BACKGROUND Intracerebral 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. METHODS Male, 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. RESULTS The 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. CONCLUSIONS DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1-mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.

中文翻译：

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DKK3 在小鼠脑出血后通过 Kremen-1 和 DVL-1 减轻 JNK 和 AP-1 诱导的炎症。


背景脑出血（ICH）是最具破坏性的中风亚型，预后较差，且行之有效的治疗方法很少。神经炎症与 ICH 引起的脑损伤和不良后果有关。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发挥着关键作用。本研究旨在评估 DKK3 对 ICH 小鼠模型中脑水肿和神经炎症的保护作用。方法 使用胶原酶注射模型对雄性成年 CD1 小鼠进行假手术或 ICH 手术。 ICH 动物接受重组 DKK3、Kremen-1 siRNA 或 DVL-1 siRNA。在 ICH 诱导后 24 小时、72 小时和 28 天评估神经行为缺陷。采用蛋白质印迹和免疫荧光法检测 DKK3、Kremen-1、Dishevelled-1 (DVL-1)、c-JUN N 末端激酶 (JNK)、Activator Protein-1 (AP-1)、cleaved 的表达和定位。大脑中的 caspase-1、NF-κB 和 IL-1β。结果与假手术组相比，ICH后内源性DKK3和DVL-1的表达短暂降低。与ICH小鼠相比，外源性rDKK3给药降低了ICH小鼠的脑含水量并影响神经功能。此外，DKK3 与小胶质细胞中的 Kremen-1 共定位。使用 Kremen-1 或 DVL-1 siRNA 诱导的体内敲低方法，我们证明 DKK3 对 ICH 的作用至少部分是由 Kremen-1 和 DVL-1 途径介导的。结论 DKK3 可能通过减少 JNK/AP-1 介导的炎症来改善神经系统结果，从而改善 ICH 后的短期和长期后遗症。