title: CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage.
abstract: Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2+ Ly6C(hi) inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2+ Ly6C(hi) inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2(-/-) mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2(-/-) hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.
authors.affiliation: Department of Neuroscience and Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut 06030, Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Internal Medicine II, University Hospital Regensberg, 93053 Regensberg, Germany, and Department of Neurology and Department of Neurosurgery, Hartford Hospital, Hartford, Connecticut 06102.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hammond
authors.forename: Roslyn A
authors.initials: RA
authors.lastname: Taylor
authors.forename: Michael T
authors.initials: MT
authors.lastname: Mullen
authors.forename: Youxi
authors.initials: Y
authors.lastname: Ai
authors.forename: Hector L
authors.initials: HL
authors.lastname: Aguila
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kasner
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.forename: Lauren H
authors.initials: LH
authors.lastname: Sansing
mesh_terms: D000208:Acute Disease; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics* / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002543:Cerebral Hemorrhage / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000097:blood; D004185:Disability Evaluation; D004660:Encephalitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D009069:Movement Disorders / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D011446:Prospective Studies; D054390:Receptors, CCR2 / Q000235:genetics* / Q000276:immunology; D020521:Stroke / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
chemical_list: D000950:Antigens, Ly; C111835:CCL2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2
keywords: CCL2; CCR2; bone marrow chimeras; intracerebral hemorrhage; monocytes; neuroinflammation