Identification of periplakin as a major regulator of lung injury and repair in mice
Valérie Besnard, Rania Dagher, Tania Madjer, Audrey Joannes, Madeleine Jaillet, Martin Kolb, Philippe Bonniaud, Lynne A. Murray, Matthew A. Sleeman, Bruno Crestani
Valérie Besnard, Rania Dagher, Tania Madjer, Audrey Joannes, Madeleine Jaillet, Martin Kolb, Philippe Bonniaud, Lynne A. Murray, Matthew A. Sleeman, Bruno Crestani
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Research Article Inflammation Pulmonology

Identification of periplakin as a major regulator of lung injury and repair in mice

Abstract

Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury. Deletion of the Ppl gene in mice improved survival and reduced lung fibrosis development after bleomycin-induced injury. Notably, Ppl deletion promoted an antiinflammatory alveolar environment linked to profound changes in type 2 alveolar epithelial cells, including overexpression of antiinflammatory cytokines, decreased expression of profibrotic mediators, and altered cell signaling with a reduced response to TGF-β1. These results identify periplakin as a previously unidentified regulator of the response to injury in the lung.

Authors

Valérie Besnard, Rania Dagher, Tania Madjer, Audrey Joannes, Madeleine Jaillet, Martin Kolb, Philippe Bonniaud, Lynne A. Murray, Matthew A. Sleeman, Bruno Crestani

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Figure 3

Ppl–/– mice were protected from bleomycin injury.

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Ppl–/– mice were protected from bleomycin injury. (A) Kaplan-Meier plot...
(A) Kaplan-Meier plot of survival of Ppl+/+ and Ppl–/– mice after bleomycin exposure. Eight-week-old Ppl+/+ and Ppl–/– mice received an intratracheal instillation of bleomycin or saline (NaCl) at day0. Survival of Ppl–/– mice (n =23) after bleomycin was significantly increased compared with controls (n = 40). P < 0.0001 by Log-rank test. (B–E) Lung histology of Ppl+/+ and Ppl–/– mice after bleomycin treatment. Lung sections of Ppl+/+ and Ppl–/– mice were prepared at D0, D3, D7, and D14 after bleomycin exposure and stained with H&E to assess lung morphology. (F) Soluble collagen content, assessed by Sircol assay in lung homogenates, was decreased in Ppl–/– mice compared with Ppl+/+ mice (n = 10 mice per group). (G–J) Collagen deposition was assessed by immunostaining for type I collagen (COL1, black staining) on lung sections of Ppl+/+ (G and I) and Ppl–/– mice (H and J) prepared at D0 and D14 after bleomycin exposure. The figure is representative of at least 6 individual mice at each time. Magnification ×20. (K) Immunoblotting for collagen 1 (COL1) and fibronectin (FN) was performed on Ppl+/+ and Ppl–/– lungs on D0, D3, D7, and D14 after bleomycin instillation. Western blot analysis demonstrated a marked decrease in both COL1 and FN proteins in Ppl–/– lungs compared with Ppl+/+. *P < 0.05 vs. (D0, Ppl+/+); **P < 0.01 vs. (D0, Ppl+/+); ***P < 0.001 vs. (D0, Ppl+/+); #P < 0.05 vs. (D0, Ppl–/–); ##P < 0.01 vs. (D0, Ppl–/–), Mann Whitney U test.