Recruitment of Beneficial M2 Macrophages to Injured Spinal Cord Is Orchestrated by Remote Brain Choroid Plexus

By R. Shechter, Omer Miller, Gili Yovel, Neta Rosenzweig, Anat London, J. Ruckh, Ki-Wook Kim, E. Klein, V. Kalchenko, P. Bendel and 3 more. Immunity, 2013

620 citations recorded by the source corpus.

SUMMARY 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 (Ly6chiCX3CR1lo) derived from monocytes homed in a CCL2 chemokine-dependent manner through the adjacent SC leptomeninges. The resolving M2 macrophages (Ly6cloCX3CR1hi) 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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/17151929ba94e376adde23cd8f53fb4cc64a6b22

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. O’Banion
2. V. Perry
3. S. David
4. C. Iadecola
5. Amanda Sierra
6. A. Kroner

In Neurology

1. C. Iadecola
2. N. Quan
3. D. DiSabato
4. Jonathan P. Godbout
5. J. Anrather
6. S. David
7. A. Kroner
8. V. Perry

In Pathology and Forensic Medicine

1. Jonathan P. Godbout
2. N. Quan
3. D. DiSabato
4. S. David
5. C. Iadecola
6. A. Kroner

Citations in the corpus

• Role of neuroinflammation in neurodegeneration development (2023, background): “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.(146) IFN-γ was verified as the crucial player in the expression of resol”
• High‐Dimensional Single‐Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease (2018, neutral): “…is a compartmentalized organ comprising the parenchyma, the ventricles containing the choroid plexus and cerebrospinal fluid (CSF), the meningeal layers that envelop the parenchyma, and several ‘‘absolute’’ (BBB) and semi-permeable barriers (bloodCSF, blood-leptomeningeal) (Shechter et al., 2013).”
• Neuroinflammation and M2 microglia: the good, the bad, and the inflamed (2014, result): “This has been shown in several other cases, where M2 cell induction appeared to alleviate spinal cord injury pathology [86-89].”
• Neuroinflammation: The Devil is in the Details (2016, positive): “Interestingly, this balance between classic (M1) and alternative (M2) activation states in the CNS is influenced by the method of entry of the infiltrating leukocytes to the CNS (Shechter et al. 2013).”
• Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain (2017, background): “The contribution of patrolling monocytes (CX3CR1/CCR2 ) was not studied by our approach and cannot be excluded, although these cells have been shown to infiltrate the CNS only under pathological conditions (Shechter et al., 2013).”
• Immune responses to stroke: mechanisms, modulation, and therapeutic potential. (2020, background): “CD73, an ecto-ATPase expressed on choroid plexus epithelial cells and lymphocytes, mediated monocyte/macrophage trafficking across the choroid plexus in a model of spinal cord injury (106).”
• Microglial M1/M2 polarization and metabolic states (2016, background): “While the initial response of macrophages to injury has been known for some time, positive influences on tissue remodelling have been recognized more recently (Longbrake et al., 2007; Ruffell et al., 2009; Deng et al., 2012; Novak and Koh, 2013; Shechter and Schwartz, 2013; Shechter et al., 2013).”
• TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. (2014, positive): “Another recent study showed that the M2 macrophages enter the injured spinal cord via the central canal and are neuroprotective (Shechter et al., 2013).”