Extended Data Fig. 7: Intervening the STING-PERK-eIF2α axis ameliorates the progression of fibrotic pulmonary diseases.
(A) Pulmonary fibrosis was induced by bleomycin in WT and STING KO C57BL/6 mice (top panel). Genetic ablation of STING substantially ameliorated lung fibrosis symptoms, as evidenced by the diminished areas of collagen and declined Ashcroft fibrosis scores. Scale bars=100 μm. Data shown represent mean ± SEM (n = 4 mice in the saline group; n = 8 mice in the other groups), and P values were indicated by one-way ANOVA with the Bonferroni correction. (B-C) Bleomycin-induced pulmonary fibrosis was markedly attenuated in STING-deficient mice (B) or upon the treatment of PERK inhibitor (C), as revealed by immunoblotting for the reduced levels of α-SMA and collagen I. (D) Schematic figure showed the design, generation, and verification of the Eif2ak3 heterozygotes, and the gRNA target sequence (5’-TGGACAGGAGGTGCCTCGTTGGG-3’) was located in the exon 1 of murine Eif2ak3 gene. (E) PERK heterozygotes (Eif2ak3 + /-) were largely normal in appearance and weight and were fertile, while its homozygotes were embryonic lethal. (F) Bleomycin-induced pulmonary fibrosis was markedly attenuated in PERK half-deficiency mice, as revealed by immunoblotting for α-SMA and collagen I. (G) Immunoblottings for α-SMA and collagen I showed that Bleomycin-induced pulmonary fibrosis was severely prevented by PERK inhibition, but not the inhibition of the UPR. Images of lung sections for individual mice in Extended Data Fig. 7 were provided in Supplementary Information. Data in B, C, F and G represent three independent experiments.
