Defective immunometabolism pathways in cystic fibrosis macrophages.
Defective immunometabolism pathways in cystic fibrosis macrophages.
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DOI：
10.1016/j.jcf.2020.10.006
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Amer AO
中科院分区：
文献类型：
--
作者：
Hamilton K;Krause K;Badr A;Daily K;Estfanous S;Eltobgy M;Khweek AA;Anne MNK;Carafice C;Baetzhold D;Tonniges JR;Zhang X;Gavrilin MA;Parinandi NL;Amer AO
线粒体在免疫防御途径中发挥关键作用，特别是巨噬细胞。我们和其他人之前已经证明囊性纤维化（CF）巨噬细胞表现出较弱的自噬活性和加重的炎症反应。既往研究发现CF上皮细胞线粒体存在缺陷，但迄今为止，线粒体功能缺陷与CF巨噬细胞免疫失调之间的关系尚未完全阐明。在这里，我们提出了CF巨噬细胞线粒体功能障碍的表征。采用海马细胞外通量分析仪测定野生型（WT）和CF型F508del/F508del小鼠巨噬细胞的线粒体功能。透射电子和共聚焦显微镜观察线粒体形态。采用TMRM和MitoSOX Red荧光染料分别测定线粒体膜电位（MMP）和线粒体活性氧（mROS）。所有的检测都是在基线和感染结核杆菌后进行的，结核杆菌是一种在CF患者中引起有害感染的多重耐药细菌。我们已经确定了CF巨噬细胞的耗氧量受损，没有和有结核杆菌感染。我们还观察到CF巨噬细胞在感染后线粒体断裂增加。最后，我们观察到CF巨噬细胞中MMP增加和mROS产生受损。鉴定的线粒体缺陷是巨噬细胞对感染反应的关键组成部分。它们的存在表明线粒体功能障碍导致CF巨噬细胞中细菌杀伤功能受损。我们目前的研究将增强我们对CF的病理生物学的理解，并导致CF的新的线粒体治疗靶点的鉴定。
Mitochondria play a key role in immune defense pathways, particularly for macrophages. We and others have previously demonstrated that cystic fibrosis (CF) macrophages exhibit weak autophagy activity and exacerbated inflammatory responses. Previous studies have revealed that mitochondria are defective in CF epithelial cells, but to date, the connection between defective mitochondrial function and CF macrophage immune dysregulation has not been fully elucidated. Here, we present a characterization of mitochondrial dysfunction in CF macrophages. Mitochondrial function in wild-type (WT) and CF F508del/F508del murine macrophages was measured using the Seahorse Extracellular Flux analyzer. Mitochondrial morphology was investigated using transmission electron and confocal microscopy. Mitochondrial membrane potential (MMP) as well as mitochondrial reactive oxygen species (mROS) were measured using TMRM and MitoSOX Red fluorescent dyes, respectively. All assays were performed at baseline and following infection by Burkholderia cenocepacia, a multi-drug resistant bacterium that causes detrimental infections in CF patients. We have identified impaired oxygen consumption in CF macrophages without and with B. cenocepacia infection. We also observed increased mitochondrial fragmentation in CF macrophages following infection. Lastly, we observed increased MMP and impaired mROS production in CF macrophages following infection with B. cenocepacia. The mitochondrial defects identified are key components of the macrophage response to infection. Their presence suggests that mitochondrial dysfunction contributes to impaired bacterial killing in CF macrophages. Our current study will enhance our understanding of the pathobiology of CF and lead to the identification of novel mitochondrial therapeutic targets for CF.
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影响因子：
64.8
作者：
West, A. Phillip;Brodsky, Igor E.;Rahner, Christoph;Woo, Dong Kyun;Erdjument-Bromage, Hediye;Tempst, Paul;Walsh, Matthew C.;Choi, Yongwon;Shadel, Gerald S.;Ghosh, Sankar
通讯作者：
Ghosh, Sankar
影响因子：
17.1
作者：
Riquelme, Sebastian A.;Lozano, Carmen;Prince, Alice
通讯作者：
Prince, Alice
影响因子：
28.3
作者：
Lachmandas, Ekta;Boutens, Lily;Stienstra, Rinke
通讯作者：
Stienstra, Rinke
DOI：
10.1016/j.bbrc.2012.06.066
发表时间：
2012-07-27
影响因子：
3.1
作者：
Kopp, Benjamin T.;Abdulrahman, Basant A.;Amer, Amal O.
通讯作者：
Amer, Amal O.
影响因子：
3
作者：
Atlante, Anna;Favia, Maria;Reshkin, Stephan Joel
通讯作者：
Reshkin, Stephan Joel