Monocyte Chemotactic Protein-1 Regulates Voltage-Gated K+ Channels and Macrophage Transmigration

• Published in: Journal of neuroimmune pharmacology 2009-03, Vol.4 (1), p.47-59
• Main Authors: Gendelman, Howard E., Ding, Shengyuan, Gong, Nan, Liu, Jianuo, Ramirez, Servio H., Persidsky, Yuri, Lee Mosley, R., Wang, Tong, Volsky, David J., Xiong, Huangui
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Blood-Brain Barrier - cytology; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiology; Cell Biology; Cell Movement - physiology; Cell Separation; Cells, Cultured; Chemokine CCL2 - genetics; Chemokine CCL2 - physiology; Chemokines - physiology; Chemotaxis, Leukocyte - drug effects; Human immunodeficiency virus; Humans; Immunohistochemistry; Immunology; In Vitro Techniques; Macrophages - physiology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Neurosciences; Original Article; Patch-Clamp Techniques; Pharmacology/Toxicology; Potassium Channels, Voltage-Gated - agonists; Potassium Channels, Voltage-Gated - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA - isolation & purification; Tomography, Emission-Computed, Single-Photon; Virology
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-008-9135-1

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.