FcgammaRI ligation leads to a complex with BLT1 in lipid rafts that enhances rat lung macrophage antimicrobial functions.
Leukotriene (LT) B(4) is generated in response to engagement of the Fc gamma receptor (Fc gamma R) and potently contributes to Fc gamma R-mediated antimicrobial functions in pulmonary alveolar macrophages. In this study, we report that the LTB(4) receptor leukotriene B(4) receptor 1 (BLT1) redistributes from nonlipid raft (LR) to LR membrane microdomains upon immunoglobulin G-red blood cell, but not LTB(4), challenge. Cholesterol depletion to disrupt LRs abolished LTB(4)-induced enhancement of phagocytosis, microbicidal activity, and signaling. The dependence on LR integrity for BLT1 signaling correlated with formation of a complex consisting of BLT1, its primary coupled G protein G alpha i3, Src kinase, and Fc gamma RI within LRs. This association was dependent on Src-mediated phosphorylation of BLT1. These data identify a novel form of regulation in which engagement of a macrophage immunoreceptor recruits a stimulatory G protein-coupled receptor into a LR microdomain with resultant enhanced antimicrobial signaling.
Serezani
Carlos H
CH
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109-5642, USA.
Aronoff
David M
DM
Sitrin
Robert G
RG
Peters-Golden
Marc
M
D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007152:Immunologic Capping; D007710:Klebsiella Infections / Q000235:genetics / Q000378:metabolism*; D007711:Klebsiella pneumoniae; D007975:Leukotriene B4 / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
C485701:Fcgr1 protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D002784:Cholesterol; D019061:src-Family Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse