NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis
NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis
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DOI：
10.4049/jimmunol.1700899
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Peters, Nathan C.
中科院分区：
文献类型：
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作者：
Carneiro, Matheus B. H.;Roma, Eric H.;Peters, Nathan C.
由NADPH吞噬细胞氧化酶亚型（NOX 2）产生的活性氧（ROS）对于许多感染中细胞内病原体的消除至关重要。尽管它们的重要性，ROS感染后的真核病原体利什曼原虫的作用尚未完全阐明。我们探讨了ROS在C57 BL/6小鼠皮内感染亚马逊利什曼原虫后的作用。尽管与野生型（WT）小鼠相比，寄生虫负荷相当，但由于缺乏gp 91亚基（gp 91（phox-/-））而导致NOX 2产生ROS缺陷的小鼠在感染后期具有显著更严重的病理学。gp 91（phox-/-）小鼠的病理学与CD 4（+）T细胞介导的免疫力的改变无关，但在皮肤感染部位的中性粒细胞积聚增加之前。感染与未感染中性粒细胞的离体分析显示，与WT小鼠相比，gp 91（phox-/-）小鼠在感染驱动的细胞凋亡方面存在缺陷。在早期和慢性时间点，gp 91（phox-/-）小鼠呈现出较高百分比的健康或坏死中性粒细胞，但较低百分比的凋亡中性粒细胞。在体外感染gp 91（phox-/-）与WT中性粒细胞也显示减少凋亡和CD 95的表达，但增加感染后10小时的细胞坏死。以H2 O2形式提供外源性ROS逆转了坏死表型，并恢复了感染的gp 91（phox-/-）中性粒细胞上的CD 95表达。虽然ROS的产生通常被视为促炎事件，我们的观察确定ROS在介导适当的中性粒细胞凋亡的重要性和慢性感染期间的炎症和病理中的凋亡的重要性。
Reactive oxygen species (ROS) produced by NADPH phagocyte oxidase isoform (NOX2) are critical for the elimination of intracellular pathogens in many infections. Despite their importance, the role of ROS following infection with the eukaryotic pathogen Leishmania has not been fully elucidated. We addressed the role of ROS in C57BL/6 mice following intradermal infection with Leishmania amazonensis. Despite equivalent parasite loads compared with wild-type (WT) mice, mice deficient in ROS production by NOX2 due to the absence of the gp91 subunit (gp91(phox-/-)) had significantly more severe pathology in the later stages of infection. Pathology in gp91(phox-/-) mice was not associated with alterations in CD4(+) T cell-mediated immunity but was preceded by enhanced neutrophil accumulation at the dermal infection site. Ex vivo analysis of infected versus uninfected neutrophils revealed a deficiency in infection-driven apoptosis in gp91(phox-/-) mice versus WT mice. gp91(phox-/-) mice presented with higher percentages of healthy or necrotic neutrophils but lower percentages of apoptotic neutrophils at early and chronic time points. In vitro infection of gp91(phox-/-) versus WT neutrophils also revealed reduced apoptosis and CD95 expression but increased necrosis in infected cells at 10 h postinfection. Provision of exogenous ROS in the form of H2O2 reversed the necrotic phenotype and restored CD95 expression on infected gp91(phox-/-) neutrophils. Although ROS production is typically viewed as a proinflammatory event, our observations identify the importance of ROS in mediating appropriate neutrophil apoptosis and the importance of apoptosis in inflammation and pathology during chronic infection.