DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage
DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage
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DKK3 通过 Kremen-1 和 DVL-1 减轻小鼠脑出血后 JNK 和 AP-1 诱导的炎症
DOI：
10.1186/s12974-020-01794-5
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发表时间：
2020
影响因子：
9.3
通讯作者：
Tang Jiping
中科院分区：
文献类型：
--
作者：
Xu Yang;Nowrangi Derek;Liang Hui;Wang Tian;Yu Lingyan;Lu Tai;Lu Zhengyang;Zhang John H.;Luo Benyan;Tang Jiping
研究背景脑出血（Intracerebral hemorrhage，ICH）是最具破坏性的脑卒中亚型，预后差，治疗方法少.神经炎症与ICH诱导的脑损伤和不良结局相关。越来越多的证据表明Dickkopf（DKK）3在脑出血后的适应性抗炎和神经保护反应中起关键作用。本研究旨在评估DKK 3对脑水肿和神经炎症的小鼠模型ICH.MethodsMale，成年CD 1小鼠进行假手术或ICH手术使用胶原酶注射模型的保护作用。ICH动物接受重组DKK 3、Kremen-1 siRNA或DVL-1 siRNA。分别于诱导后24 h、72 h和28 d评价神经行为缺陷。Western blot和免疫荧光法检测DKK 3、Kremen-1、Dishevelled-1（DVL-1）、c-JUN N-末端激酶（JNK）、激活蛋白-1（AP-1）、裂解型caspase-1、NF-κB B和IL-1β在脑内的表达和定位。与脑出血小鼠相比，外源性rDKK 3可降低脑含水量，影响神经功能。此外，DKK 3与Kremen-1在小胶质细胞中共定位。通过Kremen-1或DVL-1 siRNA诱导的体内敲低方法，我们证明DKK 3抗脑出血的作用至少部分是通过Kremen-1和DVL-1途径介导的。结论DKK 3可能通过减少JNK/AP-1介导的炎症反应，从而改善脑出血后的短期和长期后遗症。
BackgroundIntracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinflammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH.MethodsMale, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1β in the brain.ResultsThe expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated, at least partly, by the Kremen-1 and DVL-1 pathways.ConclusionsDKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1-mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.