The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis.
The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis.
复制标题
DOI：
10.3390/ijms222212189
复制
发表时间：
2021-11-10
影响因子：
5.6
通讯作者：
Phelan JJ
中科院分区：
文献类型：
--
作者：
Cahill C;Cox DJ;O'Connell F;Basdeo SA;Gogan KM;Ó'Maoldomhnaigh C;O'Sullivan J;Keane J;Phelan JJ
结核病（TB）仍然是全球性的健康挑战。药物敏感和耐药结核病患者需要接受长期、艰苦和复杂的治疗方案，通常涉及多种抗菌药物。虽然这些药物最初是基于其杀菌作用而实施的，但一些研究表明，结核病抗菌剂也可以直接影响免疫系统的细胞，改变其免疫功能。由于这些抗菌药物的使用已经成为结核病治疗的支柱超过50年，因此了解这些抗菌药物如何影响免疫系统的关键途径比以往任何时候都更重要。一个这样的中心途径，其支持对各种感染的免疫应答，是免疫代谢，即糖酵解和氧化磷酸化（OXPHOS）。我们假设，除了对结核分枝杆菌（Mtb）的直接杀菌作用外，目前的TB抗菌剂还可以调节免疫代谢谱并改变原代人巨噬细胞中的线粒体功能。人单核细胞衍生的巨噬细胞（hMDM）从分离自健康献血者的PBMC分化，并在用iH 37 Rv-Mtb或脂多糖（LPS）刺激后三小时用四种一线和六种二线TB抗微生物剂处理。刺激后24小时，使用Seahorse胞外通量分析仪测定基线代谢和线粒体功能。还使用Meso Scale Discovery Multi-Array技术测定了这些抗微生物剂对细胞因子和趋化因子产生的影响。我们表明，测试的一些TB抗微生物剂可以显著改变未感染的iH 37 Rv-Mtb和LPS刺激的hMDM中的OXPHOS和糖酵解。我们还证明了这些抗菌剂诱导的免疫代谢效应如何与线粒体功能的改变有关。我们的研究结果表明，结核病抗菌剂，特别是氯法齐明，可以修改宿主的免疫代谢和线粒体功能。此外，氯法齐明显著增加了用iH 37 Rv-Mtb刺激的人巨噬细胞中IL-6的产生。这为使用这些结核病抗菌剂作为早期和活动性疾病患者的潜在宿主导向疗法提供了进一步的见解，这可能有助于为未来的结核病治疗策略提供信息。
Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on Mycobacterium tuberculosis (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future.
登录
查看更多内容
DOI：
10.18632/aging.100983
发表时间：
2016-08
期刊：
Aging
影响因子：
--
作者：
Fiorillo M;Lamb R;Tanowitz HB;Cappello AR;Martinez-Outschoorn UE;Sotgia F;Lisanti MP
通讯作者：
Lisanti MP
影响因子：
2.6
作者：
Ahadpour, Morteza;Eskandari, Mohammad Reza;Hosseini, Mir-Jamal
通讯作者：
Hosseini, Mir-Jamal
影响因子：
3.1
作者：
Ladel, CH;Blum, C;Kaufmann, SHE
通讯作者：
Kaufmann, SHE
影响因子：
7.7
作者：
Cumming BM;Addicott KW;Adamson JH;Steyn AJ
通讯作者：
Steyn AJ
DOI：
10.1073/pnas.1521988112
发表时间：
2015-12-22
影响因子：
11.1
作者：
Feng, Xinxin;Zhu, Wei;Oldfield, Eric
通讯作者：
Oldfield, Eric