title: Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice.
abstract: Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in long-term spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltrating MDMs exhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGFβ, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke.
  
  
  CONCLUSIONS
  For decades, any involvement of circulating immune cells in CNS repair was completely denied. Only over the past few years has involvement of monocyte-derived macrophages (MDMs) in CNS repair received appreciation. We show here, for the first time, that MDMs recruited to the injured brain early after ischemic stroke contribute to long-term spontaneous functional recovery through inflammation-resolving activity. Our data raise the possibility that inadequate recruitment of MDMs to the brain after stroke underlies the incomplete functional recovery seen in patients and that boosting homing of MDMs with an anti-inflammatory bias to the injured brain tissue may be a new therapeutic approach to promote long-term improvement after stroke.
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Somsak
authors.initials: S
authors.lastname: Wattananit
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-4812-4091
authors.initials: D
authors.lastname: Tornero
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, 7610001, Rehovot, Israel, and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Graubardt
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and I. Javakhishvili Tbilisi State University, 0179, Tbilisi, Georgia.
authors.forename: Tamar
authors.identifier: http://orcid.org/0000-0003-0094-9278
authors.initials: T
authors.lastname: Memanishvili
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Monni
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Jemal
authors.initials: J
authors.lastname: Tatarishvili
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Giedre
authors.initials: G
authors.lastname: Miskinyte
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Ge
authors.affiliation: Stem Cells, Aging, and Neurodegeneration Group, Lund Stem Cell Center, University Hospital, 221 84, Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ahlenius
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and.
authors.forename: Olle
authors.initials: O
authors.lastname: Lindvall
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, 7610001, Rehovot, Israel, and.
authors.forename: Michal
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Laboratory of Stem Cells and Restorative Neurology and zaal.kokaia@med.lu.se.
authors.forename: Zaal
authors.initials: Z
authors.lastname: Kokaia
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D002678:Chimera; D007839:Functional Laterality; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D037102:Lectins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000473:pathology; D009473:Neuronal Plasticity / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis / Q000235:genetics; D000098902:CD163 Antigen
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D037102:Lectins; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases
keywords: macrophage; microglia; monocyte; neuroinflammation; stroke