CD4^(+)T细胞相关的细胞因子促使由诱导性多能干细胞衍生的中脑星形胶质细胞表现出慢性促炎症表型  

CD4+T Cell-associated Cytokines Induce a Chronic Pro-inflammatory Phenotype in Induced Pluripotent Stem Cell-derived Midbrain Astrocytes

作　　者：Adina N MacMahon Copas Sarah F McComish Andreea Petrasca Rachel McCormack Daniel Ivers Anna Stricker Jean M Fletcher Maeve A Caldwell 唐颖馨 

机构地区：[1]Discipline of Physiology,School of Medicine,Trinity Biomedical Sciences Institute,Trinity College Dublin,Dublin,Ireland [2]Trinity College Institute for Neuroscience,Trinity College,Dublin,Ireland [3]School of Biochemistry and Immunology,Trinity Biomedical Sciences Institute,Trinity College Dublin,Dublin,Ireland [4]School of Medicine,Trinity Biomedical Sciences Institute,Trinity College Dublin,Dublin,Ireland [5]不详

出　　处：《神经损伤与功能重建》2024年第8期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：星形胶质细胞是维持稳态的介质,但在帕金森病(Parkinson’s disease,PD)中参与神经炎症。越来越多的证据表明外周免疫细胞参与了PD的发病机制。因此,本研究旨在确定外周免疫细胞分泌的细胞因子在调节中脑星形胶质细胞反应性中的潜在作用。人类诱导性多能干细胞(iPSC)衍生的中脑星形胶质细胞暴露于5%和10%的CD4^(+)T细胞条件培养基(CD4CM)24小时、72小时和7天,以评估长期暴露的影响。此外,星形胶质细胞还暴露于Th17细胞细胞因子IL-17A(10 ng/mL),单独或与TNF-α(0.3 ng/mL)结合,在24小时、72小时和7天评估2种细胞因子可能的协同效应。CD4CM在中脑星形胶质细胞中引起了急性及长期的变化。观察到了NFκB向细胞核的转移增加,以及在24小时时促炎基因IL-1β和CXCL10的表达增加;在24小时和48小时时C3、LCN2和IL-6的表达增加;同时在这些时间点促炎细胞因子IL-6和CXCL10的释放也有所增加。IL-17A和TNF-α的组合对增加促炎基因表达和细胞因子释放产生了协同效应。IL-17A和TNF-α在24小时时增加了S100β的强度,在72小时时减少了细胞核面积并增加了星形胶质细胞的圆度。在72小时时观察到了γH2AX强度的协同效应,并且在7天时观察到了乳酸脱氢酶(LDH)释放的增加。我们的结果表明,IL-17A和TNF-α协同作用,增强了中脑星形胶质细胞的反应性,其程度类似于CD4CM。这突出了外周免疫细胞分泌的细胞因子在增强中脑星形胶质细胞反应状态方面的重要性,并提示了它们在PD发病机制中的可能作用。Astrocytes are mediators of homeostasis but contribute to neuroinflammation in Parkinson’s disease(PD).Mounting evidence suggests involvement of peripheral immune cells in PD pathogenesis.Therefore,this study aimed to determine the potential role of peripheral immune secreted cytokines in modulating midbrain astrocyte reactivity.Human iPSC-derived midbrain astrocytes were exposed to 5%and 10%CD4+T cell conditioned media(CD4CM)for 24 h,72 h,and 7 days to assess chronic exposure.Additionally,astrocytes were exposed to the Th17 cell cytokine,IL-17A(10 ng/mL),alone and in combination with TNF-α(0.3 ng/mL)to assess potential synergistic effects of both cytokines at 24 h,72 h,and 7 days.CD4CM induced acute and chronic alterations in midbrain astrocytes.Increased NFκB translocation to the nucleus,increased expression of the pro-inflammatory genes,IL-1β,CXCL10 at 24 h,C3,LCN2,IL-6 at 24 and 48 h,as well as an increase in their release of pro-inflammatory cytokines IL-6 and CXCL10 at both these time points were observed.A synergistic response to the combination of IL-17A and TNF-αon increasing inflammatory gene expression and cytokine release occurred.IL-17A and TNF-αincreased intensity of S100βat 24 h,decreased nuclear area and increased circularity of astrocytes at 72 h.A synergistic effect onγH2AX intensity at 72 h and an increase in LDH release at 7 days was observed.Our results demonstrate that IL-17A and TNF-αact synergisti-cally,enhancing midbrain astrocyte reactivity to a similar degree as CD4CM.This highlights the importance of the pe-ripheral immune secreted cytokines in increasing the reactivity status of midbrain astrocytes,implicating their role in PD.

关 键 词：帕金森病 星形胶质细胞 细胞因子 诱导性多能干细胞 神经炎症 反应性星形胶质细胞 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]