title: Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2.
abstract: HIV-associated neurologic disorders are a mounting problem despite the advent of highly active antiretroviral therapy. To address mechanisms of HIV-associated neurologic disorders, we used an SIV pigtailed macaque model to study innate immune responses in brain that suppress viral replication during acute infection. We previously reported that during acute infection in brain, noncanonical type I IFN signaling occurs, where IFN-β mRNA is induced while IFN-α is simultaneously suppressed. Two downstream IFN-stimulated genes, MxA and TRAIL, also show differential expression patterns. In this study, we show that differential signaling is due to interactions between macrophages and astrocytes. Astrocytes produce high levels of CCL2 upon SIV infection, which binds to CCR2 receptors on macrophages, leading to a selective suppression of IFN-α and the IFN-stimulated gene TRAIL while simultaneously inducing IFN-β and MxA. The interactions between chemokine and cytokine pathways are a novel finding that may specifically occur in the CNS.
authors.affiliation: Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Luna Alammar
authors.initials: LA
authors.lastname: Zaritsky
authors.forename: Lucio
authors.initials: L
authors.lastname: Gama
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000821:virology; D002450:Cell Communication; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D064547:Myxovirus Resistance Proteins; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D018932:Chemokine CCL2; D016898:Interferon-alpha; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D053221:TNF-Related Apoptosis-Inducing Ligand; D016899:Interferon-beta; D019204:GTP-Binding Proteins