Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease
Aran Singanayagam, … , Patrick Mallia, Sebastian L. Johnston
Aran Singanayagam, … , Patrick Mallia, Sebastian L. Johnston
Published March 3, 2022
Citation Information: J Clin Invest. 2022;132(8):e120901. https://doi.org/10.1172/JCI120901.
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Research Article Pulmonology

Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease

Abstract

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac–/–) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.

Authors

Aran Singanayagam, Joseph Footitt, Matthias Marczynski, Giorgia Radicioni, Michael T. Cross, Lydia J. Finney, Maria-Belen Trujillo-Torralbo, Maria Calderazzo, Jie Zhu, Julia Aniscenko, Thomas B. Clarke, Philip L. Molyneaux, Nathan W. Bartlett, Miriam F. Moffatt, William O. Cookson, Jadwiga Wedzicha, Christopher M. Evans, Richard C. Boucher, Mehmet Kesimer, Oliver Lieleg, Patrick Mallia, Sebastian L. Johnston

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Figure 2

Airway MUC5AC expression and correlation with immunopathology during experimental RV infection.

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Airway MUC5AC expression and correlation with immunopathology during exp...
(A) Experimental outline. Fourteen patients with COPD and 10 healthy control volunteers underwent sampling at baseline and the indicated time points after RV-A16 infection. (B) Sputum MUC5AC concentrations in patients with COPD and healthy individuals, measured during RV-A16 infection. (C) Comparison of baseline (BL) and peak (i.e., maximal concentration detected during the infection for each individual) concentrations of MUC5AC in patients with COPD and healthy individuals. Individual data points are shown; red lines indicate the mean concentration. (D) Sputum MUC5AC to MUC5B ratio measured by mass spectrometry for 11 individuals with COPD and 10 healthy participants. (E) Correlation of peak sputum MUC5AC concentrations with inflammatory cell numbers and cytokine concentrations in sputum. Correlations between peak sputum MUC5AC levels and (F) sputum viral loads and (G) sputum neutrophil elastase. Change from baseline concentrations of (H) SLPI and (I) elafin. (J) Sputum MUC5AC concentrations in patients with COPD with positive (+ve) or negative (–ve) sputum bacterial cultures during experimental RV infection. Box and whisker plots in J show the median (line within the box), the IQR (box), and the minimum-to-maximum values (whiskers). (K) Correlation of peak sputum MUC5AC with bacterial loads as assessed by 16S qPCR. 16S qPCR was not measured for all patients because of a lack of sample availability, so only the data measured are shown. (L) Upper respiratory tract symptom scores. (M) Lower respiratory tract symptom scores. (N) PEFR change from baseline. (B and D) *P < 0.05 and **P < 0.01 (COPD vs. healthy); #P < 0.05 (day 3 vs. baseline in patients with COPD). (C) *P < 0.05 and **P < 0.01, by Wilcoxon matched-pairs, signed-rank test for baseline versus peak values, and Mann Whitney U test for comparison of peak values between patients with COPD and healthy individuals. (J) *P < 0.05, by Mann Whitney U test. (E) **P < 0.01 and ***P < 0.001, by Spearman’s correlation analysis of pooled data on healthy volunteers and patients with COPD. (F–I and K–N) Nonparametric Spearman’s correlation analysis was performed on pooled data on healthy volunteers and patients with COPD.