2. Academic Validation
  3. Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli

Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli

  • J Clin Invest. 2024 Oct 1;134(19):e176828. doi: 10.1172/JCI176828.
Xiuyu Lin 1,  Weicheng Chen 2,  Guilin Yang 1,  Jiazhu Zhang 1,  Huilin Wang 3,  Zeyu Liu 4,  Ying Xi 5,  Tao Ren 4,  Bo Liu 3,  Pengfei Sui 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai , University of Chinese Academy of Sciences, China.
  • 2 Cardiothoracic Surgery Department, Children's Hospital of Fudan University, Shanghai, China.
  • 3 Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
PMID: 39352385 DOI: 10.1172/JCI176828
Abstract

Severe viral pneumonia can induce rapid expansion of KRT5+ basal-like cells in small airways and alveoli; this forms a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. In this study, we investigated the mechanism by which viral Infection induced this remodeling response. Through comparing different lung-injury models, we demonstrated that Infection induced strong IFN-γ signal-stimulated dysplastic KRT5+ cell formation. Inactivation of interferon receptor 1 (Ifngr1) reduced dysplastic cell formation, ameliorated lung fibrosis, and improved lung-function recovery. Mechanistically, IFN-γ regulated dysplastic cell formation via the focal adhesion kinase (FAK)/Yes-associated protein 1 (YAP) pathway. Inhibiting FAK/Src diminished IFN-γ-induced YAP nuclear translocation and dysplastic cell formation. Inhibiting YAP during viral Infection prevented dysplastic cell formation, whereas inhibiting YAP in persistent KRT5+ cells led to their conversion into distal club cells. Importantly, human dysplastic cells exhibited elevated FAK and YAP activity, and IFN-γ treatment promoted the transformation of human alveolar progenitor cells into dysplastic cells. These findings uncover the role of infection-induced inflammatory response in alveolar remodeling and may provide potential therapeutic avenues for the treatment of alveolar remodeling in patients with severe viral pneumonia.

Keywords

Adult stem cells; Influenza; Pulmonology.

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