Vimentin is an endogenous ligand for the pattern recognition receptor Dectin-1
Vimentin is an endogenous ligand for the pattern recognition receptor Dectin-1
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DOI：
10.1093/cvr/cvt117
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发表时间：
2013-08-01
影响因子：
10.8
通讯作者：
Cathcart, Martha K.
中科院分区：
文献类型：
--
作者：
Thiagarajan, Praveena S.;Yakubenko, Valentin P.;Cathcart, Martha K.
动脉粥样硬化是一种慢性炎症性疾病，胆固醇沉积在动脉壁内的单核细胞衍生的巨噬细胞（MDM）中，导致血管管腔受到撞击。在动脉粥样硬化病变中，MDM是NADPH氧化酶衍生的超氧阴离子（O-2）的主要来源，诱导低密度脂蛋白（LDL）氧化，导致氧化LDL的不受调节的摄取和泡沫细胞形成。我们最近发现酵母聚糖通过非Toll模式识别受体（PRR）Dectin-1有效激活单核细胞NADPH氧化酶。其他PRR结合内源性人配体，但尚未鉴定出Dectin-1的此类配体。我们的假设是？人：抗酵母聚糖抗体用于鉴定人动脉粥样硬化组织提取物中相似的交叉反应性表位。免疫印迹分析显示一致的抗体反应蛋白带的一维和二维凝胶电泳。通过质谱法在不同组织样品的免疫反应条带中鉴定波形蛋白。使用BIACORE观察波形蛋白与Dectin-1的直接结合。进一步的数据显示，波形蛋白诱导人单核细胞产生O-2。对人类动脉粥样硬化病变的分析显示，在坏死核心和活动性炎症区域的细胞外检测到波形蛋白。波形蛋白还与Dectin-1共定位于富含O-2的巨噬细胞区域，我们得出结论，波形蛋白是Dectin-1的内源性活化配体。它存在于动脉壁炎症和O-2产生的区域，表明波形蛋白激活Dectin-1，并有助于动脉粥样硬化中脂质的氧化和胆固醇的积累。
Atherosclerosis is a chronic inflammatory disorder of cholesterol deposition in monocyte-derived macrophages (MDM) within the arterial wall leading to impingement on the lumen of the vessel. In atherosclerotic lesions, MDM are the primary source of NADPH oxidase-derived superoxide anion (O-2) inducing low-density lipoprotein (LDL) oxidation leading to their unregulated uptake of oxidized LDL and foam cell formation. We recently discovered that zymosan potently activates monocyte NADPH oxidase via the non-toll pattern recognition receptor (PRR), Dectin-1. Other PRRs bind endogenous human ligands, yet no such ligands have been identied for Dectin-1. Our hypothesis was that in?ammation generates endogenous ligands for Dectin-1 that activate O-2 production and thereby contributes to atherogenesis.Human: anti-zymosan antibodies were used to identify similar, cross-reactive epitopes in human atherosclerotic tissue extracts. Immunoblot analysis revealed consistent antibody reactive protein bands on one- and two-dimensional gel electrophoreses. Vimentin was identified by mass spectrometry in the immunoreactive bands across different tissue samples. Direct binding of vimentin to Dectin-1 was observed using BIACORE. Further data revealed that vimentin induces O-2 production by human monocytes. Analysis of human atherosclerotic lesions revealed that vimentin was detected extracellularly in the necrotic core and in areas of active inflammation. Vimentin also co-localized with Dectin-1 in macrophage-rich regions where O-2 is produced.We conclude that vimentin is an endogenous, activating ligand for Dectin-1. Its presence in areas of artery wall inflammation and O-2 production suggests that vimentin activates Dectin-1 and contributes to the oxidation of lipids and cholesterol accumulation in atherosclerosis.