Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge.
Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge.
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DOI：
10.1016/j.bbi.2010.05.011
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发表时间：
2010-10
影响因子：
15.1
通讯作者：
Godbout, Jonathan P.
中科院分区：
文献类型：
--
作者：
Wynne, Angela M.;Henry, Christopher J.;Huang, Yan;Cleland, Anthony;Godbout, Jonathan P.
脑中的Fractalkine（CX 3CL 1）与Fractalkine受体（CX 3CR 1）的相互作用参与小胶质细胞活化的调节。我们最近的研究结果表明，在炎症挑战期间，老年大脑中存在小胶质细胞过度活跃。老年大脑中这种放大的小胶质细胞反应的根本原因尚不清楚。因此，本研究的目的是确定在腹膜内（i. p.）注射脂多糖（LPS）。在这里，我们表明，CX 3CL 1蛋白在老年（18-22个月）BALB/c小鼠的大脑相比，成年（3-6个月）控制减少。然而，CX 3CL 1蛋白不受LPS注射的影响。接下来，在LPS注射后4和24 h，通过Percol密度梯度分离法分离小胶质细胞（CD 11b +/CD 45低），测定CX 3CR 1水平。流式细胞术和mRNA分析结果显示，LPS注射后4 h，小胶质细胞CX 3CR 1表达显著下降，IL-1β表达显著升高。虽然CX 3CR 1的表面表达在成年小鼠的小胶质细胞上增强了24小时，但它在老年小鼠的小胶质细胞亚群上仍然显著下调。这种CX 3CR 1的长期减少与老年大脑中疾病行为的延迟恢复、IL-1β诱导的延长和TGFβ表达的减少相对应。在最后一组研究中，使用BV 2小胶质细胞来确定TGFβ对CX 3CR 1的影响。这些结果表明，TGFβ增强了CX 3CR 1的表达，并减弱了LPS诱导的IL-1β表达的增加。
Fractalkine (CX3CL1) to fractalkine receptor (CX3CR1) interactions in the brain are involved in the modulation of microglial activation. Our recent findings indicate that there is microglial hyperactivity in the aged brain during an inflammatory challenge. The underlying cause of this amplified microglial response in the aged brain is unknown. Therefore, the purpose of this study was to determine the degree to which age-associated impairments of CX3CL1 and CX3CR1 in the brain contribute to exaggerated microglial activation after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Here we show that CX3CL1 protein was reduced in the brain of aged (18–22 mo) BALB/c mice compared to adult (3–6 mo) controls. CX3CL1 protein, however, was unaltered by LPS injection. Next, CX3CR1 levels were determined in microglia (CD11b+/CD45low) isolated by Percoll-density gradient separation at 4 and 24 h after LPS injection. Flow cytometric and mRNA analyses of these microglia showed that LPS-injection caused a marked decrease of CX3CR1 and a simultaneous increase of IL-1β at 4 h after LPS injection. While surface expression of CX3CR1 was enhanced on microglia of adult mice by 24 h, it was still significantly downregulated on a subset of microglia from aged mice. This protracted reduction of CX3CR1 corresponded with a delayed recovery from sickness behavior, prolonged IL-1β induction, and decreased TGFβ expression in the aged brain. In the last set of studies BV2 microglia were used to determine effect of TGFβ on CX3CR1. These results showed that TGFβ enhanced CX3CR1 expression and attenuated the LPS-induced increase in IL-1β expression.
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影响因子：
4.4
作者：
Boehme, SA;Lio, FM;Conlon, PJ
通讯作者：
Conlon, PJ
影响因子：
15.1
作者：
Chen, Jing;Buchanan, Jessica B.;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.
影响因子：
3.3
作者：
Godbout, JP;Berg, GM;Johnson, RW
通讯作者：
Johnson, RW
DOI：
10.1073/pnas.95.18.10896
发表时间：
1998-09-01
影响因子：
11.1
作者：
Harrison, JK;Jiang, Y;Feng, LL
通讯作者：
Feng, LL
影响因子：
3.3
作者：
Chen, SZ;Luo, DF;Harrison, JK
通讯作者：
Harrison, JK