Calpain regulates neutrophil chemotaxis
Calpain regulates neutrophil chemotaxis
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DOI：
10.1073/pnas.0636533100
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发表时间：
2003-04-01
影响因子：
11.1
通讯作者：
Huttenlocher, A
中科院分区：
文献类型：
--
作者：
Lokuta, MA;Nuzzi, PA;Huttenlocher, A
定向细胞迁移需要细胞极化。我们研究了钙依赖性蛋白酶calpain在中性粒细胞趋化过程中的作用，发现在缺乏外源激活剂的情况下，calpain抑制可诱导中性粒细胞粘附、极化和快速趋化。静息中性粒细胞显示组成型钙蛋白酶活性，in-钙蛋白酶是主要的活性亚型。我们的研究结果表明，静止中性粒细胞中的组成性钙蛋白酶活性可能作为突起和迁移的负调节因子。特异性抑制mu-calpain，而非m-calpain，诱导中性粒细胞极化和趋化运动。与il -8诱导的趋化运动相反，百日咳毒素存在时，抑制calpain诱导的趋化运动不减少，这表明calpain在G蛋白偶联受体下游起作用。此外，钙蛋白酶抑制和IL-8和甲酰基met - leu - phe （fMLP）的刺激均诱导Cdc42和Rac活化的增加。这些发现与钙蛋白酶参与趋化途径是一致的。因此，calpain抑制降低了中性粒细胞趋化性和IL-8和fMLP梯度的定向持久性。综上所述，这些数据揭示了calpain在中性粒细胞中的一种以前未被描述的功能，并表明calpain活性的局部调节可能调节g蛋白偶联受体下游的中性粒细胞趋化性。
Cell polarization is required for directed cell migration. We investigated the role of the calcium-dependent protease calpain during neutrophil chemotaxis and found that calpain inhibition induced neutrophil adhesion, polarization, and rapid chemokinesis in the absence of exogenous activators. Resting neutrophils display constitutive calpain activity with in-calpain being the predominant active isoform. Our findings suggest that constitutive calpain activity in resting neutrophils may function as a negative regulator of protrusion and migration. Specific inhibition of mu-calpain, but not m-calpain, induced neutrophil polarization and chemokinesis. In contrast to IL-8-induced chemokinesis, the chemokinesis induced by calpain inhibition was not reduced in the presence of pertussis toxin, suggesting that calpain functions downstream of G protein-coupled receptors. Further, both calpain inhibition and stimulation with IL-8 and formyl-Met-Leu-Phe (fMLP) induced an increase in Cdc42 and Rac activation. These findings are consistent with the involvement of calpain in chemotaxis pathways. Accordingly, calpain inhibition decreased neutrophil chemotaxis and directional persistence in a gradient of IL-8 and fMLP. Together, these data reveal a previously uncharacterized function for calpain in neutrophils and suggest that localized modulation of calpain activity may regulate neutrophil chemotaxis downstream of G-protein-coupled receptors.