Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity.
Membrane cholesterol modulates the fluid shear stress response of polymorphonuclear leukocytes via its effects on membrane fluidity.
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DOI：
10.1152/ajpcell.00458.2010
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发表时间：
2011-08
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影响因子：
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通讯作者：
Xiaoyan Zhang;Jonathan Hurng;D. Rateri;A. Daugherty;G. Schmid-Schönbein;H. Shin
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文献类型：
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作者：
Xiaoyan Zhang;Jonathan Hurng;D. Rateri;A. Daugherty;G. Schmid-Schönbein;H. Shin
持续暴露于循环血液动力学的多形核白细胞（PMNLs）指出，流体流动是其活性的生物物理调节器。具体来说，流体流动产生的剪切应力通过作用于细胞表面蛋白质的构象活性而使白细胞失活。由于膜性质影响膜结合蛋白的活性，我们假设细胞膜物理性质的变化会影响PMNL对流体剪切应力的敏感性。为此，我们对PMNL膜进行了修饰，结果表明，无论我们增加、减少或破坏脂质双分子层内胆固醇的组织，细胞对剪切的机械敏感性都会受到损害。值得注意的是，富含膜胆固醇的PMNLs对剪切表现出减弱的假足缩回反应，这种反应可以通过选定浓度的苯甲醇（一种膜流化器）恢复。事实上，PMNL对剪切的响应正相关(R(2) = 0.96；P < 0.0001)与胆固醇相关的膜流动性有关。此外，在喂食高脂肪饮食（高胆固醇血症模型）的低密度脂蛋白受体缺陷（LDLr(-/-)）小鼠中，PMNL剪切反应相关(R(2) = 0.5；P < 0.01)与血中未酯化（即游离）胆固醇浓度有关。在这方面，PMNLs的剪切反应逐渐减弱，并最终在高脂肪饮食的8周内随着血液中游离胆固醇水平的升高而逆转。总的来说，我们的结果提供了证据，证明胆固醇是PMNL机械转导能力的重要组成部分，膜胆固醇升高至少部分地通过其对膜流动性的影响损害PMNL剪切反应。这种与胆固醇相关的扰动可能导致与高胆固醇血症相关的PMNL活性失调（如慢性炎症），并导致心血管疾病（如动脉粥样硬化）。
Continuous exposure of polymorphonuclear leukocytes (PMNLs) to circulatory hemodynamics points to fluid flow as a biophysical regulator of their activity. Specifically, fluid flow-derived shear stresses deactivate leukocytes via actions on the conformational activities of proteins on the cell surface. Because membrane properties affect activities of membrane-bound proteins, we hypothesized that changes in the physical properties of cell membranes influence PMNL sensitivity to fluid shear stress. For this purpose, we modified PMNL membranes and showed that the cellular mechanosensitivity to shear was impaired whether we increased, reduced, or disrupted the organization of cholesterol within the lipid bilayer. Notably, PMNLs with enriched membrane cholesterol exhibited attenuated pseudopod retraction responses to shear that were recovered by select concentrations of benzyl alcohol (a membrane fluidizer). In fact, PMNL responses to shear positively correlated (R(2) = 0.96; P < 0.0001) with cholesterol-related membrane fluidity. Moreover, in low-density lipoprotein receptor-deficient (LDLr(-/-)) mice fed a high-fat diet (a hypercholesterolemia model), PMNL shear-responses correlated (R(2) = 0.5; P < 0.01) with blood concentrations of unesterified (i.e., free) cholesterol. In this regard, the shear-responses of PMNLs gradually diminished and eventually reversed as free cholesterol levels in blood increased during 8 wk of the high-fat diet. Collectively, our results provided evidence that cholesterol is an important component of the PMNL mechanotransducing capacity and elevated membrane cholesterol impairs PMNL shear-responses at least partially through its impact on membrane fluidity. This cholesterol-linked perturbation may contribute to dysregulated PMNL activity (e.g., chronic inflammation) related to hypercholesterolemia and causal for cardiovascular pathologies (e.g., atherosclerosis).