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Reciprocal Interplay Between Astrocytes and CD4+ Cells Affects Blood-Brain Barrier and Neuronal Function in Response to β Amyloid.
Frontiers in Molecular Neuroscience ( IF 4.8 ) Pub Date : 2020-06-10 , DOI: 10.3389/fnmol.2020.00120
Simona Federica Spampinato 1 , Sara Merlo 1 , Evelina Fagone 2 , Mary Fruciano 2 , Yasuteru Sano 3 , Takashi Kanda 3 , Maria Angela Sortino 1
Affiliation  

Background: In Alzheimer’s disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined. CD4+ cells interact with astrocytes able to release several factors and cytokines that can modulate T cell polarization; similarly, astrocytic properties are modulated after interaction with T cells.

Methods: In in vitro models, astrocytes were primed with β-amyloid (Aβ; 2.5 μM, 5 h) and then co-cultured with magnetically isolated CD4+ cells. Cytokines expression was evaluated both in co-cultured CD4+ cells and astrocytes. The effects of this crosstalk were further evaluated by co-culturing CD4+ cells with the neuronal-like SH-SY5Y cell line and astrocytes with endothelial cells.

Results: The pattern of cytokines and trophic factors expressed by CD4+ cells were strongly modulated in the presence of Aβ-primed astrocytes. Specifically, the percentage of IL-4+ and IFNγ+ CD4+ cells was significantly increased and reduced, respectively. Further, increased BDNF mRNA levels were observed in CD4+ cells. When SH-SY5Y cells were co-cultured with astrocyte-conditioned CD4+ cells and exposed to Aβ, the reduction of the presynaptic protein synaptophysin was prevented with a BDNF-dependent mechanism. In astrocytes co-cultured with CD4+ cells, reduced mRNA levels of inflammatory cytokines and VEGF were observed. This was paralleled by the prevention of the reduction of claudin-5 when astrocytes were co-cultured with endothelial cells.

Conclusion: Following Aβ exposure, there exists reciprocal crosstalk between infiltrating peripheral cells and astrocytes that in turn affects not only endothelial function and thus BBB properties, but also neuronal behavior. Since astrocytes are the first cells that lymphocytes interact with and are among the principal players in neuroinflammation occurring in AD, understanding this crosstalk may disclose new potential targets of intervention in the treatment of neurodegeneration.



中文翻译:

星形胶质细胞和CD4 +细胞之间的相互影响影响对β淀粉样蛋白的反应的血脑屏障和神经元功能。

背景:在阿尔茨海默氏病(AD)中,神经元变性与神经胶质增生和外周血单核细胞(PBMC)的浸润有关,后者参与了神经炎症。血脑屏障(BBB)的缺陷促进PBMC向中枢神经系统(CNS)的迁移,特别是在AD受严重影响的地区发现了CD4 + T细胞。然而,一旦T细胞迁移到CNS中,其作用尚不明确。CD4 +细胞与星形胶质细胞相互作用,这些星形胶质细胞能够释放多种因子和细胞因子,从而调节T细胞的极化。类似地,在与T细胞相互作用后调节星形胶质细胞的特性。

方法:在 体外在模型中,星形胶质细胞用β-淀粉样蛋白(Aβ; 2.5μM,5 h)引发,然后与磁性分离的CD4 +细胞共培养。在共培养的CD4 +细胞和星形胶质细胞中都评估了细胞因子的表达。通过将CD4 +细胞与神经元样SH-SY5Y细胞系以及星形胶质细胞与内皮细胞共培养,可以进一步评估这种串扰的影响。

结果:在Aβ引发的星形胶质细胞存在下,CD4 +细胞表达的细胞因子和营养因子的模式受到强烈调节。具体而言,IL-4 +和IFNγ+ CD4 +细胞的百分比分别显着增加和减少。此外,在CD4 +细胞中观察到BDNF mRNA水平升高。当SH-SY5Y细胞与星形胶质细胞调节的CD4 +细胞共培养并暴露于Aβ时,通过BDNF依赖性机制可防止突触前蛋白突触素的减少。在与CD4 +细胞共培养的星形胶质细胞中,观察到炎性细胞因子和VEGF的mRNA水平降低。当星形胶质细胞与内皮细胞共培养时,可防止claudin-5的减少。

结论:Aβ暴露后,浸润的外周细胞和星形胶质细胞之间存在相互串扰,这不仅影响内皮功能,进而影响BBB特性,而且影响神经元行为。由于星形胶质细胞是淋巴细胞与之相互作用的第一批细胞,并且是AD中发生神经炎症的主要参与者,因此了解这种串扰可能会揭示治疗神经变性的新的潜在干预靶标。

更新日期:2020-07-03
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