Cnp Promoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis.
Cnp Promoter-Driven Sustained ERK1/2 Activation Increases B-Cell Activation and Suppresses Experimental Autoimmune Encephalomyelitis.
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DOI：
10.1177/1759091420971916
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发表时间：
2020-01
期刊：
影响因子：
4.7
通讯作者：
Wood TL
中科院分区：
文献类型：
--
作者：
Jeffries MA;Obr AE;Urbanek K;Fyffe-Maricich SL;Wood TL
ERK 1/2信号通路在发育和髓鞘再生过程中促进髓鞘包裹，并且在少突胶质细胞（OL）谱系中持续的ERK 1/2活化导致CNS的髓鞘过度形成。因此，我们假设OL谱系中增加的ERK 1/2信号传导将1）防止由于基线髓鞘厚度增加而引起的免疫介导的脱髓鞘和/或2）促进增强的髓鞘再生，从而促进实验性自身免疫性脑脊髓炎（EAE）诱导后的功能恢复。Cnp-Cre;与对照组相比，在OL谱系中表达组成型活性形式的MEK 1（ERK 1/2的上游激活剂）的Mek 1DD-eGFP/+小鼠表现出EAE临床严重程度的显著降低。然而，使用他莫昔芬诱导型Plp-CreERT; Mek 1DD-eGFP/+或Pdgfrα-CreERT; Mek 1DD-eGFP小鼠的实验显示，这不仅仅是由于特异性在OL谱系中MEK 1DD表达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; Mek 1DD-eGFP/+脾免疫细胞的重组。令人惊讶的是，当Cre表达由Cnp启动子驱动时，注意到GFP+重组的CD 19 + B细胞、CD 11b+单核细胞和CD 3 + T细胞。虽然单核细胞和T细胞中的ERK 1/2信号传导与促炎活化相关，但很少有研究检查B细胞群体中的ERK 1/2信号传导。体外刺激后，与对照组相比，表达MEK 1DD的B细胞的CD 138+浆母细胞增加了3倍，CD 5 + CD 1dhi B细胞增加了5倍。刺激的表达MEK 1DD的B细胞也表现出IL-10的上调，已知IL-10在由CD 5 + CD 1dhi调节性B细胞产生时抑制EAE的起始。综上所述，我们的数据支持这样的结论，即持续的ERK 1/2激活的B细胞抑制免疫介导的脱髓鞘通过增加激活的调节B10细胞。
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-CreERT;Mek1DD-eGFP/+ or Pdgfrα-CreERT;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+CD1dhi 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+CD1dhi 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.
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DOI：
10.4049/jimmunol.1103015
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chang CF;D'Souza WN;Ch'en IL;Pages G;Pouyssegur J;Hedrick SM
通讯作者：
Hedrick SM
影响因子：
16.2
作者：
Kang, Shin H.;Fukaya, Masahiro;Yang, Jason K.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
7.3
作者：
Kubo M;Motomura Y
通讯作者：
Motomura Y
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA
影响因子：
4.8
作者：
Jacob, A;Cooney, D;Coggeshall, KM
通讯作者：
Coggeshall, KM