Journal of the American Heart Association · 2025
Circulating Cathepsin D Exacerbates Injury-Induced Brain Damage by Promoting Neutrophil Infiltration Into the Brain.
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Liang Yu, Zhao Dan, Wu Peng-Fei, Liang Yong-Qi, Zhang Xue-Wei, Xing Jia, Sun Xue, An Ming-Xin, Shi Jun-Xiu, Gao Qing-Hua, Tian Li, Sun Hong-Zan, Xue Bin, Jiang Li-Bo, Chen Yu-Hua, Zhao Wei-Dong
Аннотация
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 hCTSDhi 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 hCTSDhi mice. Additionally, transgenic CTSDMono 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 hCTSDhi mice showed increased brain neutrophil infiltration in response to the brain injury. Severe motor deficit and delayed behavioral recovery were observed in hCTSDhi 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.
METHODS: To resolve this issue, two groups of transgenic hCTSDhi 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 hCTSDhi mice. Additionally, transgenic CTSDMono 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 hCTSDhi mice showed increased brain neutrophil infiltration in response to the brain injury. Severe motor deficit and delayed behavioral recovery were observed in hCTSDhi 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.