title: Scavenger receptor function of mouse Fcγ receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice.
abstract: Recent studies showed loss of CD36 or scavenger receptor-AI/II (SR-A) does not ameliorate atherosclerosis in a hyperlipidemic mouse model, suggesting receptors other than CD36 and SR-A may also contribute to atherosclerosis. In this report, we show that apolipoprotein E (apoE)-CD16 double knockout (DKO; apoE-CD16 DKO) mice have reduced atherosclerotic lesions compared with apoE knockout mice. In vivo and in vitro foam cell analyses showed apoE-CD16 DKO macrophages accumulated less neutral lipids. Reduced foam cell formation in apoE-CD16 DKO mice is not due to change in expression of CD36, SR-A, and LOX-1. This led to a hypothesis that CD16 may have scavenger receptor activity. We presented evidence that a soluble form of recombinant mouse CD16 (sCD16) bound to malondialdehyde-modified low-density lipoprotein (MDALDL), and this binding is blocked by molar excess of MDA- modified BSA and anti-MDA mAbs, suggesting CD16 specifically recognizes MDA epitopes. Interestingly, sCD16 inhibited MDALDL binding to macrophage cell line, as well as soluble forms of recombinant mouse CD36, SR-A, and LOX-1, indicating CD16 can cross-block MDALDL binding to other scavenger receptors. Anti-CD16 mAb inhibited immune complex binding to sCD16, whereas it partially inhibited MDALDL binding to sCD16, suggesting MDALDL binding site may be in close proximity to the immune complex binding site in CD16. Loss of CD16 expression resulted in reduced levels of MDALDL-induced proinflammatory cytokine expression. Finally, CD16-deficient macrophages showed reduced MDALDL-induced Syk phosphorylation. Collectively, our findings suggest scavenger receptor activity of CD16 may, in part, contribute to the progression of atherosclerosis.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Hang Pong
authors.initials: HP
authors.lastname: Ng
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lai
authors.affiliation: Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Craigo
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Pruthvi S
authors.initials: PS
authors.lastname: Nagilla
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Summer Undergraduate Research Program, University of Pittsburgh, Pittsburgh, PA 15261; and Arizona State University, Tempe, AZ 85287.
authors.forename: Pooja
authors.initials: P
authors.lastname: Raghani
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; nagarajans@upmc.edu.
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Nagarajan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology; D006949:Hyperlipidemias / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D051116:Receptors, Scavenger / Q000235:genetics / Q000276:immunology*; D000072377:Syk Kinase
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; C485700:Fcgr3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D051116:Receptors, Scavenger; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse