Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli
Xiuyu Lin, … , Bo Liu, Pengfei Sui
Xiuyu Lin, … , Bo Liu, Pengfei Sui
Published October 1, 2024
Citation Information: J Clin Invest. 2024;134(19):e176828. https://doi.org/10.1172/JCI176828.
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Research Article Pulmonology

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

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.

Authors

Xiuyu Lin, Weicheng Chen, Guilin Yang, Jiazhu Zhang, Huilin Wang, Zeyu Liu, Ying Xi, Tao Ren, Bo Liu, Pengfei Sui

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Figure 5

YAP is required for the maintenance of dysplastic KRT5+ cells.

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YAP is required for the maintenance of dysplastic KRT5+ cells. (A) Illus...
(A) Illustration of strategy to trace dysplastic KRT5+ cell fate while inactivating Yap. (B–D) Immunofluorescence images and quantification of percentages of lineage-traced KRT5+ dysplastic cells or SCGB1A1+ club cells in Krt5creERT2/+;R26Td, Krt5creERT2/+;Yapfl/+;R26Td, and Krt5creERT2/+;Yapfl/fl;R26Td mice at 35 dpi (14 days after tamoxifen injection) (n = 5 mice per group). Scale bar: 50 μm. (E) No Krt5creERT2 lineage-traced cells were found expressing SFTPC in Krt5creERT2/+;R26Td, Krt5creERT2/+;Yapfl/+;R26Td, and Krt5creERT2/+;Yapfl/fl;R26Td mice at 35 dpi. Data are representative of sections from 3 mice. Scale bar: 50 μm. (F) Immunofluorescence staining of DCLK1 in Krt5creERT2/+;R26Td, Krt5creERT2/+;Yapfl/+;R26Td, and Krt5creERT2/+;Yapfl/fl;R26Td mice at 35 dpi (arrows indicate lineage-labeled DCLK+ tuft cells). Scale bar: 50 μm. (G) Quantification of percentages of tuft cells in total lineage-traced cells (n = 3 mice per group). **P < 0.01; ***P < 0.001. Error bars represent means ± SEM. One-way ANOVA (C, D, and G).