title: Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE.
abstract: BACKGROUND
  The CC chemokine receptors CCR1, CCR2 and CCR5 are critical for the recruitment of mononuclear phagocytes to the central nervous system (CNS) in multiple sclerosis (MS) and other neuroinflammatory diseases. Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons. In this study, we characterize the regional, temporal and cellular expression of CCR1, CCR2 and CCR5 mRNA in the spinal cord of rats with myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE). While resembling human MS, this animal model allows unique access to CNS-tissue from various time-points of relapsing neuroinflammation and from various lesional stages: early active, late active, and inactive completely demyelinated lesions.
  
  
  METHODS
  The expression of CCR1, CCR2 and CCR5 mRNA was studied with in situ hybridization using radio labelled cRNA probes in combination with immunohistochemical staining for phenotypic cell markers. Spinal cord sections from healthy rats and rats with MOG-EAE (acute phase, remission phase, relapse phase) were analysed. In defined lesion stages, the number of cells expressing CCR1, CCR2 and CCR5 mRNA was determined. Data were statistically analysed by the nonparametric Mann-Whitney U test.
  
  
  RESULTS
  In MOG-EAE rats, extensive up-regulation of CCR1 and CCR5 mRNA, and moderate up-regulation of CCR2 mRNA, was found in the spinal cord during episodes of active inflammation and demyelination. Double staining with phenotypic cell markers identified the chemokine receptor mRNA-expressing cells as macrophages/microglia. Expression of all three receptors was substantially reduced during clinical remission, coinciding with diminished inflammation and demyelination in the spinal cord. Healthy control rats did not show any detectable expression of CCR1, CCR2 or CCR5 mRNA in the spinal cord.
  
  
  CONCLUSIONS
  Our results demonstrate that the acute and chronic-relapsing phases of MOG-EAE are associated with distinct expression of CCR1, CCR2, and CCR5 mRNA by cells of the macrophage/microglia lineage within the CNS lesions. These data support the notion that CCR1, CCR2 and CCR5 mediate recruitment of both infiltrating macrophages and resident microglia to sites of CNS inflammation. Detailed knowledge of expression patterns is crucial for the understanding of therapeutic modulation and the validation of CCR1, CCR2 and CCR5 as feasible targets for therapeutic intervention in MS.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunology Unit, Karolinska Institute, Stockholm, Sweden. Sana.Eltayeb@ki.se <Sana.Eltayeb@ki.se>
authors.forename: Sana
authors.initials: S
authors.lastname: Eltayeb
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Berg
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Erik
authors.initials: E
authors.lastname: Wallström
authors.forename: Maria
authors.initials: M
authors.lastname: Nilsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Anders
authors.initials: A
authors.lastname: Ericsson-Dahlstrand
authors.forename: Dan
authors.initials: D
authors.lastname: Sunnemark
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000633:toxicity*; D063308:Myelin-Oligodendrocyte Glycoprotein; D051381:Rats; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors
chemical_list: C515300:CCR1 protein, human; C515334:CCR2 protein, human; C515302:Ccr1 protein, rat; C515336:Ccr2 protein, rat; C571326:MOG protein, human; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine