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).

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

“…A recent study showed that SMS1 deficiency suppressed B-cell activation and lupus-like autoimmunity such as systemic lupus erythematosus (SLE). 115 In an in vitro culture system of B cells, IgM-mediated activation and differentiation into plasma cells were suppressed in SMS1 deficient cells. Interestingly, supplementation of SM in the culture media recovered both activation and differentiation in SMS1-KO B cells.…”

SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center

“…In addition, although 2OHOA can activate both SMS1 and SMS2, we believe that its therapeutic effect on lupus is achieved via activation of SMS2. This is because a recent study showed that systemic SMS1 deficiency attenuated the pathogenesis of lupus in pristane and bm12 models (Wang et al, 2019), in which innate immune responses play a central regulatory role in pathogenesis (Han et al, 2017;Shi et al, 2014;Zhao et al, 2007). Therefore, the evidence points to SMS2 as the primary target of 2OHOA in autoreactive dsDNA-specific GC B cells, in keeping with the highly upregulated expression of SMS2, but not SMS1, in these cells (Figure 4).…”

A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency

“…47 Moreover, T-and B-cell activations through their receptors were prevented by SM depletion of DRMs in SMS1-KO mice, resulting in SM-deficient amelioration of hepatitis or systemic lupus erythematosus, but not in SMS2-KO mice. 19,48 Furthermore, JEV can achieve infection by attaching to target cell membranes through SMS1-generated SM. 23 Consequently, SMS1-KO mice are protected from JEV infection and JEV-mediated encephalitis.…”