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Peer-reviewedCC BY-NC-NDJournal of neuroinflammation

Endothelial KLK10 maintains blood-brain barrier integrity and mitigates ischemic stroke by limiting the cGAS-STING pathway.

  • Xiaoyu Wu1
  • Kegui Zhou2
  • Cong Wang2
  • Yi Zhang3
  • Jiamin Chen1
  • Richard Milner4
  • Jiapei Dai5
  • Longxuan Li6
6 affiliations
  1. 1Dept. of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Rd, Yangpu District, Shanghai, 200092, P. R. China.
  2. 2The Graduate School, Ningxia Medical University, Yinchuan, Ningxia, 750004, P. R. China.
  3. 3Dept. of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
  4. 4San Diego Biomedical Research Institute, 3525 John Hopkins Court, Suite 200, San Diego, CA, 92121, USA. [email protected].
  5. 5Wuhan Institute for Neuroscience and Neuroengineering, South-Central Minzu University, Wuhan, 430074, P. R. China. [email protected].
  6. 6Dept. of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Rd, Yangpu District, Shanghai, 200092, P. R. China. [email protected].
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Abstract

Background

Despite significant advances in acute ischemic stroke (AIS) reperfusion therapies, blood-brain barrier (BBB) dysfunction continues to drive poor clinical outcomes. While endogenous vascular protective mechanisms remain incompletely characterized, kallikrein-related peptidase 10 (KLK10) - a serine protease with unexplored neurovascular functions - represents a promising candidate for BBB regulation.Methods

We employed a translational strategy to characterize KLK10 expression in plasma samples from 182 AIS patients, human postmortem stroke brain tissues, and a mouse model of middle cerebral artery occlusion (MCAO). We elucidated KLK10's functional mechanisms through studies using genetic knockout mice, endothelial-specific KLK10 knockdown models, recombinant KLK10 (rKLK10) administration, KLK10 overexpression in cultured brain endothelial cells (BECs), pharmacological inhibition, and primary BEC cultures.Results

We demonstrate that KLK10 is markedly upregulated in both human postmortem stroke brain tissues and MCAO mouse brains, with predominant expression in cerebrovascular endothelial cells. Clinically, plasma KLK10 levels in AIS patients correlate with both disease severity and 3-month prognosis. Functional studies reveal that KLK10 protects against brain injury and BBB disruption by suppressing endothelial inflammatory cell adhesion molecules, and preserving junctional integrity. Mechanistically, KLK10 may exert its protective effects by limiting the cerebrovascular endothelial cyclic GMP-AMP synthase - stimulator of interferon genes - nuclear factor kappa B (cGAS-STING-NF-κB) pathway, a previously unrecognized regulatory mechanism in stroke-associated endothelial dysfunction.Conclusions

Our study suggests that KLK10 may serve as a candidate prognostic indicator and potential therapeutic target for AIS, exerting its protective effects via maintaining BBB integrity and via the novel regulation of the cerebrovascular cGAS-STING-NF-κB pathway, thereby offering new insights for vascular protection in stroke and related neuroinflammatory conditions.

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Cite

BibTeXRIS
BibTeX
@article{wu2026endothelial,
  title = {{Endothelial KLK10 maintains blood-brain barrier integrity and mitigates ischemic stroke by limiting the cGAS-STING pathway.}},
  author = {Xiaoyu Wu and Kegui Zhou and Cong Wang and Yi Zhang and Jiamin Chen and Richard Milner and Jiapei Dai and Longxuan Li},
  journal = {Journal of neuroinflammation},
  year = {2026},
  month = jul,
  doi = {10.1186/s12974-026-03987-w},
  url = {https://europepmc.org/article/MED/42958279},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Endothelial KLK10 maintains blood-brain barrier integrity and mitigates ischemic stroke by limiting the cGAS-STING pathway.
AU  - Xiaoyu Wu
AU  - Kegui Zhou
AU  - Cong Wang
AU  - Yi Zhang
AU  - Jiamin Chen
AU  - Richard Milner
AU  - Jiapei Dai
AU  - Longxuan Li
PY  - 2026
DA  - 2026/07/30
JO  - Journal of neuroinflammation
DO  - 10.1186/s12974-026-03987-w
UR  - https://europepmc.org/article/MED/42958279
AB  - Background  Despite significant advances in acute ischemic stroke (AIS) reperfusion therapies, blood-brain barrier (BBB) dysfunction continues to drive poor clinical outcomes. While endogenous vascular protective mechanisms remain incompletely characterized, kallikrein-related peptidase 10 (KLK10) - a serine protease with unexplored neurovascular functions - represents a promising candidate for BBB regulation.Methods  We employed a translational strategy to characterize KLK10 expression in plasma samples from 182 AIS patients, human postmortem stroke brain tissues, and a mouse model of middle cerebral artery occlusion (MCAO). We elucidated KLK10's functional mechanisms through studies using genetic knockout mice, endothelial-specific KLK10 knockdown models, recombinant KLK10 (rKLK10) administration, KLK10 overexpression in cultured brain endothelial cells (BECs), pharmacological inhibition, and primary BEC cultures.Results  We demonstrate that KLK10 is markedly upregulated in both human postmortem stroke brain tissues and MCAO mouse brains, with predominant expression in cerebrovascular endothelial cells. Clinically, plasma KLK10 levels in AIS patients correlate with both disease severity and 3-month prognosis. Functional studies reveal that KLK10 protects against brain injury and BBB disruption by suppressing endothelial inflammatory cell adhesion molecules, and preserving junctional integrity. Mechanistically, KLK10 may exert its protective effects by limiting the cerebrovascular endothelial cyclic GMP-AMP synthase - stimulator of interferon genes - nuclear factor kappa B (cGAS-STING-NF-κB) pathway, a previously unrecognized regulatory mechanism in stroke-associated endothelial dysfunction.Conclusions  Our study suggests that KLK10 may serve as a candidate prognostic indicator and potential therapeutic target for AIS, exerting its protective effects via maintaining BBB integrity and via the novel regulation of the cerebrovascular cGAS-STING-NF-κB pathway, thereby offering new insights for vascular protection in stroke and related neuroinflammatory conditions.
SN  - 1742-2094
ER  -