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.
Graphical Abstract
Abbreviations
- AIS:
-
Acute ischemic stroke
- ASPECTS:
-
Alberta Stroke Program Early CT Score
- BBB:
-
Blood-brain barrier
- BEC:
-
Brain endothelial cell
- cGAS:
-
Cyclic GMP-AMP synthase
- ELISA:
-
Enzyme-linked immunosorbent assay
- ICAM-1:
-
Intercellular adhesion molecule-1
- KLK10:
-
Kallikrein-related peptidase 10
- KO:
-
Knockout
- MCAO:
-
Middle cerebral artery occlusion
- NES1:
-
Normal epithelial cell-specific 1
- NF-κB:
-
Nuclear factor kappa B
- STING:
-
Stimulator of interferon genes
- TIA:
-
Transient ischemic attack
- VCAM-1:
-
Vascular cell adhesion molecule-1
- VE-cadherin:
-
Vascular endothelial cadherin
- WT:
-
Wild-type
- ZO-1:
-
Zonula occludens-1
Acknowledgements
None.
Funding
This study was supported by the National Natural Science Foundation of China (No. 82371465, 82571675, 82171462). All sources of funding for the research declare that they have no competing financial or personal interests and that none of the author’s institutions have contracts relating to this research through which it may stand to gain financially now or in the future.
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The study was conducted in accordance with the principles of the Helsinki Declaration and approved by the local ethics committee (2024-83). All participants provided written informed consent prior to enrollment. For animal studies, all procedures strictly adhered to the National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) of Xinhua Hospital. Regarding human tissue samples, permission for brain autopsy and use of the brain material and medical records for research purposes were obtained in accordance with the CBBC and the human body donation program. Appropriate consent was secured either from the donors themselves or from relatives and were also approved by the Biomedical Research Ethics Committee of South-Central Minzu University (no.2024-scuec-046).
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Wu, X., Zhou, K., Wang, C. et al. Endothelial KLK10 maintains blood-brain barrier integrity and mitigates ischemic stroke by limiting the cGAS-STING pathway. J Neuroinflammation (2026). https://doi.org/10.1186/s12974-026-03987-w
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DOI: https://doi.org/10.1186/s12974-026-03987-w