Butyrophilin 3A1 Contributes to Inflammation and Induces a Lupus-Like Disease by Inhibiting the IL-38-Ferroptosis Axis

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Recent evidence has linked butyrophilin 3A1 (BTN3A1) to immune dysregulation. This study was to elucidate the relationship of BTN3A1 in SLE. Expression of BTN3A1 in plasma and peripheral blood mononuclear cells from SLE patients and healthy controls explored the association between BTN3A1 and SLE. We found that BTN3A1 mRNA, plasma levels, and expression in CD4⁺ T cells were significantly elevated in SLE patients. In BTN3A1 gene knock-in (BTN3A1^KI) mice, inflammation and lupus-like manifestations occurred, including increased proportions of Th1, Th2, and Th17 cells, decreased Treg cells, elevated levels of inflammatory cytokines and anti-dsDNA antibodies, renal injury, and suppressed IL-38 serum levels. Intraperitoneal injection of IL-38 in pristane-treated BTN3A1^KI mice notably alleviated these pathological changes. Mechanistic investigations revealed that CD4⁺ T cells and the ferroptosis pathway were closely associated with the effects mediated by the BTN3A1-IL-38 axis. In vitro experiments showed that IL-38 stimulation reduced proliferation, apoptosis, and decreased the expression of ferroptosis-related proteins, Fe²⁺, glutathione, and malondialdehyde in CD4⁺BTN3A1^+/+ T and BTN3A1^+/+ Jurkat T cells. Overall, BTN3A1 plays a crucial role in SLE pathogenesis by regulating CD4⁺ T cell function.