Sphingomyelin synthase 1 enhances BCR signaling to promote lupus-like autoimmune response.

ABSTRACT: BACKGROUND:Sphingomyelin synthase 1 (SMS1) has been reported to participate in hepatitis and atherosclerosis. However, its role in autoimmune response is not clear. This study investigates the possible involvement of SMS1 in B-cell activation and lupus-like autoimmunity. METHODS:SMS1 knockout lupus-like animal model and SLE patient samples were utilized. B-cell activation and associated signal transduction were detected by flow cytometry, confocal analysis and western blotting. The SMS1 expression in B cells was measured by real-time qPCR. FINDINGS:SMS1 deficiency suppressed B-cell activation in culture, which was restored by exogenous SM supplementation. 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 24?h 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 anti-dsDNA level, IgG and globulin titers. INTERPRETATION:These data suggest that SMS1 is involved in lupus-like autoimmunity via regulating BCR signal transduction and B cell activation. (Word count for the abstract: 230).

SUBMITTER: Wang C 

PROVIDER: S-EPMC6642282 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature