Human mesenchymal stromal cells inhibit Mycobacterium avium replication in clinically relevant models of lung infection.

IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Thorax Pub Date : 2024-07-16 DOI:10.1136/thorax-2023-220819
Timothy D Shaw, Anna D Krasnodembskaya, Gunnar N Schroeder, Declan F Doherty, Johnatas Dutra Silva, Shikha M Tandel, Yue Su, David Butler, Rebecca J Ingram, Cecilia M O'Kane
{"title":"Human mesenchymal stromal cells inhibit <i>Mycobacterium avium</i> replication in clinically relevant models of lung infection.","authors":"Timothy D Shaw, Anna D Krasnodembskaya, Gunnar N Schroeder, Declan F Doherty, Johnatas Dutra Silva, Shikha M Tandel, Yue Su, David Butler, Rebecca J Ingram, Cecilia M O'Kane","doi":"10.1136/thorax-2023-220819","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Novel therapeutic strategies are urgently needed for <i>Mycobacterium avium</i> complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD.</p><p><strong>Methods: </strong>Human monocyte-derived macrophages (MDMs) were infected with <i>M. avium</i> Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of <i>M. avium</i> Chester. Mice were treated with 1×10<sup>6</sup> intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA.</p><p><strong>Results: </strong>MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls.</p><p><strong>Conclusion: </strong>MSCs can modulate inflammation and reduce intracellular <i>M. avium</i> growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.</p>","PeriodicalId":23284,"journal":{"name":"Thorax","volume":" ","pages":"778-787"},"PeriodicalIF":9.0000,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287638/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Thorax","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/thorax-2023-220819","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD.

Methods: Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA.

Results: MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls.

Conclusion: MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
在临床相关的肺部感染模型中,人间质基质细胞可抑制分枝杆菌的复制。
导言:复合分枝杆菌肺病(MAC-PD)迫切需要新的治疗策略。人间质基质细胞(MSCs)可直接抑制分枝杆菌的生长,但其对细胞内分枝杆菌的影响尚不清楚。我们研究了人类间充质干细胞在MAC感染巨噬细胞和MAC-PD小鼠模型中减少细菌复制和炎症的能力。方法:用M. avium Chester菌株感染人类单核细胞衍生巨噬细胞(MDM),并用人类骨髓间充质干细胞处理。72小时后对细胞内和细胞外的集落形成单位(CFU)进行计数。六周大的雌性 balb/c 小鼠通过雾化感染 M. avium Chester。感染后 21 天和 28 天,小鼠静脉注射 1×106 人间充质干细胞或生理盐水对照。感染后 42 天收获肺、肝和脾,进行细菌计数。用酶联免疫吸附法对细胞因子进行量化:结果:间充质干细胞在 72 小时内减少了 MDMs 细胞内的细菌数量(中位数减少 35%,P=0.027)。间充质干细胞治疗增加了前列腺素 E2(PGE2)的细胞外浓度(中位数增加 10.1 倍,p=0.002),并减少了肿瘤坏死因子-α(中位数减少 28%,p=0.025)。用塞来昔布抑制环氧化酶-2(COX-2)来阻断间叶干细胞 PGE2 的产生,可减弱抗菌效果,而加入外源性 PGE2 则可恢复抗菌效果。与对照组相比,间叶干细胞治疗小鼠的肺部CFU较低(中位数减少18%,P=0.012),但脾脏或肝脏CFU无明显变化:结论:在慢性 MAC-PD 小鼠模型中,间叶干细胞可通过 COX-2/PGE2 信号调节炎症,减少人巨噬细胞内的 M. avium 生长,并抑制肺部细菌复制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Thorax
Thorax 医学-呼吸系统
CiteScore
16.10
自引率
2.00%
发文量
197
审稿时长
1 months
期刊介绍: Thorax stands as one of the premier respiratory medicine journals globally, featuring clinical and experimental research articles spanning respiratory medicine, pediatrics, immunology, pharmacology, pathology, and surgery. The journal's mission is to publish noteworthy advancements in scientific understanding that are poised to influence clinical practice significantly. This encompasses articles delving into basic and translational mechanisms applicable to clinical material, covering areas such as cell and molecular biology, genetics, epidemiology, and immunology.
期刊最新文献
Neuropsychiatric side effects of montelukast: time to change prescribing practice? Neuropsychiatric diagnoses after montelukast initiation in paediatric patients with asthma A structural and metabolic framework for classifying pre-clinical tuberculosis infection phenotypes using 18F-FDG PET-CT: a prospective cohort analysis following M. tuberculosis exposure. Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease. Multiple lung cyst formation caused by metastatic bladder cancer.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1