Yap/Taz regulate alveolar regeneration and resolution of lung inflammation

J Clin Invest. 2019 Apr 15;129(5):2107-2122. doi: 10.1172/JCI125014.


Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Here, we show that sublethal infection of mice with Streptococcus pneumoniae, the most common pathogen of community-acquired pneumonia, led to exclusive damage in lung alveoli, followed by alveolar epithelial regeneration and resolution of lung inflammation. We show that surfactant protein C-expressing (SPC-expressing) alveolar epithelial type II cells (AECIIs) underwent proliferation and differentiation after infection, which contributed to the newly formed alveolar epithelium. This increase in AECII activities was correlated with increased nuclear expression of Yap and Taz, the mediators of the Hippo pathway. Mice that lacked Yap/Taz in AECIIs exhibited prolonged inflammatory responses in the lung and were delayed in alveolar epithelial regeneration during bacterial pneumonia. This impaired alveolar epithelial regeneration was paralleled by a failure to upregulate IκBa, the molecule that terminates NF-κB-mediated inflammatory responses. These results demonstrate that signals governing resolution of lung inflammation were altered in Yap/Taz mutant mice, which prevented the development of a proper regenerative niche, delaying repair and regeneration of alveolar epithelium during bacterial pneumonia.

Keywords: Adult stem cells; Bacterial infections; Pulmonology; Stem cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alveolar Epithelial Cells / cytology*
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Epithelial Cells / metabolism
  • Epithelium / microbiology
  • HEK293 Cells
  • Humans
  • Inflammation / metabolism
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Pneumonia, Pneumococcal / pathology*
  • Pulmonary Surfactant-Associated Protein C / metabolism*
  • Regeneration
  • Signal Transduction
  • Stem Cells / cytology
  • Streptococcus pneumoniae
  • Trans-Activators / metabolism*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • NF-kappa B
  • Pulmonary Surfactant-Associated Protein C
  • Sftpc protein, mouse
  • Trans-Activators
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse