Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening
Recombinant Human Soluble Thrombomodulin Suppresses Monocyte Adhesion by Reducing Lipopolysaccharide-Induced Endothelial Cellular Stiffening
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DOI：
10.3390/cells9081811
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发表时间：
2020-07
期刊：
影响因子：
6
通讯作者：
Takayuki Okamoto;E. Kawamoto;Haruki Usuda;Tetsuya Tanaka;T. Nikai;K. Asanuma;Koji Suzuki;M. Shimaoka;K. Wada
中科院分区：
文献类型：
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作者：
Takayuki Okamoto;E. Kawamoto;Haruki Usuda;Tetsuya Tanaka;T. Nikai;K. Asanuma;Koji Suzuki;M. Shimaoka;K. Wada
不仅在发炎的培养的内皮细胞中，而且在动脉粥样硬化区域的内皮中观察到内皮细胞硬化，这是单核细胞粘附和积聚的潜在原因。虽然重组可溶性血栓调节蛋白（rsTM）已被报道抑制内皮细胞的炎症反应，其在调节内皮细胞硬度的作用仍不清楚。本研究的目的是研究抗凝剂rsTM对脂多糖（LPS）诱导的内皮细胞硬化的影响。我们发现，LPS增加内皮细胞刚度通过使用原子力显微镜和rsTM降低LPS诱导的细胞硬化不仅通过衰减肌动蛋白纤维和粘着斑的形成，但也通过间隙连接功能的改善。此外，rsTM给药后，LPS刺激后，衰减LPS诱导的细胞硬化。我们还发现，内皮细胞调节白细胞粘附在基板和细胞的刚度依赖性的方式。我们的研究结果表明，LPS诱导的细胞硬化增强单核细胞THP-1细胞系的粘附，而rsTM抑制THP-1细胞粘附发炎的内皮细胞通过降低细胞硬度。内皮细胞在对炎症的反应中增加细胞硬度，从而促进单核细胞粘附。rsTM的治疗减少LPS诱导的细胞硬化和抑制单核细胞粘附在细胞硬度依赖性的方式。
Endothelial cellular stiffening has been observed not only in inflamed cultured endothelial cells but also in the endothelium of atherosclerotic regions, which is an underlying cause of monocyte adhesion and accumulation. Although recombinant soluble thrombomodulin (rsTM) has been reported to suppress the inflammatory response of endothelial cells, its role in regulating endothelial cellular stiffness remains unclear. The purpose of this study was to investigate the impact of anticoagulant rsTM on lipopolysaccharide (LPS)-induced endothelial cellular stiffening. We show that LPS increases endothelial cellular stiffness by using atomic force microscopy and that rsTM reduces LPS-induced cellular stiffening not only through the attenuation of actin fiber and focal adhesion formation but also via the improvement of gap junction functionality. Moreover, post-administration of rsTM, after LPS stimulation, attenuated LPS-induced cellular stiffening. We also found that endothelial cells regulate leukocyte adhesion in a substrate- and cellular stiffness-dependent manner. Our result show that LPS-induced cellular stiffening enhances monocytic THP-1 cell line adhesion, whereas rsTM suppresses THP-1 cell adhesion to inflamed endothelial cells by reducing cellular stiffness. Endothelial cells increase cellular stiffness in reaction to inflammation, thereby promoting monocyte adhesion. Treatment of rsTM reduced LPS-induced cellular stiffening and suppressed monocyte adhesion in a cellular stiffness-dependent manner.