Elevated transferrin receptor 1 promoting B-cell autoimmunity in systemic lupus erythematosus

Transferrin receptor 1 (TFR1), a major iron receptor for immune cells, could impair T cell metabolism and function in systemic lupus erythematosus (SLE), leading us to investigate the effects of TFR1 and possible mechanisms on lupus B cells.

B cells from lupus mouse models and systemic lupus erythematosus (SLE) patients were evaluated using flow cytometry (FCM) for levels of TFR1, intracellular iron deposition, reactive oxygen species (ROS), lipid peroxidation, and B-cell subsets. Transcript levels of TFR1 were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and upstream regulatory molecules were identified by in vitro gene silencing.

An agonist of toll-like receptor 7 (TLR7), R848 treatment significantly increased TFR1 expression in B cells from C57BL/6 (B6) mice but not those from MRL/lpr mice. In in vitro cultures of mouse splenocytes, TLR7 dose-dependently promoted TFR1 expression, and its effect was probably mediated by P53. Anti-TFR1 antibody effectively inhibited intracellular iron deposition in lupus B cells, reduced ROS and lipid peroxidation, and prevented the production of plasmablasts and autoantibodies. Among different B cell subsets, TFR1 was predominantly expressed in double negative (DN) B cells, with a more pronounced effect on DN2 B cells, which could be normalized by ROS inhibitors. Similarly, in human studies, TFR1 was highly expressed in B cells of SLE patients and closely correlated with TLR7 expression and disease activity scores, as well as iron deposition and ROS production. A significant reduction in ROS production was observed after blocking TFR1.

TLR7-regulated TFR1 may drive B-cell autoimmunity by promoting ROS production, thus contributing to SLE pathogenesis.