Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages.
Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages.
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DOI：
10.1091/mbc.e14-05-0967
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发表时间：
2014-11-01
影响因子：
3.3
通讯作者：
Grinstein S
中科院分区：
文献类型：
--
作者：
Canton J;Khezri R;Glogauer M;Grinstein S
吞噬体的pH值在M1和M2巨噬细胞中以截然相反的方式受到调节。M2吞噬体迅速且单调地酸化，而M1吞噬体因超氧化物歧化时消耗质子，随后HV1通道激活，会经历周期性的碱性振荡。
巨噬细胞通过呈现不同的功能表型来对环境刺激的变化作出反应，这种现象被称为巨噬细胞极化。我们制备了经典激活型（M1）和替代激活型（M2）极化的巨噬细胞——极化谱的两个极端——以比较它们吞噬体的特性。具体而言，我们分析了颗粒吞噬后腔内pH值的调节。与M2吞噬体相比，M1巨噬细胞的吞噬体具有相似的缓冲能力和质子（等效）渗漏通透性，但质子泵活性显著降低。结果，只有M2吞噬体经历了快速且显著的酸化。相比之下，M1吞噬体呈现碱性pH振荡，这是由超氧化物歧化时消耗质子，随后激活一种对电压和Zn²⁺敏感的渗透途径（可能是HV1通道）所导致的。M1吞噬体中V - ATP酶的缺乏与晚期内体和溶酶体融合延迟相关，并且很可能是由其导致的。反过来，成熟动力学的延迟是由M1吞噬体未能酸化所促进的。因此，在M1细胞中，以延迟酸化为代价优先通过部署杀菌性NADPH氧化酶来消除病原体。相比之下，M2吞噬体立即酸化，以便快速有效地清除凋亡小体。
Phagosomal pH is regulated in diametrically opposed ways in M1 and M2 macrophages. M2 phagosomes acidify rapidly and monotonically, whereas M1 phagosomes undergo cyclic alkaline oscillations caused by proton consumption upon dismutation of superoxide, followed by activation of HV1 channels. Macrophages respond to changes in environmental stimuli by assuming distinct functional phenotypes, a phenomenon referred to as macrophage polarization. We generated classically (M1) and alternatively (M2) polarized macrophages—two extremes of the polarization spectrum—to compare the properties of their phagosomes. Specifically, we analyzed the regulation of the luminal pH after particle engulfment. The phagosomes of M1 macrophages had a similar buffering power and proton (equivalent) leakage permeability but significantly reduced proton-pumping activity compared with M2 phagosomes. As a result, only the latter underwent a rapid and profound acidification. By contrast, M1 phagosomes displayed alkaline pH oscillations, which were caused by proton consumption upon dismutation of superoxide, followed by activation of a voltage- and Zn2+-sensitive permeation pathway, likely HV1 channels. The paucity of V-ATPases in M1 phagosomes was associated with, and likely caused by, delayed fusion with late endosomes and lysosomes. The delayed kinetics of maturation was, in turn, promoted by the failure of M1 phagosomes to acidify. Thus, in M1 cells, elimination of pathogens through deployment of the microbicidal NADPH oxidase is given priority at the expense of delayed acidification. By contrast, M2 phagosomes proceed to acidify immediately in order to clear apoptotic bodies rapidly and effectively.