J Clin Invest . Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli

[tetano]

J Clin Invest


. 2024 Oct 1;134(19):e176828.
doi: 10.1172/JCI176828. Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli

Xiuyu Lin[SUP] 1 [/SUP], Weicheng Chen[SUP] 2 [/SUP], Guilin Yang[SUP] 1 [/SUP], Jiazhu Zhang[SUP] 1 [/SUP], Huilin Wang[SUP] 3 [/SUP], Zeyu Liu[SUP] 4 [/SUP], Ying Xi[SUP] 5 [/SUP], Tao Ren[SUP] 4 [/SUP], Bo Liu[SUP] 3 [/SUP], Pengfei Sui[SUP] 1 [/SUP]



Affiliations

• 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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[tetano]

J Clin Invest


. 2024 Oct 1;134(19):e185072.
doi: 10.1172/JCI185072. IFN-γ and YAP lead epithelial cells astray after severe respiratory infection

Bradley E Hiller[SUP] 1 2 [/SUP], Joseph P Mizgerd[SUP] 1 2 3 4 [/SUP]



Affiliations

• PMID: 39352386
• DOI: 10.1172/JCI185072

Abstract

Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.


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