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

Abstract

Summary 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.

The Role of Cathepsins in Memory Functions and the Pathophysiology of Psychiatric Disorders

“…In an ASD murine model, elevated CTSB protein expression in neutrophils was observed (43). Given the role of neuroinflammation and microglia activation in the pathophysiology of ASD (44) this finding points to a mechanistic role of CTSB in inducing neurovascular inflammation.…”

Central nervous system diseases related to pathological microglial phagocytosis

“…The main pathological mechanism underlying ASD is distinct from other CNS diseases with regard to microglial phagocytosis in that there is a reduction in microglia phagocytosis of synapses as oppose to excessive phagocytosis, leading to abnormal synaptic circuit connections. ASD is a developmental disorder characterized by abnormal social skills, communication skills, interest, and behavior patterns 65,66 . Epidemiological survey results in recent years show that the incidence rate of ASD is about 0.3% and the incidence rate is increasing year by year 67 .…”

Intravenous antagomiR‐494 lessens brain‐infiltrating neutrophils by increasing HDAC2‐mediated repression of multiple MMPs in experimental stroke

“…As there is no ideal biomarker to predict the long‐term prognosis of AIS, we speculate that miR‐494 in the peripheral blood may provide an alternative choice. Since our prior bioinformatics analysis revealed that miR‐494 could modulate the focal cell adhesion pathway 13 ; we then inspected two important adhesion molecules involved in the infiltration of neutrophils 19,20 and found that CD11b and MMP9 were significantly increased in neutrophils of AIS patients and were associated with miR‐494 levels. In addition, our clinical data also demonstrated that both N1 and N2 neutrophils were decreased in the blood of AIS patients but did not show a linear correlation with miR‐494 levels.…”