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: Xinmei Zhu, Hang Pong Ng, Yen-Chun Lai, Jodi K Craigo, Pruthvi S Nagilla, Pooja Raghani, Shanmugam Nagarajan
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 5 Pg. 2483-95 (Sep 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25038257 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Apolipoproteins E
• CD36 Antigens
• Fcgr3 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Receptors, IgG
• Receptors, Scavenger
• Protein-Tyrosine Kinases
• Syk Kinase
• Syk protein, mouse

Topics

• Animals
• Apolipoproteins E (genetics, immunology)
• Atherosclerosis (genetics, immunology, pathology)
• CD36 Antigens (genetics, immunology)
• Hyperlipidemias (genetics, immunology, pathology)
• Intracellular Signaling Peptides and Proteins (genetics, immunology)
• Mice
• Mice, Knockout
• Protein-Tyrosine Kinases (genetics, immunology)
• Receptors, IgG (genetics, immunology)
• Receptors, Scavenger (genetics, immunology)
• Syk Kinase