, Macrophages, Meninges, Mice, Inbred C57BL, Monocytes, Spinal Cord, Spinal Cord Injuries, 5'-Nucleotidase, Gene Expression, Leukocyte Common Antigens, Mice, Knockout, Microscopy, Confocal, Vascular Cell Adhesion Molecule-1, Receptors, Chemokine, Reverse Transcriptase Polymerase Chain Reaction, Integrin alpha4beta1, Green Fluorescent Proteins, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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