Genome-wide mRNA profiling identifies the NRF2-regulated lymphocyte oxidative stress status in patients with silicosis.

Abstract

Background: The immunomodulatory abnormalities of silicosis are related to the lymphocyte oxidative stress state. The potential effect of antioxidant therapy on silicosis may depend on the variation in nuclear factor erythroid 2-related factor 2 (NRF2)-regulated antioxidant genes in peripheral blood mononuclear cells (PBMCs). As NRF2 is a redox-sensitive transcription factor, its possible roles and underlying mechanism in the treatment of silicosis need to be clarified.

Methods: Ninety-two male patients with silicosis and 87 male healthy volunteers were randomly selected. PBMCs were isolated from fresh blood from patients with silicosis and healthy controls. The lymphocyte oxidative stress state was investigated by evaluating NRF2 expression and NRF2-dependent antioxidative genes in PBMCs from patients with silicosis. Key differentially expressed genes (DEGs) and signaling pathways were identified utilizing RNA sequencing (RNA-Seq) and bioinformatics technology. Gene set enrichment analysis was used to identify the differences in NRF2 signaling networks between patients with silicosis and healthy controls.

Results: The number of monocytes was significantly higher in patients with silicosis than that of healthy controls. Furthermore, RNA-Seq findings were confirmed using quantitative polymerase chain reaction and revealed that NRF2-regulated DEGs were associated with glutathione metabolism, transforming growth factor-β, and the extracellular matrix receptor interaction signaling pathway in PBMCs from patients with silicosis. The top 10 hub genes were identified by PPI analysis: SMAD2, MAPK3, THBS1, SMAD3, ITGB3, integrin alpha-V (ITGAV), von Willebrand factor (VWF), BMP4, CD44, and SMAD7.

Conclusions: These findings suggest that NRF2 signaling regulates the lymphocyte oxidative stress state and may contribute to fibrogenic responses in human PBMCs. Therefore, NRF2 might serve as a novel preventive and therapeutic candidate for silicosis.