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Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy
Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy
Published March 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e186889. https://doi.org/10.1172/JCI186889.
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Clinical Research and Public Health Immunology Pulmonology

Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence

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Abstract

BACKGROUND Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODS Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell–eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTS Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13–activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSION Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell–mucin-granulocyte cross-talk.FUNDING NIH grants HL080414, HL107202, and AI077439.

Authors

Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy

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Figure 2

MUC5AC is the principal mucin in asthma mucus plugs, and epithelial mucus plug tethering correlates with extent of mucosal folding.

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MUC5AC is the principal mucin in asthma mucus plugs, and epithelial mucu...
(A) Lung disease–free controlAsthma airway (participant ID 7018). (B) Unplugged asthma airway (participant ID 7239). (C) H&E-stained asthma mucus plug (participant ID 7016). (D) Lung disease–free controlCOPD airway (participant ID 7309). (E) Unplugged COPD airway (participant ID 7336). (F) H&E-stained COPD mucus plug (participant ID 7336). (G) Asthma mucus plugs stained for MUC5AC (green), MUC5B (magenta), and DNA (blue). (H) MUC5AC immunostaining in asthma mucus plugs is higher than in COPD mucus plugs. ***Significantly different from COPD, P < 0.001 (Mann-Whitney test). (I) COPD mucus stained for MUC5B (magenta), MUC5AC (green), and DNA (blue). (J) MUC5B immunostaining in asthma mucus plugs is lower than in COPD plugs. ****Significantly different from COPD, P < 0.0001 (Mann-Whitney test). (K) The MUC5AC/MUC5B ratio in asthma mucus plugs is higher than in COPD mucus plugs. ****Significantly different from COPD, P < 0.0001 (Mann-Whitney test). (L) Mucus strands (black arrowheads) connect the asthma mucus plug (MP) to the surface of goblet cells (GB) (participant ID 7187). (M) Mucus plug tethering percentage correlates with MUC5AC immunostaining in asthma mucus plugs (n = 61) (Spearman’s correlation). (N) Mucosal folds in mucus-plugged airways in asthma are rich in goblet cells (GB) and mucus is tethered to goblet cells at multiple points along the folds (black arrowheads) (participant ID 7237). (O) Mucus plug tethering percentage correlates with mucosal folding percentage in mucus plugs from patients with asthma (n = 61) (Spearman’s correlation). (P) Mucosal folding percentage is higher in mucus-plugged airways in asthma (asthma MP) than in unplugged airways in asthma (asthma UnP) or in lung disease–free controlAsthma airways. ****Significantly different from lung disease–free controlsAsthma, P < 0.0001; ####significantly different from unplugged asthma airways, P < 0.0001 (Kruskal-Wallis test with Dunn’s correction). Scale bars: 200 μm.

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