Shear-Induced Resistance to Neutrophil Activation via the Formyl Peptide Receptor
Shear-Induced Resistance to Neutrophil Activation via the Formyl Peptide Receptor
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DOI：
10.1016/j.bpj.2012.03.053
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发表时间：
2012-04-18
影响因子：
3.4
通讯作者：
King, Michael R.
中科院分区：
文献类型：
--
作者：
Mitchell, Michael J.;King, Michael R.
液体剪切应力对白细胞的生理功能至关重要，包括与内皮细胞的初始粘附、假足的形成和向组织的迁移。中性粒细胞上的甲酰基肽受体（FPR）与甲酰基-甲硫基-酰基-苯丙氨酸（fMLP）结合，在中性粒细胞趋化性中起作用，被认为是控制假足形成的流体剪切应力传感器。剪切力对中性粒细胞激活的早期指标(如l -选择素脱落和α （M) β(2)整合素激活）的作用尚不清楚。在这里，在锥板粘度计中暴露于均匀剪切应力（0.1-4.0 dyn/cm(2)） 1-120分钟的人中性粒细胞在0.5 nM fMLP刺激后，α (M) β(2)整合素激活和l -选择素脱落均显著减少。中性粒细胞对活化的抵抗与流体剪切应力直接相关，因为响应以剪切应力和时间依赖的方式增加。在中性粒细胞上观察到明显的剪切诱导的FPR表面表达丧失，高分辨率共聚焦显微镜显示FPR内化在中性粒细胞内。这些结果表明，在可溶性配体存在的情况下，生理剪切力通过减少l -选择素脱落和α (M) β(2)整合素激活，通过FPR改变中性粒细胞活化。
The application of fluid shear stress on leukocytes is critical for physiological functions including initial adhesion to the endothelium, the formation of pseudopods, and migration into tissues. The formyl peptide receptor (FPR) on neutrophils, which binds to formyl-methionyl-leucyl-phenylalanine (fMLP) and plays a role in neutrophil chemotaxis, has been implicated as a fluid shear stress sensor that controls pseudopod formation. The role of shear forces on earlier indicators of neutrophil activation, such as L-selectin shedding and alpha(M)beta(2) integrin activation, remains unclear. Here, human neutrophils exposed to uniform shear stress (0.1-4.0 dyn/cm(2)) in a cone-and-plate viscometer for 1-120 min showed a significant reduction in both alpha(M)beta(2) integrin activation and L-selectin shedding after stimulation with 0.5 nM of fMLP. Neutrophil resistance to activation was directly linked to fluid shear stress, as the response increased in a shear stress force-and time-dependent manner. Significant shear-induced loss of FPR surface expression on neutrophils was observed, and high-resolution confocal microscopy revealed FPR internalized within neutrophils. These results suggest that physiological shear forces alter neutrophil activation via FPR by reducing L-selectin shedding and alpha(M)beta(2) integrin activation in the presence of soluble ligand.