A Role for the High-Density Lipoprotein Receptor SR-B1 in Synovial Inflammation via Serum Amyloid-A
A Role for the High-Density Lipoprotein Receptor SR-B1 in Synovial Inflammation via Serum Amyloid-A
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DOI：
10.2353/ajpath.2010.090014
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发表时间：
2010-04-01
影响因子：
6
通讯作者：
Fearon, Ursula
中科院分区：
文献类型：
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作者：
Mullan, Ronan Hugh;McCormick, Jennifer;Fearon, Ursula
急性期载脂蛋白血清淀粉样蛋白A （A- saa）在类风湿关节炎滑膜（RA SM）中强烈表达，通过g偶联受体FPRL-1诱导血管生成、粘附分子表达和基质金属蛋白酶的产生。在这里，我们报告了高密度脂蛋白受体清道夫受体B类1 （SR-B1）的替代信号传导。采用Western blotting和免疫组织学/荧光技术定量评价SR-B1在RA SM、RA成纤维细胞样细胞（FLCs）和微血管内皮细胞（ECs）中的表达/定位。在RA FLCs和ec中，使用针对SR-B1或两亲性a-螺旋肽（SR-B1拮抗剂L-37pA和D-37pA）的特异性抗体检测a- saa介导的效应。采用流式细胞术和酶联免疫吸附法定量检测粘附分子表达和细胞因子的产生。与骨关节炎SM或正常对照滑膜相比，SR-B1在RA SM内膜层和内皮/血管周围区域强烈表达。RA FLC系（n = 5）和ECs中SR-B1的差异表达与A-SAA密切相关，但与肿瘤坏死因子a诱导的细胞间粘附分子-1上调无关。在抗sr - b1存在的情况下，a - saa诱导的白细胞介素-6和-8的产生在人微血管内皮细胞和RA FLCs中被抑制。此外，D-37pA和L-37pA抑制a - saa诱导的血管细胞粘附分子-1和细胞间粘附分子的表达呈剂量依赖性。由于SR-B1在RA滑膜组织中表达并介导a - saa诱导的促炎途径，因此更好地了解a - saa介导的炎症途径可能会带来新的RA治疗策略。（美国病理学杂志，2010,176:1999-2008;DOI: 10.2353/ajpath.2010.090014）
Acute phase apoprotein Serum Amyloid A (A-SAA), which is strongly expressed in rheumatoid arthritis synovial membrane (RA SM), induces angiogenesis, adhesion molecule expression, and matrix metalloproteinase production through the G-coupled receptor FPRL-1. Here we report alternative signaling through the high-density lipoprotein receptor scavenger receptor-class B type 1 (SR-B1). Quantitative expression/localization of SR-B1 in RA SM, RA fibroblast-like cells (FLCs), and microvascular endothelial cells (ECs) was assessed by Western blotting and immunohistology/fluorescence. A-SAA-mediated effects were examined using a specific antibody against SR-B1 or amphipathic a-Helical Peptides (the SR-B1 antagonists L-37pA and D-37pA), in RA FLCs and ECs. Adhesion molecule expression and cytokine production were quantified using flow cytometry and ELISA. SR-B1 was strongly expressed in the RA SM lining Layer and endothelial/perivascular regions compared with osteoarthritis SM or normal control synovium. Differential SR-B1 expression in RA FLC lines (n = 5) and ECs correlated closely with A-SAA, but not tumor necrosis factor a-induced intercellular adhesion molecule-1 upregulation. A-SAA-induced interleukin-6 and -8 production was inhibited in the presence of anti-SR-B1 in human microvascular endothelial cells and RA FLCs. Moreover, D-37pA and L-37pA inhibited A-SAA-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule expression from ECs in a dose-dependent manner. As SR-B1 is expressed in RA synovial tissue and mediates A-SAA-induced pro-inflammatory pathways, a better understanding of A-SAA-mediated inflammatory pathways may lead to novel treatment strategies for RA. (Am J Pathol 2010, 176:1999-2008; DOI: 10.2353/ajpath.2010.090014)