Nunes Paula, Demaurex Nicolas, Dinauer Mary C
Department of Cell Physiology and Metabolism, University of Geneva, 1 rue Michel-Servet, CH-1211, Geneva 4, Switzerland.
Traffic. 2013 Nov;14(11):1118-31. doi: 10.1111/tra.12115. Epub 2013 Sep 16.
The production of reactive oxygen species (ROS) within immune cell phagosomes is critical for antimicrobial activity and for correct antigen processing, and influences signaling pathways that direct host responses to infection and inflammation. Because excess oxidants can cause tissue damage and oxidative stress, phagocytes must precisely control both the location and timing of NADPH oxidase activity. How differential regulation is achieved at phagosomes is not well understood. Recent studies have revealed that the PI(3)P phosphoinositide plays an important role in locally boosting phagosomal NADPH oxidase activity through its binding to the p40(phox) NADPH oxidase subunit. Furthermore, phox subunit dynamics at phagosomes may regulate the timing of the oxidative burst. Novel elements regulating catalytic core trafficking include Rab27 and SNAP-23. In addition to trafficking events, the activity of the electrogenic oxidase is also governed by ionic fluxes, which are constrained at phagosomes owing to low intraphagosomal volume and dynamic display of channels, transporters, and pumps. New insights on the interdependence of phagosomal pH and ROS have been recently elucidated, and chloride channels important for microbicidal functions, including CFTR, and CLIC family channels, have been identified. Finally, periphagosomal calcium microdomains and calcium-dependent S100A8/9 protein recruitment may help fine-tune spatiotemporal regulation of NADPH oxidase activation for an effective immune response.
免疫细胞吞噬体内活性氧（ROS）的产生对于抗菌活性和正确的抗原加工至关重要，并影响指导宿主对感染和炎症反应的信号通路。由于过量的氧化剂会导致组织损伤和氧化应激，吞噬细胞必须精确控制NADPH氧化酶活性的位置和时间。吞噬体如何实现差异调节尚不清楚。最近的研究表明，PI(3)P磷酸肌醇通过与p40(phox)NADPH氧化酶亚基结合，在局部增强吞噬体NADPH氧化酶活性方面发挥重要作用。此外，吞噬体上phox亚基的动态变化可能调节氧化爆发的时间。调节催化核心运输的新元件包括Rab27和SNAP-23。除了运输事件外，电生氧化酶的活性还受离子通量的控制，由于吞噬体内体积小以及通道、转运体和泵的动态展示，离子通量在吞噬体处受到限制。最近已经阐明了吞噬体pH值和ROS相互依赖关系的新见解，并且已经鉴定出对杀菌功能重要的氯离子通道，包括CFTR和CLIC家族通道。最后，吞噬体周围钙微区和钙依赖性S100A8/9蛋白募集可能有助于微调NADPH氧化酶激活的时空调节，以实现有效的免疫反应。
