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":null,"pages":null},"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.
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.