Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence
Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy
Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy
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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 8

Granulocytic mucus plugs have increased numbers of extracellular DNA traps.

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Granulocytic mucus plugs have increased numbers of extracellular DNA tra...
(A) COPD mucus plugs (participant ID 6968) and granulocytic asthma mucus plugs (participant ID 7239) show extracellular histone H3 immunostaining. Paucigranulocytic mucus plug (participant ID 7188) shows histone H3 immunostaining only within the cell boundaries. Scale bar: 100 μm. (B) Mean intensity of histone H3 immunostaining in COPD mucus plugs and asthma granulocytic mucus plugs is higher than in asthma paucigranulocytic mucus plugs. *Significantly different from COPD mucus plugs, P < 0.05 (Kruskal-Wallis test with Dunn’s correction). ####Significantly different from asthma granulocytic mucus plugs, P < 0.0001 (Kruskal-Wallis test with Dunn’s correction). (C) Paucigranulocytic mucus plugs are more common in acute asthma than in chronic asthma. (D) Schematic summary of findings for mucus plugs from patients with asthma. Asthma mucus plugs form in airways that are inflamed and remodeled, displaying features such as folding of the epithelium and hyperplasia of smooth muscle cells, basal cells, and goblet cells. Two subtypes of mucus plugs are identified in asthma: paucigranulocytic, which are high in MUC5AC and low in cellular infiltration, and granulocytic, which have a balanced mix of MUC5AC and MUC5B and high numbers of infiltrating granulocytes. Granulocytes in these plugs tend to degranulate and form DNA extracellular traps. Paucigranulocytic mucus plugs likely result from acute goblet cell degranulation while granulocytic mucus plugs may be a subset of acute mucus plugs that fail to resolve and become chronic.