title: Validation of research trajectory 1 of an Exposome framework: Exposure to benzo(a)pyrene confers enhanced susceptibility to bacterial infection.
abstract: The exposome provides a framework for understanding elucidation of an uncharacterized molecular mechanism conferring enhanced susceptibility of macrophage membranes to bacterial infection after exposure to the environmental contaminant benzo(a)pyrene, [B(a)P]. The fundamental requirement in activation of macrophage effector functions is the binding of immunoglobulins to Fc receptors. FcγRIIa (CD32a), a member of the Fc family of immunoreceptors with low affinity for immunoglobulin G, has been reported to bind preferentially to IgG within lipid rafts. Previous research suggested that exposure to B(a)P suppressed macrophage effector functions but the molecular mechanisms remain elusive. The goal of this study was to elucidate the mechanism(s) of B(a)P-exposure induced suppression of macrophage function by examining the resultant effects of exposure-induced insult on CD32-lipid raft interactions in the regulation of IgG binding to CD32. The results demonstrate that exposure of macrophages to B(a)P alters lipid raft integrity by decreasing membrane cholesterol 25% while increasing CD32 into non-lipid raft fractions. This robust diminution in membrane cholesterol and 30% exclusion of CD32 from lipid rafts causes a significant reduction in CD32-mediated IgG binding to suppress essential macrophage effector functions. Such exposures across the lifespan would have the potential to induce immunosuppressive endophenotypes in vulnerable populations.
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Clark
authors.affiliation: Department of Microbiology, Meharry Medical College, Nashville, TN 37208, USA; Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Pellom
authors.affiliation: Department of Microbiology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Burthia
authors.initials: B
authors.lastname: Booker
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Aramandla
authors.initials: A
authors.lastname: Ramesh
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Tongwen
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Shanker
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Maguire
authors.affiliation: Department of Family and Preventive Medicine, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Juarez
authors.affiliation: Department of Family and Preventive Medicine, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Matthews-Juarez
authors.initials: MJ
authors.lastname: Patricia
authors.affiliation: Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Langston
authors.affiliation: Department of Global Environmental Health Sciences, School of Public Health & Tropical Medicine, Tulane University, 1440 Canal Street, New Orleans, LA 70112, USA.
authors.forename: Maureen Y
authors.initials: MY
authors.lastname: Lichtveld
authors.affiliation: Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA; Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, OH 43210, USA. Electronic address: hood.188@osu.edu.
authors.forename: Darryl B
authors.initials: DB
authors.lastname: Hood
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002478:Cells, Cultured; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D021962:Membrane Microdomains / Q000187:drug effects*; D009761:Nystatin / Q000494:pharmacology*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D000393:Air Pollutants; C445323:FCGR2A protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D009761:Nystatin; D001564:Benzo(a)pyrene
keywords: Benzo(a)pyrene; FcγRII (CD32) antibody; Immune suppression; Lipid rafts; Membrane integrity