Sphingomyelin Synthase 1 Enhances BCR Signaling to Promote Lupus-Like Autoimmune Response

Abstract

Sphingomyelin synthase 1 (SMS1) has been reported to participate in hepatitis and athereosclerosis. However, its role in autoimmune response is not clear. In this study, we investigate the possible involvement of SMS1 in B-cell activation and lupus-like autoimmunity. SMS1 knockout lupus-like animal model and SLE patient samples were utilized. We found that SMS1 deficiency suppressed B-cell activation in culture, which was restored by exogenous SM supplementation. Accordingly, the BCR-mediated early signal transduction including the colocalization of BCR with F-actin or pY/pBtk, and the phosphorylation of intracellular Fyn and Syk were impaired in SMS1 knockout B cells. Furthermore, SMS1 knockout mice showed reduced production and deposition of autoantibodies, accompanied by less severe kidney pathological changes after pristane induction. SMS1 deficiency also displayed lower autoantibody titers and 24h urine protein excretion in bm12-induced lupus, which were associated with reduced B-cell activation. Adoptively transferred wide-type B cells partially recovered B-cell activation and autoantibody production in SMS1 deficient bm12-induced lupus mice. Moreover, the SMS1 mRNA level in B cells of SLE patients was increased and positively correlated with the serum IgG production and globulin titers. These data suggest that SMS1 is involved in lupus-like autoimmunity via regulating BCR signal transduction and B cell activation. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (no. 31270965 and 81771754 to Lingli Dong) and Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST to Lingli Dong and Xiangping Yang. Declaration of Interests: The authors declare that there is no conflict of interest in this study. Ethics Approval Statement: This study was approved by the ethic committee of Tongji Hospital. Informed consents were obtained from all participants.