The ERK1/2 signaling pathway promotes myelin wrapping during development and remyelination, and sustained ERK1/2 activation in the oligodendrocyte (OL) lineage results in hypermyelination of the CNS. We therefore hypothesized that increased ERK1/2 signaling in the OL lineage would 1) protect against immune-mediated demyelination due to increased baseline myelin thickness and/or 2) promote enhanced remyelination and thus functional recovery after experimental autoimmune encephalomyelitis (EAE) induction. Cnp-Cre;Mek1DD-eGFP/+ mice that express a constitutively active form of MEK1 (the upstream activator of ERK1/2) in the OL lineage, exhibited a significant decrease in EAE clinical severity compared to controls. However, experiments using tamoxifen-inducible Plp-Cre^ERT;Mek1DD-eGFP/+ or Pdgfrα-Cre^ERT;Mek1DD-eGFP mice revealed this was not solely due to a protective or reparative effect resulting from MEK1DD expression specifically in the OL lineage. Because EAE is an immune-mediated disease, we examined Cnp-Cre;Mek1DD-eGFP/+ splenic immune cells for recombination. Surprisingly, GFP⁺ recombined CD19⁺ B-cells, CD11b⁺ monocytes, and CD3⁺ T-cells were noted when Cre expression was driven by the Cnp promoter. While ERK1/2 signaling in monocytes and T-cells is associated with proinflammatory activation, fewer studies have examined ERK1/2 signaling in B-cell populations. After in vitro stimulation, MEK1DD-expressing B-cells exhibited a 3-fold increase in CD138⁺ plasmablasts and a 5-fold increase in CD5⁺CD1d^hi B-cells compared to controls. Stimulated MEK1DD-expressing B-cells also exhibited an upregulation of IL-10, known to suppress the initiation of EAE when produced by CD5⁺CD1d^hi regulatory B-cells. Taken together, our data support the conclusion that sustained ERK1/2 activation in B-cells suppresses immune-mediated demyelination via increasing activation of regulatory B10 cells.

ERK1/2 信号通路在发育和髓鞘再生过程中促进髓鞘包裹，少突胶质细胞 (OL) 谱系中 ERK1/2 的持续激活会导致中枢神经系统髓鞘过度形成。因此，我们假设 OL 谱系中 ERK1/2 信号传导的增加将 1) 防止由于基线髓磷脂厚度增加而导致的免疫介导的脱髓鞘和/或 2) 促进髓鞘再生增强，从而在实验性​​自身免疫性脑脊髓炎 (EAE) 诱导后促进功能恢复。在 OL 谱系中表达 MEK1（ERK1/2 上游激活剂）组成型活性形式的Cnp-Cre;Mek1DD-eGFP/+小鼠，与对照组相比，EAE 临床严重程度显着降低。然而，使用他莫昔芬诱导的Plp-Cre ^ERT ;Mek1DD-eGFP/+或Pdgfrα-Cre ^ERT ;Mek1DD-eGFP小鼠的实验表明，这不仅仅是由于 MEK1DD 在 OL 谱系中的表达所产生的保护或修复作用。由于 EAE 是一种免疫介导的疾病，我们检查了Cnp-Cre ； Mek1DD-eGFP/+脾免疫细胞用于重组。令人惊讶的是，当 Cnp 启动子驱动 Cre 表达时，注意到 GFP ⁺重组 CD19 ⁺ B 细胞、CD11b ⁺单核细胞和 CD3 ⁺ T 细胞。虽然单核细胞和 T 细胞中的 ERK1/2 信号传导与促炎症激活相关，但很少有研究检查 B 细胞群中的 ERK1/2 信号传导。体外刺激后，与对照组相比，表达 MEK1DD 的 B 细胞的 CD138 ⁺浆母细胞增加了 3 倍，CD5 ⁺ CD1d ^hi B 细胞增加了 5 倍。 受刺激的表达 MEK1DD 的 B 细胞还表现出 IL-10 的上调，已知当 CD5 ⁺ CD1d ^hi调节 B 细胞产生时，IL-10 会抑制 EAE 的启动。综上所述，我们的数据支持这样的结论：B 细胞中持续的 ERK1/2 激活通过增加调节性 B10 细胞的激活来抑制免疫介导的脱髓鞘。