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

Nat Commun. 2025 Sep 29;16(1):8551. doi: 10.1038/s41467-025-63544-6.

Jinman Chen ¹ ² ³ ⁴, Jie Wang ¹ ² ³, Wenjing Zheng ¹ ² ³, Wenhao Ding ¹ ² ³, Zixin Zhuang ⁵, Hao Xu ¹ ² ³, Wenchao Ding ¹ ² ³, Tianhao Xu ¹ ² ³, Linmei Wang ⁶, Ning Li ¹ ² ³ ⁴, Yongjian Zhao ¹ ² ³, Qi Shi ¹ ² ³, Lianping Xing ⁷, Yongjun Wang ⁸ ⁹ ¹⁰ ¹¹, Qianqian Liang ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1 Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2 Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
3 Key Laboratory of Theory and Therapy of Muscles and Bones, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
4 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
5 Shanghai Fifth Rehabilitation Hospital, Shanghai, China.
6 Department of Anatomy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
7 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA. Lianping_xing@urmc.rochester.edu.
8 Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. wangyongjun@shutcm.edu.cn.
9 Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China. wangyongjun@shutcm.edu.cn.
10 Key Laboratory of Theory and Therapy of Muscles and Bones, Shanghai University of Traditional Chinese Medicine, Shanghai, China. wangyongjun@shutcm.edu.cn.
11 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. wangyongjun@shutcm.edu.cn.
12 Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. liangqianqian@shutcm.edu.cn.
13 Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China. liangqianqian@shutcm.edu.cn.
14 Key Laboratory of Theory and Therapy of Muscles and Bones, Shanghai University of Traditional Chinese Medicine, Shanghai, China. liangqianqian@shutcm.edu.cn.
15 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. liangqianqian@shutcm.edu.cn.

PMID: 41022690 DOI: 10.1038/s41467-025-63544-6

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.

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HY-15533

LY 3000328

99.50%, Cathepsin S Inhibitor

Cathepsin

Inflammation/Immunology

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