Differential expression of the chemokine receptors CX3CR1 and CCR1 by microglia and macrophages in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis.
Chemokines are important for the recruitment of immune cells into sites of inflammation. To better understand their functional roles during inflammation we have here studied the in vivo expression of receptors for the chemokines CCL3/CCL5/CCL7 (MIP-1alpha/RANTES/MCP-3) and CX3CL1 (fractalkine), CCR1 and CX3CR1, respectively, in rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Combined in situ hybridization and immunohistochemistry demonstrated intensely upregulated CCR1 mRNA expression in early, actively demyelinating plaques, whereas CX3CR1 displayed a more generalized expression pattern. CX3CR1 mRNA expressing cells were identified as microglia on the basis of their cellular morphology and positive GSA/B4 lectin staining. In contrast, CCR1 mRNA was preferentially expressed by ED1+ GSA/B4+ macrophages. The notion of differential chemokine receptor expression in microglia and monocyte-derived macrophages was corroborated at the protein level by extraction and flow cytometric sorting of cells infiltrating the spinal cord using gating for the surface markers CD45, ED-2 and CD11b. These observations suggest a differential receptor expression between microglia and monocyte-derived macrophages and that mainly the latter cell type is responsible for active demyelination. This has great relevance for the possibility of therapeutic intervention in demyelinating diseases such as multiple sclerosis, for example by targeting signaling events leading to monocyte recruitment.
Sunnemark
Dan
D
Department of Molecular Sciences, Local Discovery Research Area CNS and Pain Control, AstraZeneca AB, Södertälje, Sweden. dan.sunnemark@astrazeneca.com
Eltayeb
Sana
S
Wallström
Erik
E
Appelsved
Lena
L
Malmberg
Asa
A
Lassmann
Hans
H
Ericsson-Dahlstrand
Anders
A
Piehl
Fredrik
F
Olsson
Tomas
T
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D053331:Ectodysplasins; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D007091:Image Processing, Computer-Assisted; D007114:Immunization / Q000379:methods; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C515302:Ccr1 protein, rat; D004268:DNA-Binding Proteins; D053331:Ectodysplasins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496489:Hnf1a protein, rat; D008565:Membrane Proteins; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta