Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage

Jinman Chen,Zixin Zhuang,Chinyun Wang,Yangkang Zheng,Hao Xu,Lianping Xing,Qianqian Liang,Zibin Guo,Yongjun Wang,Xuefei Li,Shaohua Chen,Linmei Wang

doi:10.1038/s41467-020-16851-z

Abstract

Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH). Meningeal lymphatics have been reported to drain macromolecules and immune cells from CSF into cervical lymph nodes (CLNs). However, whether meningeal lymphatics are involved in clearing extravasated erythrocytes in CSF after SAH remains unclear. Here we show that a markedly higher number of erythrocytes are accumulated in the lymphatics of CLNs and meningeal lymphatics after SAH. When the meningeal lymphatics are depleted in a mouse model of SAH, the degree of erythrocyte aggregation in CLNs is significantly lower, while the associated neuroinflammation and the neurologic deficits are dramatically exacerbated. In addition, during SAH lymph flow is increased but without significant lymphangiogenesis and lymphangiectasia. Taken together, this work demonstrates that the meningeal lymphatics drain extravasated erythrocytes from CSF into CLNs after SAH, while suggesting that modulating this draining may offer therapeutic approaches to alleviate SAH severity.

Highlights

Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH)
Proteins, and labeled T cells injected into the brain or CSF are found in cervical lymph nodes (CLNs), indicating the drainage function by meningeal lymphatics[14,20]
We show that the extravasated erythrocytes in the subarachnoid space (SAS) are drained into deep CLNs (dCLNs) and mandibular LNs through the meningeal lymphatics and that the depletion of meningeal lymphatics blocks the clearance of extravasated blood

Summary

Introduction

Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH). When the meningeal lymphatics are depleted in a mouse model of SAH, the degree of erythrocyte aggregation in CLNs is significantly lower, while the associated neuroinflammation and the neurologic deficits are dramatically exacerbated. This work demonstrates that the meningeal lymphatics drain extravasated erythrocytes from CSF into CLNs after SAH, while suggesting that modulating this draining may offer therapeutic approaches to alleviate SAH severity. Lymphatic vessels have been rediscovered and characterized in the meninges surrounding the central nervous system[11,12] These lymphatics are responsible for the drainage of cerebrospinal fluid (CSF) macromolecules and immune cells to the cervical lymph nodes (CLNs)[13,14]. As noted above, while meningeal lymphatics drain immune cells and macromolecules from CSF, it is still unclear whether they clear the extravasated blood after SAH. Our findings demonstrate that meningeal lymphatics participate in the drainage of RBCs into CLNs during the very early stage of SAH and may be a potent target in the treatment of this pathology

Methods

Results

Conclusion