title: Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus.
abstract: 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.
authors.affiliation: Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel. ravid.shechter@weizmann.ac.il
authors.forename: Ravid
authors.initials: R
authors.lastname: Shechter
authors.forename: Omer
authors.initials: O
authors.lastname: Miller
authors.forename: Gili
authors.initials: G
authors.lastname: Yovel
authors.forename: Neta
authors.initials: N
authors.lastname: Rosenzweig
authors.forename: Anat
authors.initials: A
authors.lastname: London
authors.forename: Julia
authors.initials: J
authors.lastname: Ruckh
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Kim
authors.forename: Eugenia
authors.initials: E
authors.lastname: Klein
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Kalchenko
authors.forename: Peter
authors.initials: P
authors.lastname: Bendel
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Michal
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002831:Choroid Plexus / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008578:Meninges / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D004791:Enzyme Inhibitors; D039041:Integrin alpha4beta1; C494192:Ly-6C antigen, mouse; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D049452:Green Fluorescent Proteins; D000244:Adenosine Diphosphate; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D015720:5'-Nucleotidase