Inflammatory monocytes orchestrate innate antifungal immunity in the lung.
Inflammatory monocytes orchestrate innate antifungal immunity in the lung.
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DOI：
10.1371/journal.ppat.1003940
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Rivera A
中科院分区：
文献类型：
--
作者：
Espinosa V;Jhingran A;Dutta O;Kasahara S;Donnelly R;Du P;Rosenfeld J;Leiner I;Chen CC;Ron Y;Hohl TM;Rivera A
烟曲霉是一种环境真菌，可引起免疫功能低下患者的侵袭性曲霉病（IA）。虽然β-CC-趋化因子受体-2（CCR 2）和Ly 6C-表达炎性单核细胞（CCR 2 +Mo）及其衍生物启动适应性肺免疫应答，但它们在协调肺先天免疫应答中的作用仍不清楚。使用条件性和抗体介导的细胞消融策略，我们发现CCR 2 +Mo和单核细胞衍生的树突状细胞（Mo-DCs）对于对抗吸入分生孢子的先天防御是必需的。通过利用荧光曲霉报告（FLARE）分生孢子，报告真菌细胞的协会和活力在体内，我们确定了两种机制，CCR 2 +Mo和Mo-DCs发挥先天抗真菌活性。首先，CCR 2 +Mo和Mo-DC调节肺部炎症环境以增加嗜中性粒细胞杀分生孢子活性。第二，CCR 2 +Mo的分生孢子吸收时间上与它们分化成Mo-DC一致，这是导致直接分生孢子杀伤的过程。我们的研究结果说明了CCR 2 +Mo及其衍生物在肺部先天抗真菌免疫中的间接和直接功能。尽管真菌感染对人类健康有重大影响，但我们对这些病原体的免疫力的理解仍然不完整。人类真菌病与高发病率和死亡率相关，即使使用现代抗真菌治疗。烟曲霉是侵袭性曲霉病（IA）最常见的病原体，IA是一种严重的感染，发生在免疫缺陷患者中。在这项研究中，我们采用细胞消融策略的组合来检查CCR 2 + Ly 6C+炎性单核细胞（CCR 2 +Mo）在对抗烟曲霉分生孢子肺部感染的先天性应答中的作用。我们发现，CCR 2+钼和它们的衍生物树突状细胞（Mo-DCs）是防御IA所需的，缺乏这些细胞的小鼠死于烟曲霉感染。我们的研究表明，CCR 2 +Mo和Mo-DCs通过两种主要机制发挥关键的先天抗真菌防御作用：1）CCR 2 +Mo和Mo-DCs是增加中性粒细胞杀伤能力的炎症介质的重要来源，2）CCR 2 +Mo的分生孢子摄取与它们分化为Mo-DCs一致，Mo-DCs通过部分NADPH氧化酶依赖性机制直接杀死真菌分生孢子。总的来说，我们的研究发现了一种新的基本功能，CCR 2+钼在先天防御肺真菌病原体介导的间接和直接遏制真菌细胞在感染的门户。
Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2+Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2+Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2+Mo and Mo-DCs exert innate antifungal activity. First, CCR2+Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2+Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2+Mo and their derivatives in innate antifungal immunity in the lung. Despite the significant impact of fungal infections to human health our understanding of immunity to these pathogens remains incomplete. Human mycoses are associated with high morbidity and mortality, even with modern antifungal therapies. Aspergillus fumigatus is the most common etiologic agent of invasive aspergillosis (IA), a serious infection that develops in immunodeficient patients. In this study we employ a combination of cell ablation strategies to examine the role of CCR2+Ly6C+ inflammatory monocytes (CCR2+Mo) in innate responses against a pulmonary infection with A.fumigatus conidia. We find that CCR2+Mo and their derivative dendritic cells (Mo-DCs) are required for defense against IA and that mice lacking these cells succumb to infection with A.fumigatus. Our studies indicate that CCR2+Mo and Mo-DCs exert crucial innate antifungal defense by two main mechanisms: 1) CCR2+Mo and Mo-DCs are a significant source of inflammatory mediators that augment the killing capacity of neutrophils and 2) conidial uptake by CCR2+Mo is coincident with their differentiation into Mo-DCs that directly kill fungal conidia via partially NADPH oxidase-dependent mechanisms. In aggregate, our studies find a novel essential function for CCR2+Mo in innate defense against a pulmonary fungal pathogen by mediating indirect and direct containment of fungal cells at the portal of infection.
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DOI：
10.1086/591969
发表时间：
2008-10-15
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Garcia-Vidal C;Upton A;Kirby KA;Marr KA
通讯作者：
Marr KA
影响因子：
30.3
作者：
Ersland K;Wüthrich M;Klein BS
通讯作者：
Klein BS
影响因子：
30.3
作者：
Hohl TM;Rivera A;Lipuma L;Gallegos A;Shi C;Mack M;Pamer EG
通讯作者：
Pamer EG
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.1
作者：
Cortez, KJ;Lyman, CA;Walsh, TJ
通讯作者：
Walsh, TJ