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

Autor:	Shaw TD; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Krasnodembskaya AD; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Schroeder GN; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Doherty DF; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Silva JD; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Tandel SM; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Su Y; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Butler D; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., Ingram RJ; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK., O'Kane CM; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK c.okane@qub.ac.uk.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2024 Jul 16; Vol. 79 (8), pp. 778-787. Date of Electronic Publication: 2024 Jul 16.
DOI:	10.1136/thorax-2023-220819
Abstrakt:	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 1×10 6 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. Competing Interests: Competing interests: TDS reports grant support from a UKRI MRC Clinical Research Training Fellowship (MR/R017867/1), the Dowager Countess Eleanor Peel Trust and the Queen’s University Global Research Partnership Development award. ADK reports grant support from UKRI MRC, Wellcome Trust, Northern Ireland Health and Social Care Research and Development office, EU Marie Skłodowska-Curie and the Royal Society as well as travel support from the International Forum for Stem Cells (2020), EERS Lung Science Conference (2020) and International Mitochondrial Society (2022). She served on the grant review committee for the California Institute for Regenerative Medicine in 2020– 2023. GNS is a committee member on the Irish Division of the Microbiology Society UK. CMO’K reports grant support from UKRI MRC, Wellcome Trust, Northern Ireland Health and Social Care Research and Development Office. She has received consulting fees from INSMED regarding treatment of non-tuberculous mycobacterial pulmonary disease and served on the grant review committee for the California Institute for Regenerative Medicine. She is an editor-in-chief of Thorax. The remaining authors report no potential conflicts of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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