1,2-bis(2,4,6-tribromophenoxy) ethane, a novel brominated flame retardant, induces hepatic fibrosis: New insights into crosstalk between macrophage extracellular traps and stellate cell activation.

As a novel brominated flame retardant widely used in life, 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE) will be released into the environment. This leads to its exposure to living organisms, so it is important to explore its toxic mechanism. The liver is a major accumulation organ of BTBPE. When the liver sustains repeated damage leading to abnormal proliferation of connective tissue, this triggers hepatic fibrosis; should this process continue to progress, it will ultimately evolve into cirrhosis. In our study, BTBPE was administered to Sprague-Dawley (SD) rats, rat macrophages (RMa-bm cells) and rat hepatic stellate cells (HSCs) (HSC-T6 cells) in vivo or in vitro, respectively. This study found that BTBPE exposure caused hepatic fibrosis. This hepatic fibrosis is caused by the crosstalk between macrophage extracellular traps (METs) and HSCs activation. Firstly, exposure to BTBPE activates the miR-3570/IRX3/NOS2 axis in macrophages, thereby inducing METs. Subsequently, METs come into contact with HSCs, inhibiting the PPAR pathway in HSCs, thereby activating HSCs and producing excessive collagen and αSMA, ultimately leading to hepatic fibrosis. It is worth noting that the DNA structure in METs contributes significantly to the HSCs activation. This study for the first time discovered that the miR-3570/IRX3/NOS2 axis is involved in regulating METs, and found a relationship between METs and HSCs activation. It also found that the PPAR pathway is one of the signaling pathways involved in METs stimulating HSCs activation. This study enriches the understanding of the mechanisms of hepatic fibrosis caused by BTBPE exposure, provides new directions for the study of fibrosis, and identifies important therapeutic targets and pathways for adverse outcomes in environmental harmful factors-induced hepatic fibrosis.