Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions
Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions
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DOI：
10.1186/s12974-019-1628-8
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发表时间：
2019-11-22
影响因子：
9.3
通讯作者：
Aymerich, Maria S.
中科院分区：
文献类型：
--
作者：
Angel Abellanas, Miguel;Zamarbide, Marta;Aymerich, Maria S.
炎症是神经退行性疾病中神经元死亡进展的关键过程。小胶质细胞在神经炎症中起核心作用，并可能影响神经元的易损性。下一代测序显示了小胶质细胞的分子异质性；然而，它们对病理输入的反应的可变性仍然未知。方法采用脂多糖（LPS）外周给药，观察小鼠皮层、海马、中脑和纹状体的炎症状态，确定炎症刺激对小胶质细胞的影响。通过荧光激活细胞分选、下一代RNA测序、实时PCR和免疫组织化学技术，分析了从不同脑区获得的单细胞悬液中小胶质细胞的激活和与免疫系统的相互作用。通过分离细胞诱导OT-II转基因小鼠纯化的CD4(+) T细胞克隆扩增的能力来评估小胶质细胞的抗原提呈特性。结果在稳态条件下，中脑呈现高度免疫警戒状态，其特征是存在两种独特的小胶质亚群，一种表达主要组织相容性复合体II类（MHC-II）并充当抗原呈递细胞，另一种表达toll样受体4(TLR4)，并且存在更高比例的浸润性CD4(+) T细胞。这种状态在皮层、海马体或纹状体中没有检测到。全身性LPS诱导经典促炎细胞因子、共抑制性程序性死亡配体1 （PD-L1）和细胞毒性T淋巴细胞抗原4 （CTLA-4）受体的普遍增加，以及所有脑区浸润效应T细胞的减少。有趣的是，在中脑中观察到特异性免疫抑制反应，其特征是MHC-II小胶质细胞表达下调，抗炎细胞因子IL10和TGF β上调，浸润性调节性T细胞增加。这些数据表明，当暴露于炎症刺激时，中脑在稳态条件下呈现高免疫警觉状态，引起特异性免疫抑制反应。这种特定的炎症基调和反应可能对神经元的活力有影响。
Background Inflammation is a critical process for the progression of neuronal death in neurodegenerative disorders. Microglia play a central role in neuroinflammation and may affect neuron vulnerability. Next generation sequencing has shown the molecular heterogeneity of microglial cells; however, the variability in their response to pathological inputs remains unknown. Methods To determine the effect of an inflammatory stimulus on microglial cells, lipopolysaccharide (LPS) was administered peripherally to mice and the inflammatory status of the cortex, hippocampus, midbrain, and striatum was assessed. Microglial activation and interaction with the immune system were analyzed in single cell suspensions obtained from the different brain regions by fluorescence-activated cell sorting, next generation RNA sequencing, real-time PCR, and immunohistochemical techniques. Antigen-presenting properties of microglia were evaluated by the ability of isolated cells to induce a clonal expansion of CD4(+) T cells purified from OT-II transgenic mice. Results Under steady-state conditions, the midbrain presented a high immune-alert state characterized by the presence of two unique microglial subpopulations, one expressing the major histocompatibility complex class II (MHC-II) and acting as antigen-presenting cells and another expressing the toll-like receptor 4 (TLR4), and by the presence of a higher proportion of infiltrating CD4(+) T cells. This state was not detected in the cortex, hippocampus, or striatum. Systemic LPS administration induced a general increase in classic pro-inflammatory cytokines, in co-inhibitory programmed death ligand 1 (PD-L1), and in cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors, as well as a decrease in infiltrating effector T cells in all brain regions. Interestingly, a specific immune-suppressive response was observed in the midbrain which was characterized by the downregulation of MHC-II microglial expression, the upregulation of the anti-inflammatory cytokines IL10 and TGF beta, and the increase in infiltrating regulatory T cells. Conclusions These data show that the midbrain presents a high immune-alert state under steady-state conditions that elicits a specific immune-suppressive response when exposed to an inflammatory stimulus. This specific inflammatory tone and response may have an impact in neuronal viability.