Class A scavenger receptor-mediated macrophage adhesion requires coupling of calcium-independent phospholipase A(2) and 12/15-lipoxygenase to Rac and Cdc42 activation.
Class A scavenger receptors (SR-A) participate in multiple macrophage functions including adhesion to modified extracellular matrix proteins present in various inflammatory disorders such as atherosclerosis and diabetes. By mediating macrophage adhesion to modified proteins and increasing macrophage retention, SR-A may contribute to the inflammatory process. Eicosanoids produced after phospholipase A(2) (PLA(2))-catalyzed release of arachidonic acid (AA) are important regulators of macrophage function and inflammatory responses. The potential roles of AA release and metabolism in SR-A-mediated macrophage adhesion were determined using macrophages adherent to modified protein. SR-A-dependent macrophage adhesion was abolished by selectively inhibiting calcium-independent PLA(2) (iPLA(2)) activity and absent in macrophages isolated from iPLA(2) beta(-/-) mice. Our results further demonstrate that 12/15-lipoxygenase (12/15-LOX)-derived, but not cyclooxygenase- or cytochrome P450-dependent epoxygenase-derived AA metabolites, are specifically required for SR-A-dependent adhesion. Because of their role in regulating actin polymerization and cell adhesion, Rac and Cdc42 activation were also examined and shown to be increased via an iPLA(2)- and LOX-dependent pathway. Together, our results identify a novel role for iPLA(2)-catalyzed AA release and its metabolism by 12/15-LOX in coupling SR-A-mediated macrophage adhesion to Rac and Cdc42 activation.
Nikolic
Dejan M
DM
Departments of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, 40536.
Gong
Ming C
MC
Department of Physiology, University of Kentucky, Lexington, Kentucky 40536.
Turk
John
J
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Post
Steven R
SR
Departments of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, 40536. Electronic address: spost@uky.edu.
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D002448:Cell Adhesion; D015971:Gene Expression Regulation, Enzymologic; D054522:Group VI Phospholipases A2 / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D054467:Phospholipases A2 / Q000378:metabolism*; D020033:Protein Isoforms; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
C475064:12-15-lipoxygenase; D020033:Protein Isoforms; D051117:Scavenger Receptors, Class A; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; C516476:Pla2g6 protein, mouse; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins