DAPTA, a C-C Chemokine Receptor 5 (CCR5), Leads to the Downregulation of Notch/NF-κB Signaling and Proinflammatory Mediators in CD40(+) Cells in Experimental Autoimmune Encephalomyelitis Model in SJL/J Mice.
DAPTA, a C-C Chemokine Receptor 5 (CCR5), Leads to the Downregulation of Notch/NF-κB Signaling and Proinflammatory Mediators in CD40(+) Cells in Experimental Autoimmune Encephalomyelitis Model in SJL/J Mice.
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DOI：
10.3390/biomedicines11061511
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发表时间：
2023-05-23
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
多发性硬化（MS）是中枢神经系统的自身免疫性炎性疾病，其特征在于运动缺陷、认知障碍、疲劳、疼痛以及感觉和视觉功能障碍。CD 40在B细胞中高度表达，在MS发病机制中起重要作用。MS的实验性自身免疫性脑脊髓炎（EAE）小鼠模型已经很好地建立，以及其在MS患者中的相关性。本研究旨在评价DAPTA（一种选择性C-C趋化因子受体5（CCR 5）拮抗剂）在MS小鼠模型中的治疗潜力，并扩大对其作用机制的认识。在诱导EAE后，将DAPTA（0.01mg/kg，i. p.）从第14天至第42天每天。我们使用流式细胞术研究了DAPTA对CD 40+脾B细胞中NF-κB p65、IκBα、Notch-1、Notch-3、GM-CSF、MCP-1、iNOS和TNF-α的影响。此外，我们还使用qRT-PCR分析了DAPTA对脑组织中NF-κB p65、IκBα、Notch-1、Notch-3、GM-CSF、MCP-1、iNOS和TNF-α mRNA表达水平的影响。用DAPTA处理的EAE小鼠显示NF-κB p65、Notch-1、Notch-3、GM-CSF、MCP-1、iNOS和TNF-α显著降低，但CD 40 + B淋巴细胞的IκBα增加。此外，经DAPTA处理的EAE小鼠显示NF-κB p65、Notch-1、Notch-3、GM-CSF、MCP-1、iNOS和TNF-α降低，但IκBα mRNA表达水平升高。DAPTA可能通过下调炎症介质和NF-κB/Notch信号通路发挥神经保护作用。总的来说，DAPTA可能具有用于MS治疗的潜在治疗靶点。
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by motor deficits, cognitive impairment, fatigue, pain, and sensory and visual dysfunction. CD40, highly expressed in B cells, plays a significant role in MS pathogenesis. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS has been well established, as well as its relevance in MS patients. This study aimed to evaluate the therapeutic potential of DAPTA, a selective C-C chemokine receptor 5 (CCR5) antagonist in the murine model of MS, and to expand the knowledge of its mechanism of action. Following the induction of EAE, DAPTA was administrated (0.01 mg/kg, i.p.) daily from day 14 to day 42. We investigated the effects of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α in CD40+ spleen B cells using flow cytometry. Furthermore, we also analyzed the effect of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α mRNA expression levels using qRT-PCR in brain tissue. EAE mice treated with DAPTA showed substantial reductions in NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α but an increase in the IκBα of CD40+ B lymphocytes. Moreover, EAE mice treated with DAPTA displayed decreased NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α and but showed increased IκBα mRNA expression levels. This study showed that DAPTA has significant neuroprotective potential in EAE via the downregulation of inflammatory mediators and NF-κB/Notch signaling. Collectively, DAPTA might have potential therapeutic targets for use in MS treatment.
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影响因子：
3.7
作者：
Dishowitz MI;Mutyaba PL;Takacs JD;Barr AM;Engiles JB;Ahn J;Hankenson KD
通讯作者：
Hankenson KD
影响因子：
3.3
作者：
Balkowiec-Iskra, E.;Vermehren-Schmaedick, A.;Balkowiec, A.
通讯作者：
Balkowiec, A.
GM-CSF通过改变中枢神经系统渗透细胞的组成来促进实验性自身免疫性脑脊髓炎的慢性残疾，但可用于疾病诱导。
DOI：
10.4049/jimmunol.1701484
发表时间：
2018-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Duncker PC;Stoolman JS;Huber AK;Segal BM
通讯作者：
Segal BM
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
6
作者：
Fresegna D;Bullitta S;Musella A;Rizzo FR;De Vito F;Guadalupi L;Caioli S;Balletta S;Sanna K;Dolcetti E;Vanni V;Bruno A;Buttari F;Stampanoni Bassi M;Mandolesi G;Centonze D;Gentile A
通讯作者：
Gentile A