title: Defective inflammatory monocyte development in IRF8-deficient mice abrogates migration to the West Nile virus-infected brain.
abstract: IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/- mice throughout infection. Adoptive transfer of IRF8-/- Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/- monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection.
authors.affiliation: Department of Pathology, School of Medical Sciences, Sydney Medical School, Sydney University, Sydney, N.S.W., Australia.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Terry
authors.forename: Celine
authors.initials: C
authors.lastname: Deffrasnes
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Carsten
authors.initials: C
authors.lastname: Minten
authors.forename: Caryn
authors.initials: C
authors.lastname: van Vreden
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ashhurst
authors.forename: Meghann T
authors.initials: MT
authors.lastname: Getts
authors.forename: Rui Dan Vicki
authors.initials: RD
authors.lastname: Xie
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000172:deficiency*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014902:West Nile virus / Q000276:immunology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D000950:Antigens, Ly; D039041:Integrin alpha4beta1; D050835:Interferon Regulatory Factors; D054390:Receptors, CCR2; D000099185:Interferon Regulatory Factor-8; C515335:Ccr2 protein, mouse; C494192:Ly-6C antigen, mouse