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

J Clin Invest. 2022 Apr 15;132(8):e120901. doi: 10.1172/JCI120901.


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.

Keywords: COPD; Innate immunity; Pulmonology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Disease Models, Animal
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mucin 5AC* / genetics
  • Mucin 5AC* / metabolism
  • Mucin-5B / genetics
  • Mucin-5B / metabolism
  • Mucus / metabolism
  • Pulmonary Disease, Chronic Obstructive* / metabolism
  • Pulmonary Disease, Chronic Obstructive* / virology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology


  • Muc5ac protein, mouse
  • Mucin 5AC
  • Mucin-5B
  • Adenosine Triphosphate