title: Monocyte chemotactic protein-1 regulates voltage-gated K+ channels and macrophage transmigration.
abstract: Progressive human immunodeficiency virus (HIV)-1 infection and virus-induced neuroinflammatory responses effectuate monocyte-macrophage transmigration across the blood-brain barrier (BBB). A key factor in mediating these events is monocyte chemotactic protein-1 (MCP-1). Upregulated glial-derived MCP-1 in HIV-1-infected brain tissues generates a gradient for monocyte recruitment into the nervous system. We posit that the inter-relationships between MCP-1, voltage-gated ion channels, cell shape and volume, and cell mobility underlie monocyte transmigration across the BBB. In this regard, MCP-1 serves both as a chemoattractant and an inducer of monocyte-macrophage ion flux affecting cell shape and mobility. To address this hypothesis, MCP-1-treated bone marrow-derived macrophages (BMM) were analyzed for gene and protein expression, electrophysiology, and capacity to migrate across a laboratory constructed BBB. MCP-1 enhanced K+ channel gene (KCNA3) and channel protein expression. Electrophysiological studies revealed that MCP-1 increased outward K+ currents in a dose-dependent manner. In vitro studies demonstrated that MCP-1 increased BMM migration across an artificial BBB, and the MCP-1-induced BMM migration was blocked by tetraethylammonium, a voltage-gated K+ channel blocker. Together these data demonstrated that MCP-1 affects macrophage migratory movement through regulation of voltage-gated K+ channels and, as such, provides a novel therapeutic strategy for neuroAIDS.
authors.affiliation: Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198-5880, USA. hegendel@unmc.edu
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Shengyuan
authors.initials: S
authors.lastname: Ding
authors.forename: Nan
authors.initials: N
authors.lastname: Gong
authors.forename: Jianuo
authors.initials: J
authors.lastname: Liu
authors.forename: Servio H
authors.initials: SH
authors.lastname: Ramirez
authors.forename: Yuri
authors.initials: Y
authors.lastname: Persidsky
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Volsky
authors.forename: Huangui
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D018925:Chemokines / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000819:agonists / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000199:Actins; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D024642:Potassium Channels, Voltage-Gated; D012313:RNA