DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B-cell activation and differentiation

Systemic lupus erythematosus (SLE) is characterized by the excessive production of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Recent studies have shown that DNA damage responses play a crucial role in B cell activity in SLE, and DNA damage induced transcript 3 (DDIT3) is involved in the innate immune response. However, the exact role of DDIT3 in humoral immune response and the pathogenesis of SLE is still unknown. In this study, we aim to investigate the regulatory role of DDIT3 in B-cell homeostasis and lupus pathogenesis. We observed an increased expression of DDIT3 in B cells from SLE patients, and this expression was positively correlated with disease activity. In DDIT3 deficient mice, we observed disturbances in B cell development and differentiation, as well as inhibition of B cell activation, actin cytoskeleton reorganization, and BCR signaling. Furthermore, DDIT3 deficiency resulted in a reduction in T-cell dependent humoral immune response and germinal center reaction. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Additionally, in the BM12-induced lupus model, we found that DDIT3 deficiency attenuated lupus symptoms and decreased germinal center responses, levels of anti-dsDNA antibodies, plasmablast cell differentiation, and renal damage. In conclusion, our study reveals for the first time the regulatory role of DDIT3 in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for intervention in the treatment of SLE.