Work

Circulating Cathepsin D Exacerbates Injury‐Induced Brain Damage by Promoting Neutrophil Infiltration Into the Brain

Year: 2025

Type: article

Abstract: Background Communication between the vascular endothelium and peripheral leukocytes is an important process controlling inflammatory responses in the brain. Increased plasma levels of CTSD (cathepsin D) have been associated with vascular events, but whether circulating CTSD may affect the functional status of the endothelium remains unknown. Methods To resolve this issue, two groups of transgenic hCTSD hi mice with high levels of circulating CTSD were subjected to traumatic and ischemic injury, respectively. Then, single‐cell RNA sequencing was performed to characterize gene expression changes in the brains of hCTSD hi mice. Additionally, transgenic CTSD Mono knockout mice with reduced plasma CTSD levels were generated to investigate whether CTSD downregulation confers protection against ischemic injury and traumatic brain injury‐induced brain damage. Results We found the hCTSD hi mice showed increased brain neutrophil infiltration in response to the brain injury. Severe motor deficit and delayed behavioral recovery were observed in hCTSD hi mice after brain traumatic and ischemic injury. Mechanistically, the circulating CTSD was characterized as the nonenzymatic prototype CTSD, pro‐CTSD. We further found the circulating nonenzymatic pro‐CTSD was able to activate brain endothelium by upregulating VCAM‐1 (vascular cell adhesion molecule 1) expression, which is necessary for the transmigration of neutrophils into the brain. Furthermore, genetic reduction of CTSD effectively attenuated the ischemic injury‐induced neutrophil infiltration and motor deficits. Conclusions Taken together, these results demonstrate that circulating prototype CTSD exacerbates the injury‐induced brain damage by upregulating brain endothelial VCAM‐1 and promoting neutrophil transmigration into the brain.

Source: Journal of the American Heart Association

DOI: 10.1161/jaha.125.043416