Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, Republic of Korea.
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea.
Front Immunol. 2023 Jun 20;14:1151511. doi: 10.3389/fimmu.2023.1151511. eCollection 2023.
Multiple sclerosis (MS) is a potentially disabling disease that damages the brain and spinal cord, inducing paralysis of the body. While MS has been known as a T-cell mediated disease, recent attention has been drawn to the involvement of B cells in its pathogenesis. Autoantibodies from B cells are closely related with the damage lesion of central nervous system and worse prognosis. Therefore, regulating the activity of antibody secreting cell could be related with the severity of the MS symptoms.
Total mouse B cells were stimulated with LPS to induce their differentiation into plasma cells. The differentiation of plasma cells was subsequently analyzed using flow cytometry and quantitative PCR analysis. To establish an experimental autoimmune encephalomyelitis (EAE) mouse model, mice were immunized with MOG/CFA emulsion.
In this study, we found that plasma cell differentiation was accompanied by upregulation of autotaxin, which converts sphingosylphosphorylcholine (SPC) to sphingosine 1-phosphate in response to LPS. We observed that SPC strongly blocked plasma cell differentiation from B cells and antibody production . SPC downregulated LPS-stimulated IRF4 and Blimp 1, which are required for the generation of plasma cells. SPC-induced inhibitory effects on plasma cell differentiation were specifically blocked by VPC23019 (S1PR1/3 antagonist) or TY52159 (S1PR3 antagonist), but not by W146 (S1PR1 antagonist) and JTE013 (S1PR2 antagonist), suggesting a crucial role of S1PR3 but not S1PR1/2 in the process. Administration of SPC against an EAE mouse model significantly attenuated the symptoms of disease, showing decreased demyelinated areas of the spinal cord and decreased numbers of cells infiltrated into the spinal cord. SPC markedly decreased plasma cell generation in the EAE model, and SPC-induced therapeutic effects against EAE were not observed in μMT mice.
Collectively, we demonstrate that SPC strongly inhibits plasma cell differentiation, which is mediated by S1PR3. SPC also elicits therapeutic outcomes against EAE, an experimental model of MS, suggesting SPC as a new material to control MS.
多发性硬化症（MS）是一种潜在的致残性疾病，可损害大脑和脊髓，导致身体瘫痪。虽然 MS 被认为是一种 T 细胞介导的疾病，但最近人们越来越关注 B 细胞在其发病机制中的作用。B 细胞产生的自身抗体与中枢神经系统损伤病变和预后不良密切相关。因此，调节抗体分泌细胞的活性可能与 MS 症状的严重程度有关。
用 LPS 刺激总小鼠 B 细胞诱导其分化为浆细胞。随后使用流式细胞术和定量 PCR 分析来分析浆细胞的分化。为了建立实验性自身免疫性脑脊髓炎（EAE）小鼠模型，用 MOG/CFA 乳剂免疫小鼠。
在这项研究中，我们发现浆细胞分化伴随着自分泌酶的上调，自分泌酶在 LPS 刺激下将鞘氨醇磷酸胆碱（SPC）转化为 1-磷酸鞘氨醇。我们观察到 SPC 强烈抑制 B 细胞向浆细胞分化和抗体产生。SPC 下调 LPS 刺激的 IRF4 和 Blimp 1，这是产生浆细胞所必需的。SPC 对浆细胞分化的抑制作用可被 VPC23019（S1PR1/3 拮抗剂）或 TY52159（S1PR3 拮抗剂）特异性阻断，但不能被 W146（S1PR1 拮抗剂）和 JTE013（S1PR2 拮抗剂）阻断，表明 S1PR3 而不是 S1PR1/2 在该过程中起关键作用。给予 SPC 可明显减轻 EAE 小鼠模型的疾病症状，表现为脊髓脱髓鞘面积减少和脊髓浸润细胞数量减少。SPC 明显减少 EAE 模型中的浆细胞生成，并且在 μMT 小鼠中未观察到 SPC 诱导的对 EAE 的治疗作用。
综上所述，我们证明 SPC 强烈抑制浆细胞分化，这是由 S1PR3 介导的。SPC 还对 EAE（MS 的实验模型）产生治疗效果，表明 SPC 作为一种控制 MS 的新材料。
