Immethridine, histamine H(3)-receptor (H(3)R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells.
Immethridine, histamine H(3)-receptor (H(3)R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells.
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Immethridine 是组胺 H-3 受体 (H3R) 激动剂，通过抑制树突状细胞的功能缓解实验性自身免疫性脑脊髓炎
DOI：
10.18632/oncotarget.20500
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Shi Y;Li Z;Chen R;Zhang J;Hu X;He C;Su Q;Ma H;Ren H;Qian M;Cui S;Jiang W
多发性硬化症(MS)是一种以免疫介导的中枢神经系统(CNS)脱髓鞘和变性为特征的炎症性疾病。实验性自身免疫性脑脊髓炎(EAE)是多发性硬化症首选的实验啮齿动物模型。以往的研究表明，组胺H3受体(H3R)是EAE病理生理过程中的重要因素，而亚甲基吡啶是H3R选择性最强的激动剂。然而，亚甲基吡啶对EAE是否有治疗作用及其作用机制尚不清楚。本实验用MOG35-55多肽与完全弗氏佐剂免疫小鼠建立了EAE小鼠模型，并对其治疗效果进行了评价。结果表明，亚甲基吡啶治疗可减轻EAE。治疗组小鼠脾内Th1、Th17细胞百分率下降，树突状细胞表面分子CD40、CD86或MHCII表达下调。为了解亚甲基吡啶对DC的作用，制备骨髓来源的DC，并对其免疫功能进行分析。结果表明，亚甲基啶可改变DC细胞因子的表达谱，抑制共刺激分子CD40、CD86的表达。此外，亚甲基啶还抑制DC的抗原提呈功能和DC诱导的T细胞分化。信号通路分析表明，亚甲基吡啶可抑制DC中NF-κBp65的磷酸化，但不抑制ERK1/2的磷酸化。这些数据有力地提示了亚甲基吡啶对DC功能的抑制作用，并提示了其对EAE的治疗潜力。
Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Previous study demonstrated histamine H3 receptor (H3R) was an important factor in pathophysiology of EAE and immethridine was the most selective agonist of H3R. However, whether immethridine has therapeutic effect on EAE and its mechanism remained to be defined. Here we constructed EAE mouse model by immunization of MOG35-55 peptides with complete Freund’s adjuvant, immethridine was used to treat EAE and its therapeutic effect was evaluated. The results showed that the treatment of immethridine could alleviate EAE. The percentage of Th1 and Th17 in the spleen from the treated EAE mice decreased and the surface molecules such as CD40, CD86 or MHCII on dendritic cells (DCs) were also down-regulated. To understand the effect of immethridine on DCs, bone marrow-derived DCs were prepared and the immunological functions were analyzed. The data demonstrated that immethridine could change the expression profiles of cytokines in DCs and inhibit the expression of the co-stimulatory molecules such as CD40 and CD86. Furthermore, immethridine also inhibited the antigen-presenting function of DCs and T cell differentiation induced by DCs. Signaling pathway analysis demonstrated that the phosphorylation of NF-κB p65 but not ERK1/2 in DCs was inhibited after the treatment of immethridine. These data strongly suggested that immethridine could inhibit the function of DCs and indicated the therapeutic potential on EAE.