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Theranostics 2024; 14(5):1909-1938. doi:10.7150/thno.91653 This issue Cite

Research Paper

Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage

Qiang Zhang1,2,5,6,#, Yujie Chen1,3,5,6,#,✉, Yingpei Li1,5,6, Zhou Feng3,5,6, Liang Liang1,5,6, Xiaoke Hao1,5,6, Wenbo Kang1,5,6, Zhaoqi Zhang1,5,6, Xuyang Zhang1,5,6, Rong Hu1,5,6, Hua Feng1,5,6, Zhi Chen1,5,6,✉

1. Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
2. Department of Neurosurgery, The 961 st Hospital of the Chinese People's Liberation Army Joint Logistic Support Force, Qiqihar, 161000, Heilongjiang Province, China.
3. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
4. Department of Rehabilitation, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
5. Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
6. Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
#Both authors contributed equally to this work.

✉ Corresponding authors: Yujie Chen, MD, PhD; E-mail: yujiechen6886com; chenyjedu.cn; ORCID: 0000-0002-9905-9138; Phone: (86)023-68765925, Fax: (86)023-68765922. Zhi Chen, MD, PhD; E-mail: zhichenedu.cn; ORCID: 0000-0002-8404-4937 More

Citation:
Zhang Q, Chen Y, Li Y, Feng Z, Liang L, Hao X, Kang W, Zhang Z, Zhang X, Hu R, Feng H, Chen Z. Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics 2024; 14(5):1909-1938. doi:10.7150/thno.91653. https://www.thno.org/v14p1909.htm
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Abstract

Graphic abstract

Rationale: Hydrocephalus is a substantial complication after intracerebral hemorrhage (ICH) or intraventricular hemorrhage (IVH) that leads to impaired cerebrospinal fluid (CSF) circulation. Recently, brain meningeal lymphatic vessels (mLVs) were shown to serve as critical drainage pathways for CSF. Our previous studies indicated that the degradation of neutrophil extracellular traps (NETs) after ICH/IVH alleviates hydrocephalus. However, the mechanisms by which NET degradation exerts beneficial effects in hydrocephalus remain unclear.

Methods: A mouse model of hydrocephalus following IVH was established by infusing autologous blood into both wildtype and Cx3cr1-/- mice. By studying the features and processes of the model, we investigated the contribution of mLVs and NETs to the development and progression of hydrocephalus following secondary IVH.

Results: This study observed the widespread presence of neutrophils, fibrin and NETs in mLVs following IVH, and the degradation of NETs alleviated hydrocephalus and brain injury. Importantly, the degradation of NETs improved CSF drainage by enhancing the recovery of lymphatic endothelial cells (LECs). Furthermore, our study showed that NETs activated the membrane protein CX3CR1 on LECs after IVH. In contrast, the repair of mLVs was promoted and the effects of hydrocephalus were ameliorated after CX3CR1 knockdown and in Cx3cr1-/- mice.

Conclusion: Our findings indicated that mLVs participate in the development of brain injury and secondary hydrocephalus after IVH and that NETs contribute to acute LEC injury and lymphatic thrombosis. CX3CR1 is a key molecule in NET-induced LEC damage and meningeal lymphatic thrombosis, which leads to mLV dysfunction and exacerbates hydrocephalus and brain injury. NETs may be a critical target for preventing the obstruction of meningeal lymphatic drainage after IVH.

Keywords: Intraventricular hemorrhage, Hydrocephalus, Meningeal lymphatic vessels, Neutrophil extracellular traps, CX3C chemokine receptor 1

Citation styles

APA
Zhang, Q., Chen, Y., Li, Y., Feng, Z., Liang, L., Hao, X., Kang, W., Zhang, Z., Zhang, X., Hu, R., Feng, H., Chen, Z. (2024). Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics, 14(5), 1909-1938. https://doi.org/10.7150/thno.91653.

ACS
Zhang, Q.; Chen, Y.; Li, Y.; Feng, Z.; Liang, L.; Hao, X.; Kang, W.; Zhang, Z.; Zhang, X.; Hu, R.; Feng, H.; Chen, Z. Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics 2024, 14 (5), 1909-1938. DOI: 10.7150/thno.91653.

NLM
Zhang Q, Chen Y, Li Y, Feng Z, Liang L, Hao X, Kang W, Zhang Z, Zhang X, Hu R, Feng H, Chen Z. Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics 2024; 14(5):1909-1938. doi:10.7150/thno.91653. https://www.thno.org/v14p1909.htm

CSE
Zhang Q, Chen Y, Li Y, Feng Z, Liang L, Hao X, Kang W, Zhang Z, Zhang X, Hu R, Feng H, Chen Z. 2024. Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics. 14(5):1909-1938.

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