title: Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis.
abstract: In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45(int)/CD11b(+)/CD11c(-) microglia at days 6-7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of "circulating" (Gr1(-)(Ly6C(lo))CX3CR1(+)) and "inflammatory" (Gr1(hi)/Ly6C(hi)/CCR2(+)) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS-enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP(+)) microglia expressing GR1(+)(Ly6C(+)) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6C(hi)/CD115(+)) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP(+) microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.
authors.affiliation: The Discipline of Pathology, School of Medical Sciences, The University of Sydney, Sydney NSW 2006, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Terry
authors.forename: Meghann Teague
authors.initials: MT
authors.lastname: Getts
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.forename: Sabita
authors.initials: S
authors.lastname: Rana
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.forename: Jane
authors.initials: J
authors.lastname: Radford
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018932:Chemokine CCL2 / Q000276:immunology; D004002:Clodronic Acid / Q000378:metabolism; D005260:Female; D017493:Leukocyte Common Antigens / Q000276:immunology; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology*; D015996:Survival Rate; D014901:West Nile Fever / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus
chemical_list: D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008081:Liposomes; C494192:Ly-6C antigen, mouse; D004002:Clodronic Acid; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
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