6533b82dfe1ef96bd1291a10

RESEARCH PRODUCT

Role of the small heat shock protein alphaB-crystallin in pulmonary fibrosis and its implication in the signaling pathway of the Transforming Growth Factor béta1

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Idiopathic pulmonary fibrosis (IPF) has no effective current treatment. It is characterized by a sub-pleural onset and the presence of myofibroblasts, responsible for the excessive extracellular matrix synthesis. Transforming Growth Factor (TGF)-β1 is considered as the major profibrotic cytokine. Its signaling pathway occurs through the Smads proteins, including Smad4. TGF-β1 allows the differentiation of lung fibroblasts and epithelial and mesothelial cells into myofibroblasts. AB-crystallin is a small heat shock protein overexpressed in liver, renal and vascular fibrosis and can be induced by TGF-β1. In this study, we assessed the role of αB-crystallin in pleural and pulmonary fibrosis. We show that αB-crystallin is overexpressed in the lung and the pleura of IPF patients. In vivo, in three pulmonary fibrosis models (bleomycin, TGF-β1 or IL-1β overexpression) αB-crystallin KO mice are protected from fibrosis with an inhibition of the TGF-β pathway. In vitro, in epithelial and mesothelial cells or fibroblasts, αB-crystallin increases Smad4 nuclear localization. Interacting with TIF1γ, responsible for the nuclear export of Smad4, it promotes the nuclear sequestration of Smad4 and thus its profibrotic activity. Instead, αB-crystallin inhibition allows the formation of the Smad4/TIF1γ complex and promotes Smad4 nuclear export an profibrotic activity. This work shows the importance of αB-crystallin in pleuro-pulmonary fibrosis and its role on the TGF-β1 pathway. AB-crystallin appears as a putative therapeutic target for IPF.