Identification of periplakin as a major regulator of lung injury and repair in mice
Valérie Besnard, … , Matthew A. Sleeman, Bruno Crestani
Valérie Besnard, … , Matthew A. Sleeman, Bruno Crestani
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e90163. https://doi.org/10.1172/jci.insight.90163.
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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 1

Expression of PPL is decreased after lung injury.

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Expression of PPL is decreased after lung injury. (A) qPCR was performed...
(A) qPCR was performed to estimate Ppl mRNA in whole-lung homogenate from Ppl+/+ mice at indicated time points after bleomycin instillation and normalized to B2m mRNA. Results are expressed as means ± SEM of 5 animals per group. (B) Immunoblotting for PPL was performed on Ppl+/+ lungs on D0, D3, D7, and D14 after bleomycin instillation. Western blot analysis demonstrated a marked decrease in PPL protein in Ppl+/+ lungs compared with D0. IHC for PPL (black staining) was performed on mouse lungs on D0 (C) and D14 (D) after bleomycin instillation. Arrows indicate PPL staining in lung AECs. Goat isotype is shown in E. (F) MLE-15 cells were exposed to either saline (0.9% NaCl), or BALF from control (Ctrl) or (IPF) human patient for 24 hours. Ppl mRNAs were assessed by qPCR and normalized to the β2-microglobulin (B2m) gene. n = 5. (G) MLE-15 cells were exposed to either hTGF-β1 (G) or hPDGF-BB (H) for 24 and 48 hours. Ppl mRNAs were assessed by qPCR and normalized to the β2-microglobulin (B2m) gene. n = 5. *P < 0.05; **P < 0.01, Mann Whitney U test. Magnification ×40.