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

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 4

The airway epithelium of mucus-plugged airways in asthma is characterized by hyperplasia of basal cells and MUC5AC-positive goblet cells.

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The airway epithelium of mucus-plugged airways in asthma is characterize...
(A–C) Representative cell-segmented images of segmented epithelium and epithelial cell types in a lung disease–free controlAsthma airway (participant ID 7234) (A), an asthma unplugged airway (participant ID 7239) (B), and an asthma plugged airway (participant ID 7016) (C). Scale bars: 100 μm. (D) Pie chart showing the cell class diversity of cells in asthma and disease-free controlAsthma airway epithelium. (E) Epithelial cell numbers are increased in asthma mucus-plugged airways. (F) Ciliated cell numbers are similar in lung disease–free controlAsthma and asthma plugged airways. (G) Basal cell numbers are increased in asthma mucus-plugged airways. (H) Basal cell proliferation is increased in asthma mucus-plugged airways (violin plot shows the Ki-67 mean cellular expression of basal cells. and the red lines indicate the average for each subgroup). (I) Epithelial goblet cells expressing MUC5B are similar in all patient groups. (J) Epithelial goblet cells expressing MUC5AC are increased in asthma airways occluded with mucus. (K) Kernel density plot showing a higher area for epithelial goblet cells expressing MUC5AC in mucus-plugged asthma airways than that in unplugged asthma airways and in lung disease–free controlAsthma airways. *Significantly different from lung disease–free controlAsthma, P < 0.05; ***significantly different from lung disease–free controlAsthma, P < 0.001; ****significantly different from lung disease–free controlAsthma, P < 0.0001; #significantly different from asthma unplugged airways, P < 0.05; ####significantly different from asthma unplugged airways, P < 0.0001 (ordinary 1-way ANOVA with Tukey’s correction).