Reduced Atherosclerosis in apoE-inhibitory FcγRIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages.
Reduced Atherosclerosis in apoE-inhibitory FcγRIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages.
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DOI：
10.1161/atvbaha.115.305290
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发表时间：
2015-05
期刊：
影响因子：
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通讯作者：
Nagarajan S
中科院分区：
文献类型：
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作者：
Ng HP;Zhu X;Harmon EY;Lennartz MR;Nagarajan S
fcγ受体（fc - γ rs）分为激活型（fc - γ ri， III和IV）和抑制性（fc - γ rii）受体。我们已经报道了apoE−/−小鼠中激活FcγRs的缺失可以减轻动脉粥样硬化。在本报告中，我们研究了抑制FcγRIIb缺乏会加剧动脉粥样硬化的假设。产生C57BL/6基因（apoe - fc - γ riibb6−/−）的apoe - fc - γ riibbb双敲除小鼠，并评估动脉粥样硬化病变。与我们的假设相反，当与apoE- / -小鼠相比，apoE- fc γ riibb6 - / -雄性和雌性小鼠喂食饲料或高脂肪饮食时，动脉病变明显减少。将apoE- fc - γ riibb6 - / -骨髓移植到apoE- / -小鼠体内产生的嵌合小鼠病变也有所减轻。apoE- fc - γ riibb6−/−小鼠的CD4+ T细胞比apoE−/−小鼠产生更高水平的IL-10和TGF-β。由于我们的发现与之前在混合遗传背景下使用apoE-FcγRIIb129/B6 - / -小鼠的报道相冲突，我们研究了菌株差异是否有助于抗炎反应。混合遗传背景的FcγRIIb129/B6 - / -小鼠巨噬细胞对免疫复合物产生更多的IL-1β和MCP-1，而同源FcγRIIbB6 - / -小鼠产生更多的IL-10和显著减少IL-1β。有趣的是，位于小鼠1号染色体fcgr2b附近的狼疮相关slam基因的表达仅在混合FcγRIIb129/B6−/−小鼠中上调。我们的研究结果表明，在apoe - fc - γ riibb6−/−小鼠中，fc - γ riiib信号通路在动脉粥样硬化中的有害作用，以及抗炎细胞因子反应在减薄病变中的贡献。由于129/sv基因组衍生的狼疮相关基因与FcγRIIb129/B6−/−小鼠的狼疮表型有关，我们的研究结果提示可能的epistatic机制有助于减少病变。
Fcgamma receptors (FcγRs) are classified as activating (FcγRI, III, and IV) and inhibitory (FcγRII) receptors. We have reported that deletion of activating FcγRs in apoE−/− mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory FcγRIIb exacerbates atherosclerosis. ApoE-FcγRIIb double knockout mice, congenic to the C57BL/6 (apoE-FcγRIIbB6−/−) were generated and atherosclerotic lesions were assessed. Contrary to our hypothesis, when compared to apoE−/− mice, arterial lesions were significantly decreased in apoE-FcγRIIbB6−/− male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-FcγRIIbB6−/− marrow into apoE−/− mice also developed reduced lesions. CD4+ T cells from apoE-FcγRIIbB6−/− mice produced higher levels of IL-10 and TGF-β than their apoE−/− counterparts. As our findings conflict with a previous report using apoE-FcγRIIb129/B6−/− mice on a mixed genetic background, we investigated if strain differences contributed to the anti-inflammatory response. Macrophages from FcγRIIb129/B6−/− mice on a mixed genetic background produced more IL-1β and MCP-1 in response to immune complexes, while congenic FcγRIIbB6−/− mice generated more IL-10 and significantly less IL-1β. Interestingly expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed FcγRIIb129/B6−/− mice. Our findings demonstrate a detrimental role for FcγRIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-FcγRIIbB6−/− mice. As 129/sv genome derived lupus associated genes have been implicated in lupus phenotype in FcγRIIb129/B6−/− mice our findings suggest possible epistatic mechanism contributing to the decreased lesions.