Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation.
Depletion of B2 but not B1a B cells in BAFF receptor-deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation.
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DOI：
10.1371/journal.pone.0029371
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Toh BH
中科院分区：
文献类型：
--
作者：
Kyaw T;Tay C;Hosseini H;Kanellakis P;Gadowski T;MacKay F;Tipping P;Bobik A;Toh BH
我们最近在高胆固醇血症ApoE−/−小鼠中发现了传统B2细胞致动脉粥样硬化和B1 a细胞抗动脉粥样硬化。在这里，我们研究了BAFF-R缺陷型ApoE−/−小鼠动脉粥样硬化的发展，因为BAFF-R缺陷型小鼠中B2细胞而不是B1 a细胞被选择性耗尽。我们给BAFF-R−/− ApoE−/−（BaffR.ApoE DKO）和BAFF-R+/+ApoE−/−（ApoE KO）小鼠喂食高脂饮食（HFD）8周。血液、腹腔液、脾脏和外周淋巴结中的B2细胞分别明显减少82%、81%、94%、72%;而B1 a细胞和非B淋巴细胞则不受影响。通过油红-O染色的脂质积聚和CD 68+巨噬细胞积聚评估的主动脉粥样硬化病变分别减少了44%和50%。BaffR.ApoE DKO小鼠的动脉粥样硬化病变中不存在B细胞，B2细胞产生的IgG 1和IgG 2a免疫球蛋白也是如此，尽管血浆中B2细胞和IgG 1和IgG 2a免疫球蛋白浓度较低但可测量。血浆IgM和IgM沉积在动脉粥样硬化病变也减少。ApoE−/−小鼠中的BAFF-R缺陷也与VCAM-1表达减少以及病变中巨噬细胞、树突状细胞、CD 4+和CD 8 + T细胞浸润和PCNA+细胞减少相关。促炎细胞因子TNF-α、IL 1-β和促炎趋化因子MCP-1的表达也降低。体重和血浆胆固醇在BaffR.ApoE DKO小鼠中不受影响。我们的数据表明，B2细胞是动脉粥样硬化发展的重要贡献者，靶向BAFF-R以特异性减少致动脉粥样硬化的B2细胞数量，同时保留动脉粥样硬化保护性B1 a细胞数量可能是一种潜在的治疗策略，通过有效减少动脉炎症来减少动脉粥样硬化。
We have recently identified conventional B2 cells as atherogenic and B1a cells as atheroprotective in hypercholesterolemic ApoE−/− mice. Here, we examined the development of atherosclerosis in BAFF-R deficient ApoE−/− mice because B2 cells but not B1a cells are selectively depleted in BAFF-R deficient mice. We fed BAFF-R−/− ApoE−/− (BaffR.ApoE DKO) and BAFF-R+/+ApoE−/− (ApoE KO) mice a high fat diet (HFD) for 8-weeks. B2 cells were significantly reduced by 82%, 81%, 94%, 72% in blood, peritoneal fluid, spleen and peripheral lymph nodes respectively; while B1a cells and non-B lymphocytes were unaffected. Aortic atherosclerotic lesions assessed by oil red-O stained-lipid accumulation and CD68+ macrophage accumulation were decreased by 44% and 50% respectively. B cells were absent in atherosclerotic lesions of BaffR.ApoE DKO mice as were IgG1 and IgG2a immunoglobulins produced by B2 cells, despite low but measurable numbers of B2 cells and IgG1 and IgG2a immunoglobulin concentrations in plasma. Plasma IgM and IgM deposits in atherosclerotic lesions were also reduced. BAFF-R deficiency in ApoE−/− mice was also associated with a reduced expression of VCAM-1 and fewer macrophages, dendritic cells, CD4+ and CD8+ T cell infiltrates and PCNA+ cells in lesions. The expression of proinflammatory cytokines, TNF-α, IL1-β and proinflammatory chemokine MCP-1 was also reduced. Body weight and plasma cholesterols were unaffected in BaffR.ApoE DKO mice. Our data indicate that B2 cells are important contributors to the development of atherosclerosis and that targeting the BAFF-R to specifically reduce atherogenic B2 cell numbers while preserving atheroprotective B1a cell numbers may be a potential therapeutic strategy to reduce atherosclerosis by potently reducing arterial inflammation.
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