Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways
Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase/Akt and ERK pathways
复制标题
DOI：
10.4049/jimmunol.176.2.1163
复制
发表时间：
2006-01-15
影响因子：
4.4
通讯作者：
Geffner, J
中科院分区：
文献类型：
--
作者：
Martínez, D;Vermeulen, M;Geffner, J
外周组织的炎症通常与局部酸中毒的发生有关;然而，很少有研究旨在分析酸中毒对免疫细胞的影响。我们以前已经表明，细胞外酸中毒触发人中性粒细胞活化，诱导细胞内Ca 2+浓度的瞬时增加，形状变化的反应，上调CD 18的表达，和细胞凋亡的延迟。在这项研究中，我们分析了负责中性粒细胞活化的信号通路。我们发现，酸中毒触发Akt（PI 3 K的主要下游靶标）和ERK MAPK的磷酸化，但不触发p38和JNK MAPK的磷酸化。未观察到I κ B降解，支持NF-κ B在酸中毒下不活化的假设。Wortmannin或LY 294002抑制PI 3 K可显著降低酸中毒引起的形态改变反应和Ca 2+瞬变的诱导，而PD 98059或U 0126抑制MEK可显著抑制形态改变反应而不影响Ca 2+瞬变的诱导。我们还发现，酸中毒不仅诱导形状变化反应和诱导人中性粒细胞中的Ca 2+瞬变，而且还刺激FITC-OVA和FITC-葡聚糖的内吞作用。PI 3 K和MEK抑制剂可部分阻止内吞作用的刺激。总之，我们的研究结果支持这样的观点，即细胞外酸中毒对人中性粒细胞的刺激依赖于PI 3 K/Akt和ERK通路的激活。值得注意的是，使用小鼠腹膜嗜中性粒细胞，我们观察到酸中毒诱导的内吞作用的增强与通过MHC I类限制性途径呈递细胞外Ag的能力提高有关。
Inflammation in peripheral tissues is usually associated with the development of local acidosis; however, there are few studies aimed at analyzing the influence of acidosis on immune cells. We have shown previously that extracellular acidosis triggers human neutrophil activation, inducing a transient increase in intracellular Ca2+ concentration, a shape change response, the up-regulation of CD18 expression, and a delay of apoptosis. In this study, we analyzed the signaling pathways responsible for neutrophil activation. We found that acidosis triggers the phosphorylation of Akt (the main downstream target of PI3K) and ERK MAPK, but not that of p38 and JNK MAPK. No degradation of I kappa B was observed, supporting the hypothesis that NF-kappa B is not activated under acidosis. Inhibition of PI3K by wortmannin or LY294002 markedly decreased the shape change response and the induction of Ca2+ transients triggered by acidosis, whereas the inhibition of MEK by PD98059 or U0126 significantly inhibited the shape change response without affecting the induction of Ca2+ transients. We also found that acidosis not only induces a shape change response and the induction of Ca2+ transients in human neutrophils but also stimulates the endocytosis of FITC-OVA and FITC-dextran. Stimulation of endocytosis was partially prevented by inhibitors of PI3K and MEK. Together, our results support the notion that the stimulation of human neutrophils by extracellular acidosis is dependent on the activation of PI3K/Akt and ERK pathways. Of note, using mouse peritoneal neutrophils we observed that the enhancement of endocytosis induced by acidosis was associated with an improved ability to present extracellular Ags through a MHC class I-restricted pathway.