2. Academic Validation
  3. Apelin-13 attenuates microglia-mediated neuroinflammation following intracerebral hemorrhage via targeting JAK2/STAT3 signaling pathway

Apelin-13 attenuates microglia-mediated neuroinflammation following intracerebral hemorrhage via targeting JAK2/STAT3 signaling pathway

  • Exp Neurol. 2025 Dec 31:398:115633. doi: 10.1016/j.expneurol.2025.115633.
Pingping Guo 1,  Jingjing Li 1,  Xiangyu Zhang 1,  Qingli Wang 1,  Yang Liu 1,  Huizhen Zhou 1,  Yun Chen 1,  V Wee Yong 2,  Mengzhou Xue 3
Affiliations

Affiliations

  • 1 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, 2 Jingba Road, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan, China; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada.
  • 2 Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada. Electronic address: [email protected].
  • 3 Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, 2 Jingba Road, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan, China; Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada. Electronic address: [email protected].
PMID: 41482108 DOI: 10.1016/j.expneurol.2025.115633
Abstract

Background: Neuroinflammation is a critical contributor to secondary brain injury and subsequent neurological decline after intracerebral hemorrhage (ICH). Apelin-13, the most bioactive isoform of the endogenous G protein-coupled receptor (GPCR) ligand, exhibits protective roles in multiple neurological disorders. Nevertheless, its therapeutic effects and underlying mechanisms in neuroinflammation following ICH remain elusive.

Methods: In vivo, ICH was induced in mice with collagenase type VII, followed by intracerebroventricular injection of Apelin-13. In vitro, BV2 microglia were pretreated with Apelin-13 overnight, followed by lipopolysaccharide (LPS) stimulation. To investigate the mechanistic role of Apelin-13, we employed specific shRNA for APJ knockdown and the selective JAK2/STAT3 Inhibitor WP1066 for pathway blockage. Western blotting and immunofluorescence assays were applied to assess JAK2/STAT3 signaling activation and pro-inflammatory mediator expression.

Results: Apelin-13 significantly decreased hematoma volume and mitigated neurological impairments in ICH mice. Correspondingly, both in vivo and in vitro studies confirmed its efficacy in attenuating microglia-mediated neuroinflammation. Mechanistically, Apelin-13 significantly suppressed JAK2/STAT3 signaling pathway in LPS-stimulated BV2 microglia. This suppression was reversed by APJ knockdown, verifying the necessity of the Apelin-13/APJ interaction. Furthermore, combining WP1066 with Apelin-13 significantly enhanced its anti-inflammatory effects, as evidenced by a more pronounced reduction in p-JAK2/p-STAT3 levels and pro-inflammatory cytokine secretion. Finally, the inhibition of the microglial JAK2/STAT3 pathway by Apelin-13 was also confirmed in the perihematomal brain tissues of ICH mice.

Conclusions: Apelin-13 attenuated brain injury after ICH by suppressing microglia-mediated neuroinflammation through APJ receptor-dependent inhibition of the JAK2/STAT3 pathway.

Keywords

Apelin-13; Intracerebral hemorrhage; JAK2/STAT3; Microglia; Neuroinflammation.

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