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 5

TGF-β signaling was disturbed in Ppl–/– mice.

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TGF-β signaling was disturbed in Ppl–/– mice. (A) qPCR was performed to ...
(A) qPCR was performed to evaluate Tgfb1 mRNAs in whole-lung homogenate from Ppl+/+ mice after bleomycin instillation and normalized to B2m mRNA. Results are expressed as means ± SEM of 5 animals per group. Free TGF-β1 concentration was assessed by ELISA in both BALF (B) and lung homogenates (C) of Ppl+/+ and Ppl–/– mice at indicated time points after bleomycin exposure in BALF. Data represent means ± SEM. n = 7–9 mice per group. (D) Immunoblotting for Smad2 and P-Smad2 was performed on Ppl+/+ and Ppl–/– lung homogenates on D0, D3, D7, and D14 after bleomycin instillation (n = 4). Histograms show a quantitative representation of P-Smad2/Smad2 ratios. (E) Immunoblotting for Smad4 was performed on Ppl+/+ and Ppl–/– lung homogenates on D0, D3, D7, and D14 after bleomycin instillation (n = 4). Histograms show a quantitative representation of Smad4/TUB ratios. Densitometry results were expressed as arbitrary units. (F) qPCR was performed to evaluate Smad4 mRNAs in whole-lung homogenate from Ppl+/+ mice and normalized to B2m mRNA. Results are expressed as means ± SEM of 5 animals per group. qPCR was performed to evaluate Itgb6 (G) and Itgav (H) mRNAs in whole-lung homogenate from Ppl+/+ mice and normalized to B2m mRNA. Results are expressed as means ± SEM of 5 animals per group. *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 < 0.001 vs. (D0, Ppl-/-) Mann Whitney U test.