Single-Cell Sequencing of Lung Macrophages and Monocytes Reveals Novel Therapeutic Targets in COPD

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dc.contributor.authorHu, Yushan
dc.contributor.authorShao, Xiaojian
dc.contributor.authorXing, Li
dc.contributor.authorLi, Xuan
dc.contributor.authorNonis, Geoffrey M.
dc.contributor.authorKoelwyn, Graeme J.
dc.contributor.authorZhang, Xuekui
dc.contributor.authorSin, Don D.
dc.date.accessioned2023-12-15T19:18:24Z
dc.date.available2023-12-15T19:18:24Z
dc.date.copyright2023en_US
dc.date.issued2023
dc.description.abstractBackground: Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these cells in lungs of COPD patients and identified novel therapeutic targets. Methods: We analyzed the RNA sequencing (scRNA-seq) data of explanted human lung tissue from COPD (n = 18) and control (n = 28) lungs and found 16 transcriptionally distinct groups of macrophages and monocytes. We performed pathway and gene enrichment analyses to determine the characteristics of macrophages and monocytes from COPD (versus control) lungs and to identify the therapeutic targets, which were then validated using data from a randomized controlled trial of COPD patients (DISARM). Results: In the alveolar macrophages, 176 genes were differentially expressed (83 up- and 93 downregulated; Padj < 0.05, |log₂FC| > 0.5) and were enriched in downstream biological processes predicted to cause poor lipid uptake and impaired cell activation, movement, and angiogenesis in COPD versus control lungs. Classical monocytes from COPD lungs harbored a differential gene set predicted to cause the activation, mobilization, and recruitment of cells and a hyperinflammatory response to influenza. In silico, the corticosteroid fluticasone propionate was one of the top compounds predicted to modulate the abnormal transcriptional profiles of these cells. In vivo, a fluticasone–salmeterol combination significantly modulated the gene expression profiles of bronchoalveolar lavage cells of COPD patients (p < 0.05). Conclusions: COPD lungs harbor transcriptionally distinct lung macrophages and monocytes, reflective of a dysfunctional and hyperinflammatory state. Inhaled corticosteroids and other compounds can modulate the transcriptomic profile of these cells in patients with COPD.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThis research was supported by personnel grants from Canada Research Chair (CRC-2021-00136 G.J.K., CRC-2020-229002 D.D.S. and CRC-2021-00232 X.Z.), Michael Smith Health Research BC Scholar (SCH-2022-2553, X.Z.), MITACS Accelerate (IT28140, X.Z. and D.D.S.), NRC Digital Health and Geospatial Analytics Program (DHGA 121-1, S.X., L.X. and X.Z.), The Visual and Automated Disease Analytics graduate training program (Y.H.), and operating grants from the Canadian Institutes for Health Research (CIHR FDN 143226 D.D.S.), AstraZeneca (D.D.S.) and Genome BC SIP (SIP7, L.X., X.Z. and D.D.S.).en_US
dc.identifier.citationHu, Y., Shao, X., Xing, L., Li, X., Nonis, G. M., Koelwyn, G. J., Zhang, X., & Sin, D. D. (2023). Single-cell sequencing of lung macrophages and monocytes reveals novel therapeutic targets in COPD. Cells, 12(24), 2771. https://doi.org/10.3390/cells12242771en_US
dc.identifier.urihttps://doi.org/10.3390/cells12242771
dc.identifier.urihttp://hdl.handle.net/1828/15715
dc.language.isoenen_US
dc.publisherCellsen_US
dc.rightsAttribution 2.5 Canada*
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/ca/*
dc.subjectmacrophages
dc.subjectmonocytes
dc.subjectCOPD
dc.subjectsingle-cell RNA sequencing
dc.subjectfluticasone
dc.subjectdrug discovery
dc.subject.departmentDepartment of Mathematics and Statistics
dc.titleSingle-Cell Sequencing of Lung Macrophages and Monocytes Reveals Novel Therapeutic Targets in COPDen_US
dc.typeArticleen_US

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