Brain–cervical lymph node crosstalk contributes to brain injury induced by subarachnoid hemorrhage in mice

Jinman Chen, Jie Wang, Wenjing Zheng, Wenhao Ding, Zixin Zhuang, Hao Xu, Wenchao Ding, Tianhao Xu, Linmei Wang, Ning Li, Yongjian Zhao, Qi Shi, Lianping Xing (), Yongjun Wang () and Qianqian Liang ()
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Jinman Chen: Shanghai University of Traditional Chinese Medicine
Jie Wang: Shanghai University of Traditional Chinese Medicine
Wenjing Zheng: Shanghai University of Traditional Chinese Medicine
Wenhao Ding: Shanghai University of Traditional Chinese Medicine
Zixin Zhuang: Shanghai Fifth Rehabilitation Hospital
Hao Xu: Shanghai University of Traditional Chinese Medicine
Wenchao Ding: Shanghai University of Traditional Chinese Medicine
Tianhao Xu: Shanghai University of Traditional Chinese Medicine
Linmei Wang: Shanghai University of Traditional Chinese Medicine
Ning Li: Shanghai University of Traditional Chinese Medicine
Yongjian Zhao: Shanghai University of Traditional Chinese Medicine
Qi Shi: Shanghai University of Traditional Chinese Medicine
Lianping Xing: University of Rochester Medical Center
Yongjun Wang: Shanghai University of Traditional Chinese Medicine
Qianqian Liang: Shanghai University of Traditional Chinese Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Cross-talk between the brain and cervical lymph nodes (CLNs) is crucial in brain pathologies. However, the precise roles and the mechanisms of CLNs in brain damage during subarachnoid hemorrhage (SAH) remain unclear. In this study, mandibular lymph node (part of CLNs) removal attenuates brain damage in SAH mouse models. Notably, the extravasated erythrocytes following SAH are significantly engulfed by lymphatic endothelial cells (LECs) in CLNs. Single-cell RNA sequencing reveals that the differentially expressed genes in medullary LECs are enriched in lysosomes after SAH, with a notable upregulation of Ctss (which encodes cathepsin S). Importantly, the deficiency of cathepsin S specifically in LECs, achieved through transgenic mice, or the use of a cathepsin S inhibitor, significantly reduces neuroinflammation and neurological deficits induced by SAH. These findings elucidate mechanisms of how CLNs participate in brain injury following SAH in mice. Targeting this process may offer effective therapeutic strategies to alleviate SAH-related pathologies.

Date: 2025
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DOI: 10.1038/s41467-025-63544-6

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