title: Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system.
abstract: HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.
authors.affiliation: Center for Aging and Developmental Biology, Program in Neurosciences, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tong
authors.forename: S W
authors.initials: SW
authors.lastname: Perry
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: H J
authors.initials: HJ
authors.lastname: James
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: A
authors.initials: A
authors.lastname: Brooks
authors.forename: H
authors.initials: H
authors.lastname: Bal
authors.forename: S A
authors.initials: SA
authors.lastname: Kinnear
authors.forename: S
authors.initials: S
authors.lastname: Fine
authors.forename: L G
authors.initials: LG
authors.lastname: Epstein
authors.forename: D
authors.initials: D
authors.lastname: Dairaghi
authors.forename: T J
authors.initials: TJ
authors.lastname: Schall
authors.forename: H E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
authors.forename: L R
authors.initials: LR
authors.lastname: Sharer
authors.forename: H A
authors.initials: HA
authors.lastname: Gelbard
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000008:administration & dosage / Q000096:biosynthesis* / Q000502:physiology; D002648:Child; D003593:Cytoplasm / Q000378:metabolism; D018792:Encephalitis, Viral / Q000276:immunology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology; D015696:Gene Products, tat / Q000008:administration & dosage; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D018023:HIV Seronegativity / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000502:physiology; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000276:immunology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; D015696:Gene Products, tat; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010972:Platelet Activating Factor; D054322:tat Gene Products, Human Immunodeficiency Virus