Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages.

Ying Chen,Yangyang He,Chao Li,Shi Chen,Yungeng Wei,Fangwei Liu,Xiu He,Jiaqi Ban,Jie Chen

doi:10.3390/cells9010122

Ying Chen, Yangyang He + Show 7 more

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https://doi.org/10.3390/cells9010122

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Journal: Cells	Publication Date: Jan 4, 2020
Citations: 28	License type: CC BY 4.0

Affiliation: China Medical University, Hunan Normal University

Abstract

Silicosis is an occupational lung disease characterized by persistent inflammation and irreversible fibrosis. Crystalline silica (CS) particles are mainly phagocytized by alveolar macrophages (AMs), which trigger apoptosis, inflammation, and pulmonary fibrosis. Previously, we found that autophagy-lysosomal system dysfunction in AMs was involved in CS-induced inflammation and fibrosis. Induction of autophagy and lysosomal biogenesis by transcription factor EB (TFEB) nuclear translocation can rescue fibrotic diseases. However, the role of TFEB in silicosis is unknown. In this study, we found that CS induced TFEB nuclear localization and increased TFEB expression in macrophages both in vivo and in vitro. However, TFEB overexpression or treatment with the TFEB activator trehalose (Tre) alleviated lysosomal dysfunction and enhanced autophagic flux. It also reduced apoptosis, inflammatory cytokine levels, and fibrosis. Both pharmacologically inhibition of autophagy and TFEB knockdown in macrophages significantly abolished the antiapoptotic and anti-inflammatory effects elicited by either TFEB overexpression or Tre treatment. In conclusion, these results uncover a protective role of TFEB-mediated autophagy in silicosis. Our study suggests that restoration of autophagy-lysosomal function by Tre-induced TFEB activation may be a novel strategy for the treatment of silicosis.

Highlights

Silicosis is caused by the inhalation of respirable crystalline silica (CS), which causes persistent inflammation and irreversible fibrosis
transcription factor EB (TFEB) belongs to the MiT-TFE family of basic helix–loop–helix leucine-zipper transcription factors, which plays a vital role in the adaptation of cell homeostasis [31]
TFEB nuclear localization was more evident in alveolar macrophages (AMs) present in silicotic lesions as compared with the control tissue (Figure 1D)

Summary

Introduction

Silicosis is caused by the inhalation of respirable crystalline silica (CS), which causes persistent inflammation and irreversible fibrosis. Silicosis is a progressive condition that is almost always fatal even when exposure to CS dust has ceased [1,2,3]. It is generally accepted that alveolar macrophages (AMs) are the first and main target cells to contact with CS particles [4]. The primary function of resident AMs is to keep the air spaces clear by the removal of foreign substances; CS cannot be degraded and eventually causes fibrosis [5,6]. Apoptosis of AMs appears to play a critical role in silicosis. Apoptotic AMs release their contents, which can aggravate apoptosis and the inflammatory response to induce tissue damage and fibrosis [7].

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