title: Activation of signaling pathways by putative scavenger receptor class A (SR-A) ligands requires CD14 but not SR-A.
abstract: Macrophage scavenger class A type I and type II receptors (SR-A) are trimeric, integral membrane glycoproteins that bind an unusually broad array of macromolecular ligands. These ligands include modified proteins and lipoproteins, nucleic acids, and a variety of plant and microbial cell wall constituents, such as fucoidan and lipoteichoic acid. Early studies of SR-A functions indicated that the receptors bound, internalized, and degraded their ligands without provoking any macrophage activating signaling events. More recent studies have provided evidence that several SR-A ligands can activate macrophage gene expression via utilization of a receptor-linked, PI3-kinase pathway. To investigate the role of SR-A in engaging signal transduction events, we employed macrophages taken from mice lacking these receptors. Using either fucoidan or lipoteichoic acid, we confirm that both ligands stimulate tyrosine phosphorylation of PI3-kinase and production of modest levels of the cytokine, TNFalpha. However, macrophages taken from SR-A null mice did not differ from wild type macrophages in these responses, indicating that these signaling events arise independently of SR-A activity. Employing mice lacking CD14, a GPI anchored receptor that binds bacterial lipopolysaccharide and signals via activation of Toll-like receptors, we show that the fucoidan and lipoteichoic acid responses are largely abrogated when CD14 is absent. These data do not provide support for direct SR-A involvement in signal transduction events and suggest that the early characterization of these receptors as initiators of a non-phlogistic, pathogen clearance pathway was correct.
authors.affiliation: Lipid Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Woojin Scott
authors.initials: WS
authors.lastname: Kim
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ordija
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011134:Polysaccharides / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism
chemical_list: D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C495140:Msr1 protein, mouse; D011134:Polysaccharides; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; C009900:lipoteichoic acid; C007789:fucoidan