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Article Abstract
Purpose: Dry eye disease with ocular surface inflammation leads to corneal epithelial cell damage. This study aims to investigate the role of activating transcription factor 3 (ATF3) in hyperosmotic stress (HS)-induced damage in human corneal epithelial (HCE) cells and to identify new targets for dry eye disease treatment.
Methods: HCE cells were treated with isotonic or hypertonic (312 and 500 mOsM) culture media for 24 hours and added by 94 mM of NaCl to achieve hyperosmotic conditions. After siRNA-ATF3 transfection, the expression of ATF3, LncRNA nuclear-enriched abundant transcript 1 (NEAT1), human antigen R (HuR), and toll-like receptor 4 (TLR4) were detected using qRT-PCR and western blot assays. Cell proliferation was analyzed by the CCK-8 assay. LDH, ROS, TNF-α, IL-1β, and IL-6 levels were measured. Cell apoptosis was measured by flow cytometry. ATF3 enrichment on the NEAT1 promoter was analyzed. The binding of ATF3 to the NEAT1 promoter and HuR to NEAT1 and TLR4 was analyzed. TLR4 mRNA stability was measured. Overexpression of NEAT1 or TLR4 combined with ATF3 knockdown was performed to verify the mechanism.
Results: HS induced LDH release, ROS production, apoptosis, and inflammation in HCE cells and upregulated ATF3 expression. Knockdown of ATF3 alleviated above cell damage. ATF3 promoted NEAT1 expression, and NEAT1 enhanced the stability of TLR4 mRNA by binding to HuR. Overexpression of NEAT1 or TLR4 partially reversed the protective effect of ATF3 knockdown on HS-induced HCE cell damage.
Conclusions: ATF3 promotes HS-induced damage in HCE cells by increasing TLR4 expression through upregulating NEAT1 expression.
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