Roles of Adam8 in Neuroinflammation in experimental ischemic Stroke: Insights from single-cell and ribosome-bound mRNA sequencing

  • Exp Neurol. 2025 Mar 8:388:115207. doi: 10.1016/j.expneurol.2025.115207.
Jiale Liu  1 ,  Li Xu  2 ,  Jinxin Lu  1 ,  Xi Shen  1 ,  Di Li  1 ,  Lei Bai  1 ,  Xiang Li Jr  3 ,  Zhengquan Yu  4 ,  Haiying Li  5
Affiliations
  • 1. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
  • 2. Intensive Care Unit of the Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China.
  • 3. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China. Electronic address: [email protected].
  • 4. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China. Electronic address: [email protected].
  • 5. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China. Electronic address: [email protected].
PMID: 40064361 DOI: 10.1016/j.expneurol.2025.115207
Abstract

Stroke remains a leading cause of global mortality, with neuroinflammation significantly exacerbating clinical outcomes. Microglia serve as key mediators of post-stroke neuroinflammation, though the mechanisms driving their migration to injury sites remain poorly understood. In this study, using publicly available single-cell Sequencing data (GSE234052), we identified a migration-associated microglial subtype in a murine model of distal middle cerebral artery occlusion (dMCAO). Additionally, ribosome-bound mRNA Sequencing data (GSE225110) from microglia isolated from peri-infarct cortical tissue uncovered dMCAO-induced alterations in microglial mRNA translation. By integrating these datasets, we identified A Disintegrin And Metalloproteinase 8 (ADAM8) as a key gene upregulated at both the transcriptional and translational levels post-dMCAO. Protein analysis revealed that both the precursor and active forms of ADAM8 were predominantly expressed in microglia and significantly upregulated in peri-infarct regions following dMCAO. Notably, ADAM8 inhibition with BK-1361 significantly reduced ADAM8 cleavage, M1 microglial migration, inflammation, infarct size, and improved neurological outcomes. Bioinformatics analysis further identified Myo1e as a potential interacting partner of ADAM8, a finding validated through immunofluorescence co-localization. These findings highlight ADAM8 as a promising therapeutic target for mitigating post-stroke neuroinflammation and offer new insights into the mechanisms of microglial migration.

Keywords
Adam8; Distal middle cerebral artery occlusion; Ischemic Stroke; Microglia; Myo1e; Neuroinflammation; RNA sequencing.
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