Academic Journal
Single-cell profiling of BAL in preschool cystic fibrosis reveals macrophage dysregulation and ivacaftor-modified inflammatory programs in the early life lung.
| Τίτλος: | Single-cell profiling of BAL in preschool cystic fibrosis reveals macrophage dysregulation and ivacaftor-modified inflammatory programs in the early life lung. |
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| Συγγραφείς: | Maksimovic J; Computational Biology Program, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia., Shanthikumar S; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Respiratory and Sleep Medicine, Royal Children's Hospital, Parkville, VIC, Australia., Howitt G; Computational Biology Program, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia., Dixit G; Computational Biology Program, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia., Hickey PF; Cellular Genomics Projects Team, Advanced Technology and Biology Division, WEHI, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Anttila C; Cellular Genomics Projects Team, Advanced Technology and Biology Division, WEHI, Parkville, VIC, Australia., Brown DV; Cellular Genomics Projects Team, Advanced Technology and Biology Division, WEHI, Parkville, VIC, Australia., Gubbels L; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia., Senabouth A; Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia; UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, Australia., Amann-Zalcenstein D; Cellular Genomics Projects Team, Advanced Technology and Biology Division, WEHI, Parkville, VIC, Australia., Powell JE; Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia; UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW, Australia., Ranganathan SC; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Respiratory and Sleep Medicine, Royal Children's Hospital, Parkville, VIC, Australia., Oshlack A; Computational Biology Program, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia., Neeland MR; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia. Electronic address: melanie.neeland@mcri.edu.au. |
| Πηγή: | Mucosal immunology [Mucosal Immunol] 2026 Jun; Vol. 19 (3), pp. 100338. Date of Electronic Publication: 2026 Mar 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 101299742 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1935-3456 (Electronic) Linking ISSN: 19330219 NLM ISO Abbreviation: Mucosal Immunol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2023- : [New York, NY] : Elsevier Original Publication: New York, NY : Nature Pub. Group, c2008- |
| Ιατρικοί όροι (MeSH): | Quinolones*/therapeutic use , Quinolones*/pharmacology , Macrophages*/immunology , Macrophages*/drug effects , Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/immunology , Aminophenols*/therapeutic use , Aminophenols*/pharmacology , Lung*/immunology , Lung*/pathology , Bronchoalveolar Lavage Fluid*/cytology , Bronchoalveolar Lavage Fluid*/immunology, Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Humans ; Child, Preschool ; Single-Cell Analysis ; Female ; Transcriptome ; Single-Cell Gene Expression Analysis ; Male ; Gene Expression Profiling ; Inflammation |
| Περίληψη: | Aberrant inflammation and structural lung damage occurs early in life for people with cystic fibrosis (CF). Even in the era of CFTR modulators, anti-inflammatory therapy may still be needed to prevent establishment and lifelong consequences of bronchiectasis. In this study, we integrated transcriptome-wide single-cell RNA sequencing data and highly multiplexed surface protein expression to create the largest comprehensive paediatric lower airway atlas of >190,000 cells from 45 bronchoalveolar lavage (BAL) samples resulting in 43 immune and epithelial cell populations, all available for exploration on CELLxGENE. We then investigated inflammatory cell responses in children with CF to show widespread gene expression dysregulation of macrophage populations in the preschool CF lung. This included alterations in pathways associated with TNF and IFN signalling, cholesterol homeostasis, as well as pulmonary fibrosis, that were further altered by the early development of bronchiectasis. We showed that the CFTR modulator ivacaftor restores some of these macrophage-related functional deficits and reduces expression of pathways associated with neutrophil infiltration, however the modulator lumacaftor/ivacaftor did not result in any detectable changes in transcriptional response. This work represents a comprehensive, multi-omic single-cell analysis of BAL from preschool children and the results may inform the future development of anti-inflammatory therapy for children with CF. (Copyright © 2026. Published by Elsevier Inc.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: BAL; CFTR; Children; Cystic fibrosis; Macrophages |
| Substance Nomenclature: | 0 (Quinolones) 0 (Aminophenols) 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) 1Y740ILL1Z (ivacaftor) |
| Entry Date(s): | Date Created: 20260401 Date Completed: 20260612 Latest Revision: 20260612 |
| Update Code: | 20260613 |
| DOI: | 10.1016/j.mucimm.2026.03.012 |
| PMID: | 41921915 |
| Βάση Δεδομένων: | MEDLINE |
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