title: The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria.
abstract: The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages. We showed that BAI1 promoted phagosomal ROS production through activation of the Rho family guanosine triphosphatase (GTPase) Rac1, thereby stimulating NADPH oxidase activity. Primary BAI1-deficient macrophages exhibited attenuated Rac GTPase activity and reduced ROS production in response to several Gram-negative bacteria, resulting in impaired microbicidal activity. Furthermore, in a peritoneal infection model, BAI1-deficient mice exhibited increased susceptibility to death by bacterial challenge because of impaired bacterial clearance. Together, these findings suggest that BAI1 mediates the clearance of Gram-negative bacteria by stimulating both phagocytosis and NADPH oxidase activation, thereby coupling bacterial detection to the cellular microbicidal machinery.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Billings
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Chang Sup
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Owen
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: D'Souza
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA. jec9e@virginia.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Casanova
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D006090:Gram-Negative Bacteria; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases; D009479:Neuropeptides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C524949:Adgrb1 protein, mouse; D042501:Angiogenic Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein
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