Journal Article

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

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

2025

Overview

BACKGROUNDMucus 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.METHODSUsing 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.RESULTSAsthma 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.CONCLUSIONTogether, 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.FUNDINGNIH grants HL080414, HL107202, and AI077439.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Aged / Allergens / Asthma / Asthma - metabolism / Asthma - pathology / Asthma/genetics / B cells / Care and treatment / CD11b antigen / Cell Degranulation / Cells / Chronic diseases / Chronic illnesses / Chronic obstructive pulmonary disease / Clinical Research and Public Health / Degranulation / Development and progression / Disease control / ELANE protein, human / Elastase / Eosinophil Peroxidase / Eosinophil Peroxidase - metabolism / Eosinophil Peroxidase/genetics / Eosinophils / Eosinophils - metabolism / Eosinophils - pathology / Epithelial cells / Epithelial Cells/metabolism / Epithelial Cells/pathology / Female / Goblet cells / Goblet Cells - metabolism / Goblet Cells - pathology / Granulocytes / Health aspects / Histology / Human health sciences / Humans / Hyperplasia / Immune response / Immunologie & maladie infectieuse / Immunology / Immunology & infectious disease / Leukocyte Elastase / Leukocyte Elastase/genetics / Leukocyte Elastase/metabolism / Leukocytes (eosinophilic) / Leukocytes (granulocytic) / Leukocytes (neutrophilic) / Lung diseases / Lungs / Male / Medical research / Medicine, Experimental / Middle Aged / MUC5AC protein, human / Mucin / Mucin 5AC / Mucin 5AC - metabolism / Mucin 5AC/genetics / Mucins / Mucus / Mucus - metabolism / Neutrophils / Observations / Pathology / Proteomics / Pulmonary Disease, Chronic Obstructive/genetics / Pulmonary Disease, Chronic Obstructive/metabolism / Pulmonary Disease, Chronic Obstructive/pathology / Pulmonology / Respiratory failure / Sciences de la santé humaine / Smooth muscle