The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis
Jyotsana Pandey, Jennifer L. Larson-Casey, Mallikarjun H. Patil, Chao He, Nisarat Pinthong, A. Brent Carter
Jyotsana Pandey, Jennifer L. Larson-Casey, Mallikarjun H. Patil, Chao He, Nisarat Pinthong, A. Brent Carter
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Research Article Immunology Pulmonology

The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis

Abstract

Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in protein kinase RNA-like ER kinase (PERK; Eif2ak3) activation in humans with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis individuals had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3–/– Lyz2-cre mice was reduced to control levels. PERK increased activating transcription factor 4 (Atf4) expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a therapeutic target to reverse established fibrosis.

Authors

Jyotsana Pandey, Jennifer L. Larson-Casey, Mallikarjun H. Patil, Chao He, Nisarat Pinthong, A. Brent Carter

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Figure 6

Pharmacological inhibition of PERK reverses established lung fibrosis.

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Pharmacological inhibition of PERK reverses established lung fibrosis. (...
(A) Schematic of animal study. Thirteen days after exposure, GSK2656157 (GSK, 30 mg/kg i.p.) was administered daily to mice. (B) Lung macrophages were obtained by BAL from MMVF- or asbestos-exposed mice and subjected to staining for p-eIF2α and F4/80. The staining was imaged by confocal microscopy, scale bars at 10 μm or 40×. (C) Masson’s trichrome staining in representative micrographs from n = 4–5 mice per condition, scale bar at 100 μm and 10×. (D) Hydroxyproline assay in lung tissues (n = 4–5). (E) Lung macrophages were obtained by BAL from control or bleomycin-exposed mice and subjected to staining for p-eIF2α and F4/80, scale bars at 10 μm or 40×. (F) Masson’s trichrome staining in representative micrographs from (n = 4–5) mice per condition, scale bar at 100 μm and 10×. (G) Hydroxyproline assay in lung tissues (n = 4–5). Data shown as mean ± SEM. One-way ANOVA with Tukey’s post hoc comparison. ****P < 0.0001. (See also Supplemental Figure 5.)