Up-regulation of SELENBP1 in inflammatory macrophages promoted proliferation and migration of synovial fibroblasts by promoting ROS production via blocking NRF2 signaling in rheumatoid arthritis

Introduction:
The immunopathogenesis of rheumatoid arthritis (RA) is greatly affected by macro- phages. However, the precise mechanisms by which selenium-binding protein 1 (SELENBP1) regulates the interaction between macrophages and synovial fibroblasts remain incompletely understood.

Material and methods:
We used macrophages (THP-1) that were activated with lipopolysaccharide (LPS) and interferon γ (IFN-γ), combined with gene knockdown techniques and molecular biology assays, to investigate the role of SELENBP1 in oxidative stress and nuclear factor erythroid 2-related factor 2 (NRF2) signaling activation. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell assay were used to examine the regulatory effect of macrophage on proliferation and migration of synovial fibroblasts (MH7A).

Results:
Bioinformatics analysis revealed significant upregulation of SELENBP1 in RA. LPS/IFN-γ treatment significantly increased SELENBP1 expression in THP-1 cells; promoted reactive oxygen species (ROS) production and oxidative stress, downregulation of NRF2 in the THP-1 cell nucleus, and upregulation of NRF2 in the cytoplasm; and increased proliferation and migration of MH7A cells. Knockdown of SELENBP1 reversed these effects of LPS/IFN-γ on the THP-1 and MH7A cells. In addition, ML385 (NRF2 inhibitor) attenuated the inhibitory effect of SELENBP1 knockdown on the ROS production and oxidative stress of THP-1 cells, as well as proliferation and migration of MH7A cells.

Conclusions:
Inflammatory macrophages up-regulated SELENBP1, and knockdown of SELENBP1 inhibited inflammatory macrophage-induced ROS production and oxidative stress levels by activating NRF2 signaling, thereby inhibiting the proliferation and migration of synovial fibroblasts. Highly expressed SELENBP1 promoted the development of RA. These discoveries provide potential molecular targets and mechanistic insights for the development of new therapeutic strategies.