Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats.
Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats.
复制标题
Axl激活通过抑制TLR/TRAF/NF-κB通路减轻大鼠MCAO后的神经炎症
DOI：
10.1016/j.nbd.2017.11.009
复制
发表时间：
2018-03
影响因子：
6.1
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Wu G;McBride DW;Zhang JH
缺血性中风激活Toll样受体（TLR），触发快速炎症细胞因子的产生。Axl信号传导具有多种作用，包括调节细胞因子分泌、清除凋亡细胞和维持细胞存活，然而，其在缺血性卒中后炎症中的作用尚未被研究。我们假设重组生长停滞特异性蛋白6（rGas 6）激活Axl通过抑制大鼠大脑中动脉闭塞（MCAO）后TLR/TRAF/NF-κB通路来减轻神经炎症。对Sprague-Dawley大鼠进行2小时的MCAO。再灌注后1小时，给予大鼠鼻内注射rGas 6、载体或R428（Axl受体抑制剂）。分析神经功能评分、梗死体积、免疫荧光染色、Morris水迷宫、转棒试验和组织学改变。Western blot检测IL-1β、IL-6、TNF-α、Gas 6、Ax 1、STAT 1、SOCS 1、SOCS 3等促炎细胞因子及TLR/TRAF/NF-κB通路的表达。MCAO后24小时Gas 6和Axl的内源性表达显著降低。rGas 6可减少脑梗死，改善神经功能缺损评分，增加Axl的表达，降低TRAF 3、TRAF 6和炎症因子IL-1β、IL-6和TNF-α的表达。MCAO后四周，rGas 6改善了长期的神经行为和记忆。抑制Axl/TLR/TRAF/NF-κB通路可逆转rGas 6的脑保护作用。rGas 6通过TLR/TRAF/NF-κB信号通路抑制神经炎症，从而减轻神经功能缺损。rGas 6可作为缺血性脑卒中的潜在治疗药物。
Ischemic stroke activates Toll-like receptors (TLRs), triggering rapid inflammatory cytokine production. Axl signaling has multiple roles, including regulating cytokine secretion, clearing apoptotic cells, and maintaining cell survival, however, its role in inflammation after ischemic stroke has not been examined. We hypothesized that activation of Axl by recombinant Growth-arrest-specific protein 6 (rGas6) attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after middle cerebral artery occlusion (MCAO) in rats. Sprague-Dawley rats were subjected to 2 hours of MCAO. One hour after reperfusion, the rats were given an intranasal injection of rGas6, vehicle, or R428 (Axl receptor inhibitor). Neurological scores, infarct volumes, immunofluorescence staining, Morris Water Maze, rotarod test and histology alterations were analyzed. The expressions of proinflammatory cytokines, including IL-1β, IL-6, TNF-α, and Gas6, Axl, STAT1, SOCS1, SOCS3 and the TLR/TRAF/NF-κB pathway were quantified using Western blot. Endogenous expressions of Gas6 and Axl decreased significantly by 24 hours after MCAO. rGas6 reduced brain infarction and improved neurologic deficits scores, and increased expression of Axl and decreased the expressions of TRAF3, TRAF6 and inflammatory factors IL-1β, IL-6, and TNF-α. Four weeks after MCAO, rGas6 improved long-term neurological behavior and memory. Inhibition of the Axl/TLR/TRAF/NF-κB pathway reversed the brain protection by rGas6. rGas6 reduced the neurological deficits by inhibiting neuroinflammation via the TLR/TRAF/NF-κB signaling pathway. rGas6 can be used as potential treatment to ischemic stroke.
登录
查看更多内容
影响因子：
6.9
作者：
Ducruet, Andrew F.;Sosunov, Sergey A.;Zacharia, Brad E.;Gorski, Justin;Yeh, Mason L.;DeRosa, Peter;Cohen, Gregory;Gigante, Paul R.;Connolly, E. Sander, Jr.
通讯作者：
Connolly, E. Sander, Jr.
影响因子：
3
作者：
GOLDSTEIN, LB;DAVIS, JN
通讯作者：
DAVIS, JN
影响因子：
4.2
作者：
HAMM, RJ;PIKE, BR;JENKINS, LW
通讯作者：
JENKINS, LW
DOI：
10.1159/000142934
发表时间：
2008
期刊：
Nephron. Experimental nephrology
影响因子：
--
作者：
Kinsey GR;Li L;Okusa MD
通讯作者：
Okusa MD
影响因子：
13.5
作者：
Llacuna, Laura;Barcena, Cristina;Bellido-Martin, Lola;Fernandez, Laura;Stefanovic, Milica;Mari, Montserrat;Garcia-Ruiz, Carmen;Fernandez-Checa, Jose C.;Garcia de Frutos, Pablo;Morales, Albert
通讯作者：
Morales, Albert