title: Lipid rafts couple class A scavenger receptors to phospholipase A2 activation during macrophage adhesion.
abstract: SR-A mediated macrophage adhesion to modified ECM proteins in a process that involves physical attachment of SR-A to modified ECM and activation of Lyn-PI3K and PLA2-12/15-lipoxygenase signaling pathways. Structurally, SR-A-mediated cell adhesion requires a 6-aa membrane-proximal cytoplasmic motif. However, the mechanism that couples SR-A-mediated adhesion to activation of these distinct signaling pathways is not known. For other adhesion receptors, including integrins, localization in cholesterol-rich LRs is an important mechanism for coupling the receptor with the activation of specific signaling pathways. We hypothesized that SR-A-mediated macrophage adhesion might also involve LRs. Our results demonstrate that SR-A is enriched in LRs in HEK cells that heterologously express SR-A and in macrophages that endogenously expressed the receptor. We further show that a truncated SR-A construct (SR-A(Δ1-49)), which mediates cell adhesion but not ligand internalization, is also enriched in LRs, suggesting an association between LRs and SR-A-dependent cell adhesion. To examine this association more directly, we used the cholesterol chelator MβCD to deplete cholesterol and disrupt LR function. We found that cholesterol depletion significantly decreased SR-A-mediated macrophage adhesion. We further show that decreased SR-A-dependent macrophage adhesion following cholesterol depletion results from the inhibition of PLA2 but not PI3K activation. Overall, our results demonstrate an important role for LRs in selectively coupling SR-A with PLA2 activation during macrophage adhesion.
authors: Departments of Pharmacology and Toxicology and.
authors: Shanthi
authors: S
authors: Vadali
authors: Departments of Pharmacology and Toxicology and Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA spost@uams.edu.
authors: Steven R
authors: SR
authors: Post
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051117:Scavenger Receptors, Class A / Q000378:metabolism*
chemical_list: D051117:Scavenger Receptors, Class A; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases; D054467:Phospholipases A2
keywords: arachidonic acid; cholesterol; membrane domains; prostaglandin; receptor localization; signaling