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.
View: Text | PDF
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

×

Figure 2

Epithelial IFN-γ signaling is essential for IAV-induced dysplastic KRT5+ cell formation.

Options: View larger image (or click on image) Download as PowerPoint
Epithelial IFN-γ signaling is essential for IAV-induced dysplastic KRT5+...
(A and B) Immunofluorescence analysis and quantification of percentages of KRT5+PDPN+ areas in PDPN– and KRT5+ areas in control and Ifngr1EKO mice at 14 dpi (n = 15 mice per group). Scale bar: 500 μm. (C) Krt5 expression analysis in control and Ifngr1EKO mice at indicated time points (n ≥ 7 mice per group). (D and E) DCLK1+ tuft cells detected in control and Ifngr1EKO mice at 21 dpi (n = 9 mice per group). Scale bar: 50 μm. (F and G) Histological analysis of goblet cells in control and Ifngr1EKO mice at 21 dpi (n = 7 mice per group). Scale bar: 50 μm. (H–L) Experiment design and immunofluorescence analysis and quantification of lineage-traced KRT5+ and SFTPC+AT2 cells in control and Ifngr1Sox2–KO mice at 21 dpi (n = 4 mice per group). Scale bar: 50 μm. (M and N) Weight loss and survival curves of control and Ifngr1Sox2–KO mice (n = 7 mice per group in M, n = 16 mice per group in N). (O–Q) Sirius red staining and quantification of fibrotic areas in control and Ifngr1Sox2–KO mice at 60 dpi (n ≥ 4 mice per group). Scale bars: 500 μm (left row); 100 μm (middle row); 50 μm (right row). (R) Collagen content in control and Ifngr1Sox2–KO mice at 60 dpi (n = 6 mice per group). (S–U) MVV, FVC, and lung compliance in indicated mouse groups at 60 dpi (n ≥ 4 mice per group). *P < 0.05; **P < 0.01; ***P < 0.001. Error bars represent means ± SEM. Two-tailed Mann-Whitney U test (B, C, E, G, Q, and R); 2-tailed Student’s t test (K and L); multiple t test (M); Kaplan-Meier test (N); 1-way ANOVA (S and T); Brown-Forsythe and Welch’s ANOVA (U).