Microglia priming by interleukin-6 signaling is enhanced in aged mice
Microglia priming by interleukin-6 signaling is enhanced in aged mice
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DOI：
10.1016/j.jneuroim.2018.09.002
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发表时间：
2018-11-15
影响因子：
3.3
通讯作者：
Burton, Michael D.
中科院分区：
文献类型：
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作者：
Garner, Katherine M.;Amin, Ravi;Burton, Michael D.
在外周感染期间，老化大脑中过度产生的促炎细胞因子引起了过度的行为病理。虽然促炎细胞因子IL-6在大脑中随着年龄的增长而增加，但其在小胶质细胞启动中的作用尚不清楚。本研究探讨了IL-6信号在小胶质细胞启动中的功能作用。我们的假设是IL-6信号介导了老年人小胶质细胞的启动状态。一项初步研究评估了IL-6信号分子的年龄相关改变；测定幼年和老年野生型动物脑脊液中sIL-6R和sgpl30的含量。随后对C57BL6/J （IL-6(+/+)）和IL-6敲除（IL-6）小鼠分离的小胶质细胞的研究显示，与IL-6（+/+）小鼠相比，衰老IL-6中MHC-II的表达明显减少。此外，给成年和老年IL-6（+/+）和IL-6（-/-）动物注射脂多糖（LPS）来模拟外周感染；在24小时内测量疾病行为和海马细胞因子基因表达。衰老的IL-6（-/-）动物对lp诱导的疾病行为具有弹性，并且比IL-6（+/+）动物恢复得更快。在衰老的IL-6（-/-）小鼠中，与年龄相关的IL-1 β基因表达的基线增加被消除，这表明IL-6是衰老大脑中启动小胶质细胞细胞因子活性的关键驱动因素。我们采用体外研究来了解启动因子的分子机制。用sIL-6R和IL-6或单独使用IL-6治疗BV.2小胶质细胞后，检测MHC-II和促炎基因（IL-1 β、IL-10、IL-6）的表达。sIL-6R增强了促炎基因和MHC-II的表达。综上所述，这些数据表明，一生中IL-6的表达与小胶质细胞的启动有关，外周LPS刺激后IL-6的增加与老年人夸大的疾病行为有关。
During peripheral infection, excessive production of pro-inflammatory cytokines in the aged brain from primed microglia induces exaggerated behavioral pathologies. While the pro-inflammatory cytokine IL-6 increases in the brain with age, its role in microglia priming is not known. This study examined the functional role of IL-6 signaling on microglia priming. Our hypothesis is that IL-6 signaling mediates primed states of microglia in the aged. An initial study assessed age-related alteration in IL-6 signaling molecules; sIL-6R and sgpl 30 were measured in cerebrospinal fluid of young and aged wild-type animals. Subsequent studies of isolated microglia from C57BL6/J (IL-6(+/+)) and IL-6 knock-out (IL-6 mice showed significantly less MHC-II expression in aged IL-6 compared to IL-6(+/+) counterparts. Additionally, adult and aged IL-6(+/+) and IL-6(-/-) animals were administered lipopolysaccharide (LPS) to simulate a peripheral infection; sickness behaviors and hippocampal cytokine gene expression were measured over a 24 h period. Aged IL-6(-/-) animals were resilient to LPSinduced sickness behaviors and recovered more quickly than IL-6(+/+) animals. The age-associated baseline increase of IL-1 beta gene expression was ablated in aged IL-6(-/-) mice, suggesting IL-6 is a key driver of cytokine activity from primed microglia in the aged brain. We employed in vitro studies to understand molecular mechanisms in priming factors. MHC-II and pro-inflammatory gene expression (IL-1 beta, IL-10, IL-6) were measured after treating BV.2 microglia with sIL-6R and IL-6 or IL-6 alone. sIL-6R enhanced expression of both pro-inflammatory genes and MHC-II. Taken together, these data suggest IL-6 expression throughout life is involved in microglia priming and increased amounts of IL-6 following peripheral LPS challenge are involved in exaggerated sickness behaviors in the aged.