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Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke

Ge, Ruimin LU ; Tornero, Daniel LU ; Hirota, Masao LU ; Monni, Emanuela LU ; Laterza, Cecilia LU ; Lindvall, Olle LU and Kokaia, Zaal LU (2017) In Journal of Neuroinflammation 14(1).
Abstract

Background: Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Methods: Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx3cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed... (More)

Background: Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Methods: Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx3cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx3cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. Results: We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. Conclusions: Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Choroid plexus, Functional recovery, Inflammation, Stroke, Transplantation
in
Journal of Neuroinflammation
volume
14
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85026290091
ISSN
1742-2094
DOI
10.1186/s12974-017-0909-3
language
English
LU publication?
no
id
09db9583-844d-4382-ace4-f8dbfa0dbb8e
date added to LUP
2017-08-31 11:26:40
date last changed
2018-06-24 05:16:22
@article{09db9583-844d-4382-ace4-f8dbfa0dbb8e,
  abstract     = {<p>Background: Choroid plexus (CP) supports the entry of monocyte-derived macrophages (MDMs) to the central nervous system in animal models of traumatic brain injury, spinal cord injury, and Alzheimer's disease. Whether the CP is involved in the recruitment of MDMs to the injured brain after ischemic stroke is unknown. Methods: Adult male C57BL/6 mice were subjected to focal cortical ischemia by permanent occlusion of the distal branch of the right middle cerebral artery. Choroid plexus tissues were collected and analyzed for Vcam1, Madcam1, Cx<sub>3</sub>cl1, Ccl2, Nt5e, and Ifnγ expression at different timepoints after stroke using qPCR. Changes of MDMs in CP and cerebrospinal fluid (CSF) at 1 day and 3 days after stroke were analyzed using flow cytometry. Infiltration of MDMs into CP and CSF were validated using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. CD115+ monocytes were isolated using a magnetic cell separation system from bone marrow of Cx<sub>3</sub>cr1-GFP or wild-type C57BL/6 donor mice. The freshly isolated monocytes or M2-like MDMs primed in vitro with IL4 and IL13 were stereotaxically injected into the lateral ventricle of stroke-affected mice to trace for their migration into ischemic hemisphere or to assess their effect on post-stroke recovery using open field, corridor, and active avoidance behavioral tests. Results: We found that CP responded to cortical stroke by upregulation of gene expression for several possible mediators of MDM trafficking and, concomitantly, MDMs increased in CP and cerebrospinal fluid (CSF). We then confirmed that MDMs infiltrated from blood into CP and CSF after the insult using β-actin-GFP chimeric mice and Fgd5-CreERT2 x Lox-stop-lox-Tomato mice. When MDMs were directly administered into CSF following stroke, they homed to the ischemic hemisphere. If they had been primed in vitro prior to their administration to become M2-like macrophages, they promoted post-stroke recovery of motor and cognitive function without influencing infarct volume. Conclusions: Our findings suggest the possibility that autologous transplantation of M2-like MDMs into CSF might be developed into a new strategy for promoting recovery also in patients with stroke.</p>},
  articleno    = {153},
  author       = {Ge, Ruimin and Tornero, Daniel and Hirota, Masao and Monni, Emanuela and Laterza, Cecilia and Lindvall, Olle and Kokaia, Zaal},
  issn         = {1742-2094},
  keyword      = {Choroid plexus,Functional recovery,Inflammation,Stroke,Transplantation},
  language     = {eng},
  month        = {07},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Journal of Neuroinflammation},
  title        = {Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke},
  url          = {http://dx.doi.org/10.1186/s12974-017-0909-3},
  volume       = {14},
  year         = {2017},
}