Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus.
Mitochondrial Reactive Oxygen Species Regulate Immune Responses of Macrophages to Aspergillus fumigatus.
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DOI：
10.3389/fimmu.2021.641495
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发表时间：
2021
影响因子：
7.3
通讯作者：
Shekhova E
中科院分区：
文献类型：
--
作者：
Hatinguais R;Pradhan A;Brown GD;Brown AJP;Warris A;Shekhova E
活性氧簇(ROS)是一种高活性的分子，可诱导氧化应激。例如，免疫细胞的氧化爆发是众所周知的，它能够抑制入侵病原体的生长。然而，ROS也介导氧化还原信号，这对抗菌免疫的调节是重要的。在这里，我们报告了线粒体ROS(MitoROS)在巨噬细胞抗真菌反应中的关键作用。我们发现，暴露于真菌病原体烟曲霉膨胀分生孢子的小鼠巨噬细胞，与未处理的巨噬细胞或经静息分生孢子处理的巨噬细胞相比，mitoROS的产生增加。此外，巨噬细胞暴露在膨胀的分生孢子中会增加呼吸链复合体II的活性，并提高线粒体膜电位。感染巨噬细胞线粒体的这些变化表明，mitoROS是通过反向电子传输(RET)产生的。值得注意的是，用鱼藤酮或IQ位点电子泄漏的抑制剂S1QEL1.1来阻止RET产生有丝分裂原，可以降低暴露于烟曲霉膨胀分生孢子的巨噬细胞中促炎细胞因子肿瘤坏死因子-α和白介素1-β的产生。鱼藤酮和S1QEL1.1也降低了巨噬细胞对肿胀分生孢子的杀菌活性。此外，我们已经证实，NADPH氧化酶2(NOX2，也称为gp91Phox)在吞噬体膜上的募集增加发生在mitoROS生成增加之前。利用gp91Phox-/-小鼠的巨噬细胞，我们进一步证明了NOX2需要通过RET相关的mitoRos来调节细胞因子的分泌，以应对感染膨胀的分生孢子。综上所述，这些观察结果表明，在感染烟曲霉菌的巨噬细胞中，RET介导的mitoROS产生的重要性。
Reactive Oxygen Species (ROS) are highly reactive molecules that can induce oxidative stress. For instance, the oxidative burst of immune cells is well known for its ability to inhibit the growth of invading pathogens. However, ROS also mediate redox signalling, which is important for the regulation of antimicrobial immunity. Here, we report a crucial role of mitochondrial ROS (mitoROS) in antifungal responses of macrophages. We show that mitoROS production rises in murine macrophages exposed to swollen conidia of the fungal pathogen Aspergillus fumigatus compared to untreated macrophages, or those treated with resting conidia. Furthermore, the exposure of macrophages to swollen conidia increases the activity of complex II of the respiratory chain and raises mitochondrial membrane potential. These alterations in mitochondria of infected macrophages suggest that mitoROS are produced via reverse electron transport (RET). Significantly, preventing mitoROS generation via RET by treatment with rotenone, or a suppressor of site IQ electron leak, S1QEL1.1, lowers the production of pro-inflammatory cytokines TNF-α and IL-1β in macrophages exposed to swollen conidia of A. fumigatus. Rotenone and S1QEL1.1 also reduces the fungicidal activity of macrophages against swollen conidia. Moreover, we have established that elevated recruitment of NADPH oxidase 2 (NOX2, also called gp91phox) to the phagosomal membrane occurs prior to the increase in mitoROS generation. Using macrophages from gp91phox-/- mice, we have further demonstrated that NOX2 is required to regulate cytokine secretion by RET-associated mitoROS in response to infection with swollen conidia. Taken together, these observations demonstrate the importance of RET-mediated mitoROS production in macrophages infected with A. fumigatus.
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DOI：
10.4049/jimmunol.1300748
发表时间：
2013-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Carrion Sde J;Leal SM Jr;Ghannoum MA;Aimanianda V;Latgé JP;Pearlman E
通讯作者：
Pearlman E
影响因子：
7.4
作者：
Dikalov, Sergey
通讯作者：
Dikalov, Sergey
影响因子：
4.8
作者：
Godon, C;Lagniel, G;Labarre, J
通讯作者：
Labarre, J
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
30.3
作者：
Akoumianaki, Tonia;Kyrmizi, Irene;Chamilos, Georgios
通讯作者：
Chamilos, Georgios