Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production.
Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production.
复制标题
Hv1/VSOP 通过调节 ROS 产生来调节中性粒细胞定向迁移和 ERK 活性。
DOI：
10.1002/jlb.2a0320-110rr
复制
发表时间：
2020
影响因子：
5.5
通讯作者：
Okamura Y.
中科院分区：
文献类型：
--
作者：
Okochi Y;Umemoto E;Okamura Y.
中性粒细胞中高水平活性氧 (ROS) 的产生受到严格调节，因为它会损害宿主细胞。当受到细胞因子或化学引诱剂刺激时，中性粒细胞也会产生低水平的ROS，但其生物学意义仍然很大程度上未知。据报道，电压门控质子通道 (Hv1/VSOP) 活性支持中性粒细胞中 ROS 的产生；然而，我们在此表明，在低浓度的 N-甲酰基-Met-Leu-Phe (fMLF) 存在下，Hv1/VSOP 可以平衡 ROS 的产生，从而抑制中性粒细胞的定向迁移。在 1 µM 浓度的 fMLF 刺激和无刺激条件下，来自 Hvcn1 基因敲除小鼠的中性粒细胞比来自野生型小鼠的中性粒细胞产生更多的 ROS。与野生型中性粒细胞相比，它们对低浓度的 fMLF 也表现出更强的趋化反应。 Hv1/VSOP 缺陷型和野生型中性粒细胞之间对 fMLF 的受体敏感性和诱发的 Ca2+ 反应没有差异。在 Hv1/VSOP 缺陷的中性粒细胞中，fMLF 刺激后，ROS 产生增加，ERK 的激活增强并延长，但 p38 的激活没有增强和延长。抑制 ROS 产生可抑制 Hv1/VSOP 缺陷的中性粒细胞中增强的 ERK 激活及其定向迁移。这些结果表明，Hv1/VSOP 平衡 ROS 产生，以减少 ERK 信号传导并抑制响应 fMLF 的过度中性粒细胞迁移。因此，我们的研究结果揭示了 ROS 在中性粒细胞定向迁移中的新作用。
High-level reactive oxygen species (ROS) production in neutrophils is tightly regulated, as it can damage host cells. Neutrophils also undergo low-level ROS production when stimulated by cytokines or chemoattractants, but its biologic significance remains largely unknown. Voltage-gated proton channels (Hv1/VSOP) activity reportedly supports ROS production in neutrophils; however, we show here that Hv1/VSOP balances ROS production to suppress neutrophil directional migration in the presence of low concentrations of N-formyl-Met-Leu-Phe (fMLF). Neutrophils derived fromHvcn1gene knockout mice produced more ROS than neutrophils from wild-type mice in the stimulation with fMLF at concentration of 1 µM and nonstimulus condition. They also exhibited stronger chemotactic responses to low concentrations of fMLF than did wild-type neutrophils. Receptor sensitivity to fMLF and evoked Ca2+responses did not differ between Hv1/VSOP-deficient and wild-type neutrophils. Activation of ERK, but not p38, was enhanced and prolonged during the increased ROS production seen after fMLF stimulation in Hv1/VSOP-deficient neutrophils. Inhibiting ROS production suppressed the enhanced ERK activation in Hv1/VSOP-deficient neutrophils and their directional migration. These results indicate that Hv1/VSOP balances ROS production to reduce ERK signaling and suppress excessive neutrophil migration in response to fMLF. Our findings thus reveal a novel role for ROS in the directional migration of neutrophils.