Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, China.
Immunity. 2010 Sep 24;33(3):340-50. doi: 10.1016/j.immuni.2010.08.015.
Neutrophils are important in innate immunity and acute inflammatory responses. However, the regulation of their recruitment to sites of inflammation has not been well characterized. Here, we investigated the kinase PIP5K1C and showed that PIP5K1C deficiency impaired neutrophil recruitment because of an adhesion defect. PIP5K1C regulated the adhesion through facilitating RhoA GTPase and integrin activation by chemoattractants. Integrins could induce polarization of an isoform of PIP5K1C, PIP5K1C-90, in neutrophils through intracellular vesicle transport independently of exogenous chemoattractant. PIP5K1C-90 polarization was required for polarized RhoA activation at uropods and provided an initial directional cue for neutrophil polarization on the endothelium. Importantly, the polarization was also required for circumventing the inhibition of lamellipodium formation by RhoA so that neutrophils could form leading edges required for transendothelial migration. Because integrins are not known to regulate neutrophil polarization, our study revealed a previously underappreciated role of integrin signaling in neutrophil regulation.
中性粒细胞在先天免疫和急性炎症反应中起重要作用。然而，其向炎症部位募集的调节机制尚未得到很好的描述。在这里，我们研究了激酶 PIP5K1C，并表明 PIP5K1C 缺陷由于黏附缺陷而损害中性粒细胞募集。PIP5K1C 通过促进趋化因子诱导的 RhoA GTP 酶和整合素激活来调节黏附。整合素可以通过细胞内囊泡运输，独立于外源性趋化因子，诱导中性粒细胞中一种同工型 PIP5K1C（PIP5K1C-90）的极化。PIP5K1C-90 的极化对于足突处极化的 RhoA 激活是必需的，为中性粒细胞在血管内皮上的极化提供了初始的定向线索。重要的是，极化对于绕过 RhoA 抑制片状伪足形成也是必需的，以便中性粒细胞能够形成穿过内皮迁移所需的前缘。因为整合素不被认为调节中性粒细胞的极化，所以我们的研究揭示了整合素信号在中性粒细胞调节中的一个以前未被充分认识的作用。
