HDAC10-mediated acetylation of COX5A promotes inflammatory responses of silica- treated macrophages in silicosis via the ROS/NF-κβ/TNF-α pathway

Abstract BackgroundSilicosis is pneumoconiosis of the lung, which usually results from prolonged exposure to and inhalation of silicon dioxide. Currently an effective treatment for silicosis is lacking. The hallmark of silicosis is chronic inflammation of silica-treated macrophages. However, the detailed molecular mechanism underlying silicosis remains elusive. MethodsSilicotic rats were established by a single intratracheal instillation of silica suspension. The lung tissues from silicotic and control rats were obtained for pathological observation, transcriptome sequencing, tandem mass tag quantitative proteomic analysis and quantitative proteome detection by acetylation modification. We further examined silica-treated macrophage-derived inflammation and the underlying molecular mechanism using siRNAs and overexpression plasmids in vitro.Results Transcriptome sequencing revealed downregulated expression of histone deacetylase 10 (HDAC10) in lungs from silicotic rats. Knockdown of HDAC10 enhanced the acetylation level of cytochrome oxidase 5A(COX5A) in rat silicosis tissue and increased reactive oxygen species (ROS), which led to increased secretion of inflammatory factors and chemokines from silica-treated macrophages. High acetylation of COX5A aggravated silica-treated macrophage-derived inflammation by the ROS/NF-κb/TNF-α pathway.ConclusionOur results indicate that HDAC10 mediates silica-treated macrophage-derived inflammation by the ROS/NF-κb/TNF-α pathway. Targeting this pathway may help improve silicosis and represents a potential therapeutic strategy to reduce inflammation and potentially treat silicosis.