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

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.

Macrophage Autophagy and Silicosis: Current Perspective and Latest Insights

“…According to the changes in silica-induced lesions, after instilling SiO 2 suspension into the trachea, the observation of inflammation can be selected on the 7th day. Normally, typical silicon nodules can be observed after the 28th day, usually 7 days as a unit, that is, 42 days, 56 days, or longer [ 11 , 12 , 13 ]. However, whether it is SiO 2 aerosol or SiO 2 suspension, both have to have been sterilized before modeling.…”

“…Knockout of TFEB aggravates silica-induced AM apoptosis by disruption of the autophagy-lysosomal system in the silicosis mice model. However, the nuclear transfer of TFEB activated by Tre relieves silica-induced lysosome damage and disorder of autophagic substrates degradation, reducing apoptosis in the mice-derived AM or AM of silicosis patients [ 11 , 78 ].…”

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

“…Annexin A2 (ANXA2) was observed to alleviate lung fibrosis caused by BLM by combining with BLM and accelerating TFEB-mediated autophagy flux in vitro and in vivo , which was abolished by CQ and bafilomycin A1 in the ANXA2 genetic depletion mice and CRISPR-Cas9-engineered ANXA2 mutation lung epithelial cells 94 . More recently, it has been reported that the overexpression of TFEB or treatment with a TFEB activator, trehalose, suppressed the levels of inflammatory cytokine and prevented lung fibrosis by attenuating lysosomal dysfunction and augmenting autophagy flux in alveolar macrophages, which was abolished by CQ, bafilomycin A1 and TFEB knockdown 95 . Collectively, these findings support that the impairment of autophagy in IPF progression is tightly regulated by the interplay between TFEB location and lysosomal dysfunction.…”

Multi-omics study of silicosis reveals the potential therapeutic targets PGD2 and TXA2

“…Various cells and factors have been reported to participate in the crystalline silica-triggered pathogenesis of silicosis 6 . Growing studies reveal that autophagy-lysosomal system dysfunction in alveolar macrophages (AMs) involves in silica-induced inflammatory and fibrotic process 7 - 9 . Moreover, the recruitment of lymphocytes and neutrophils are reported to provoke an inflammation response that afterwards leads to fibrosis 10 - 13 .…”