Cathepsin B inhibition ameliorates leukocyte-endothelial adhesion in the BTBR mouse model of autism

Huan Wang, Yi Xuan Yin, Dong Mei Gong, Ling Juan Hong, Gang Wu, Quan Jiang, Cheng Kun Wang, Pablo Blinder, Sen Long, Feng Han*, Ying Mei Lu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Autism spectrum disorder (ASD) is a wide range of neurodevelopmental disorders involving deficits in social interaction and communication. Unfortunately, autism remains a scientific and clinical challenge owing to the lack of understanding the cellular and molecular mechanisms underlying it. This study aimed to investigate the pathophysiological mechanism underlying leukocyte-endothelial adhesion in autism-related neurovascular inflammation. Methods: Male BTBR T+tf/J mice were used as an autism model. The dynamic pattern of leukocyte-endothelial adhesion in mouse cerebral vessels was detected by two-photon laser scanning microscopy (TPLSM). Using FACS, RT-PCR, and Western blotting, we explored the expression of cell adhesion molecules, the mRNA expression of endothelial chemokine, the protein levels of cathepsin B, and inflammatory mediators. Results: We found a significant increase in leukocyte-endothelial adhesion in BTBR mice, accompanied by elevated expression of the adhesion molecule neutrophils CD11b and endothelial ICAM-1. Our data further indicate that elevated neutrophil cathepsin B levels contribute to elevated endothelial chemokine CXCL7 levels in BTBR mice. The pharmacological inhibition of cathepsin B reverses the enhanced leukocyte-endothelial adhesion in the cerebral vessels of autistic mice. Conclusion: Our results revealed the prominent role of cathepsin B in modulating leukocyte-endothelial adhesion during autism-related neurovascular inflammation and identified a promising novel approach for autism treatment.

Original languageEnglish
Pages (from-to)476-485
Number of pages10
JournalCNS Neuroscience and Therapeutics
Volume25
Issue number4
DOIs
StatePublished - Apr 2019

Funding

FundersFunder number
Science and Technology Commission Foundation of Hangzhou20172016A05
National Natural Science Foundation of China81473202, 81673417

    Keywords

    • adhesion
    • autism
    • cathepsin B
    • inflammation
    • leukocyte-endothelial

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