多发性硬化症小鼠模型中作为 IL-6 来源的小胶质细胞和树突状细胞

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Violetta S. Gogoleva, Quynh Chi Nguyen, Marina S. Drutskaya
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引用次数: 0

摘要

摘要 多发性硬化症(MS)是一种复杂的中枢神经系统(CNS)自身免疫性疾病,以髓鞘破坏和神经信号传输受损为特征。由于多发性硬化症发病早、病程长,且治疗方法仅限于对症治疗,因此了解多发性硬化症的分子机制至关重要。众所周知,细胞因子在多发性硬化症的发病机制中起着关键作用,而白细胞介素-6(IL-6)是其中的关键介质之一。本研究调查了小胶质细胞和树突状细胞产生的IL-6对实验性自身免疫性脑脊髓炎(EAE)发病的贡献,EAE是一种广泛使用的多发性硬化症小鼠模型。与野生型小鼠相比,CX3CR1+细胞(包括小胶质细胞)或CD11c+树突状细胞中IL-6条件性失活的小鼠表现出的症状较轻。在EAE高峰期,小胶质细胞IL-6缺失的小鼠表现出调节性T细胞比例升高,产生致病性IFNγ的CD4+ T细胞比例降低,同时中枢神经系统中促炎性单核细胞减少。与此同时,小胶质细胞中 IL-6 的缺失导致 CCR6+ T 细胞和产生 GM-CSF 的 T 细胞增加。相反,树突状细胞中缺乏 IL-6 的小鼠不仅出现了之前描述的调节性 T 细胞比例增加和 TH17 细胞比例减少的情况,而且继发性淋巴器官中 GM-CSF 和 IFNγ 的产生也减少了。总之,IL-6在EAE期间的功能取决于免疫反应的来源和定位:小胶质细胞的IL-6在中枢神经系统中同时发挥致病和保护功能,而树突状细胞来源的IL-6除了关键性地参与调节性T细胞和TH17细胞的平衡外,还可能刺激与T细胞致病功能相关的细胞因子的产生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Microglia and Dendritic Cells as a Source of IL-6 in a Mouse Model of Multiple Sclerosis

Microglia and Dendritic Cells as a Source of IL-6 in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease of central nervous system (CNS) characterized by the myelin sheath destruction and compromised nerve signal transmission. Understanding molecular mechanisms driving MS development is critical due to its early onset, chronic course, and therapeutic approaches based only on symptomatic treatment. Cytokines are known to play a pivotal role in the MS pathogenesis with interleukin-6 (IL-6) being one of the key mediators. This study investigates contribution of IL-6 produced by microglia and dendritic cells to the development of experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of MS. Mice with conditional inactivation of IL-6 in the CX3CR1+ cells, including microglia, or CD11c+ dendritic cells, displayed less severe symptoms as compared to their wild-type counterparts. Mice with microglial IL-6 deletion exhibited an elevated proportion of regulatory T cells and reduced percentage of pathogenic IFNγ-producing CD4+ T cells, accompanied by the decrease in pro-inflammatory monocytes in the CNS at the peak of EAE. At the same time, deletion of IL-6 from microglia resulted in the increase of CCR6+ T cells and GM-CSF-producing T cells. Conversely, mice with IL-6 deficiency in the dendritic cells showed not only the previously described increase in the proportion of regulatory T cells and decrease in the proportion of TH17 cells, but also reduction in the production of GM-CSF and IFNγ in the secondary lymphoid organs. In summary, IL-6 functions during EAE depend on both the source and localization of immune response: the microglial IL-6 exerts both pathogenic and protective functions specifically in the CNS, whereas the dendritic cell-derived IL-6, in addition to being critically involved in the balance of regulatory T cells and TH17 cells, may stimulate production of cytokines associated with pathogenic functions of T cells.

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来源期刊
Biochemistry (Moscow)
Biochemistry (Moscow) 生物-生化与分子生物学
CiteScore
4.70
自引率
3.60%
发文量
139
审稿时长
2 months
期刊介绍: Biochemistry (Moscow) is the journal that includes research papers in all fields of biochemistry as well as biochemical aspects of molecular biology, bioorganic chemistry, microbiology, immunology, physiology, and biomedical sciences. Coverage also extends to new experimental methods in biochemistry, theoretical contributions of biochemical importance, reviews of contemporary biochemical topics, and mini-reviews (News in Biochemistry).
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