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TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

Authors :
Han Wang
Wei Li
Xuan Gao
Dingding Zhang
Guang-Jie Liu
Tao Tao
Zong Zhuang
Yong-Yue Gao
Yan Zhou
Ling-Yun Wu
Chun-Hua Hang
Yue Lu
Source :
Cell Death & Disease, Cell Death and Disease, Vol 12, Iss 1, Pp 1-16 (2021)
Publication Year :
2021
Publisher :
Springer Science and Business Media LLC, 2021.

Abstract

Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

Details

ISSN :
20414889
Volume :
12
Database :
OpenAIRE
Journal :
Cell Death & Disease
Accession number :
edsair.doi.dedup.....ea2f3f508c4059e460b03519e4e26dd6
Full Text :
https://doi.org/10.1038/s41419-020-03278-z