J Neuroinflammation. 2020 Apr 24;17(1):130.doi: 10.1186/s12974-020-01794-5. (IF:9.3).

本文采用的英格恩产品: RNA-Entranster-invivo

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

Affiliations

Affiliations

  • 1 Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, 241000, Anhui, China.
  • 2 Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92350, USA.
  • 3 Department of Neurology, Wannan Medical College First Affiliated Hospital, Wuhu, 241000, Anhui, China.
  • 4 Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79, Zhejiang, 310003, Hangzhou, China.
  • 5 Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA.
  • 6 Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Qingchun Road 79, Zhejiang, 310003, Hangzhou, China. luobenyan@zju.edu.cn.
  • 7 Department of Basic Sciences, Division of Physiology, Loma Linda University School of Medicine, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92350, USA. jtang@llu.edu.

Free PMC article

Abstract

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.

Keywords: Dickkopf 3; Dishevelled-1; Inflammation; Intracerebral hemorrhage; Kremen-1.

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