Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice.
Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice.
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DOI：
10.1016/j.bbi.2013.01.002
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发表时间：
2013-05
影响因子：
15.1
通讯作者：
Johnson, Rodney W.
中科院分区：
文献类型：
--
作者：
Burton, Michael D.;Rytych, Jennifer L.;Freund, Gregory G.;Johnson, Rodney W.
在全身性感染过程中，老年小鼠大脑中会过量产生白细胞介素(IL)-6等炎性细胞因子，并导致严重的行为缺陷。然而，没有研究调查促炎IL-6反式信号是如何参与老年大脑中IL-6的过度产生的，也没有研究IL-6反式信号在多大程度上影响神经炎症、粘附分子和行为的其他标志物。因此，本研究对老年小鼠小胶质细胞中IL-6信号亚基的存在进行了研究；可溶性gp130 (sgp130) （IL-6反式信号通路的天然抑制剂）对小胶质细胞中IL-6生成的中心作用；脑室注射sgp130对内源性脂多糖（LPS）引起的神经炎症和疾病行为的影响。本研究表明，与成人小胶质细胞相比，从老年小鼠分离的小胶质细胞具有更高的IL-6受体（IL-6R）表达；老年小鼠海马区的ADAM17 mRNA水平高于成年小鼠，ADAM17是一种负责反式信号中膜结合IL-6R脱落的酶。此外，我们在老年小鼠中发现，外周LPS刺激会引起小胶质细胞中过度活跃的IL-6反应，而通过ICV注射sgp130选择性阻断反式信号传导可以减轻这种反应。sgp130相关的IL-6抑制与老年小鼠夸大和延长疾病行为的改善是平行的。综上所述，结果表明小胶质细胞是老年脑IL-6反式信号反应的重要调节因子，sgp130通过抑制IL-6信号的促炎臂发挥抗炎作用。
During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans-signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)—a natural inhibitor of the IL-6 trans-signaling pathway—on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling.
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影响因子：
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通讯作者：
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影响因子：
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通讯作者：
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