Scavenger receptor function of mouse Fcγ receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice.
Scavenger receptor function of mouse Fcγ receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice.
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DOI：
10.4049/jimmunol.1303075
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发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Nagarajan S
中科院分区：
文献类型：
--
作者：
Zhu X;Ng HP;Lai YC;Craigo JK;Nagilla PS;Raghani P;Nagarajan S
近年来的研究表明，CD 36或清道夫受体-AI/II（SR-A）的缺失并不能改善高脂血症小鼠模型的动脉粥样硬化，提示CD 36和SR-A以外的受体也可能参与动脉粥样硬化的形成。在这份报告中，我们表明，apoE-CD 16双敲除小鼠（apoE-CD 16 DKO）有减少动脉粥样硬化病变相比，apoE基因敲除小鼠。体内和体外泡沫细胞分析显示apoE-CD 16 DKO巨噬细胞积累较少的中性脂质。apoE-CD 16 DKO小鼠中泡沫细胞形成减少不是由于CD 36、SR-A和LOX-1表达的变化。这导致了一个假设，即CD 16可能具有清道夫受体活性。我们提出的证据表明，可溶性形式的重组小鼠CD 16（sCD 16）结合到丙二醛修饰的低密度脂蛋白（MDALDL），这种结合被摩尔过量的MDA-BSA和抗MDA单克隆抗体阻断，表明CD 16特异性识别MDA表位。有趣的是，sCD 16抑制MDALDL与巨噬细胞系的结合以及sCD 36、sSR-A和sLOX-1，表明CD 16可以交叉阻断MDALDL与其他清道夫受体的结合。抗CD 16单抗抑制IC与sCD 16的结合，而部分抑制MDALDL与sCD 16的结合，表明MDALDL结合位点可能与CD 16中的IC结合位点非常接近。CD 16表达的丧失导致MDALDL诱导的促炎细胞因子表达水平降低。最后，CD 16缺陷型巨噬细胞显示MDALDL诱导的Syk磷酸化减少。总的来说，我们的研究结果表明，清道夫受体活性的CD 16可能在一定程度上有助于动脉粥样硬化的进展。
Recent studies showed loss of CD36 or scavenger receptor-AI/II (SR-A) does not ameliorate atherosclerosis in hyperlipidemic mouse model, suggesting receptors other than CD36 and SR-A may also contribute to atherosclerosis. In this report, we show that apoE-CD16 double knockout mice (apoE-CD16 DKO) have reduced atherosclerotic lesions compared with apoE KO mice. In vivo and in vitro foam cells 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-BSA and anti-MDA mAbs, suggesting CD16 specifically recognizes MDA epitopes. Interestingly, sCD16 inhibited MDALDL binding to macrophage cell line as well as sCD36, sSR-A and sLOX-1, indicating CD16 can cross-block MDALDL binding to other scavenger receptors. Anti-CD16 mAb inhibited IC binding to sCD16, while partially inhibited MDALDL binding to sCD16, suggesting MDALDL binding site may be in close proximity to the IC binding site in CD16. Loss of CD16 expression resulted in reduced levels of MDALDL induced pro-inflammatory 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.
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作者：
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