Silencing of A20 Aggravates Neuronal Death and Inflammation After Traumatic Brain Injury: A Potential Trigger of Necroptosis.

Zhongyuan Bao,Ning Liu,Jing Ji,Yan Liu,Yinlong Liu,Xiupeng Xu,Liang Fan,Yongping You,Honglu Chao,Lin Zhao,Xiaoming Wang

doi:10.3389/fnmol.2019.00222

Abstract

Programmed cell death is an important biological process that plays an indispensable role in traumatic brain injury (TBI). Inhibition of necroptosis, a type of programmed cell death, is pivotal in neuroprotection and in preventing associated inflammatory responses. Our results showed that necroptosis occurred in human brain tissues after TBI. Necroptosis was also induced by controlled cortical impact (CCI) injury in a rat model of TBI and was accompanied by high translocation of high-mobility group box-1 (HMGB1) to the cytoplasm. HMGB1 was then passed through the impaired cell membrane to upregulate the receptor for advanced glycation end-products (RAGE), nuclear factor (NF)-κB, and inflammatory factors such as interleukin-6 (IL-6), interleukin-1 (IL-1β), as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3). Necroptosis was alleviated by necrostatin-1 and melatonin but not Z-VAD (a caspase inhibitor), which is consistent with the characteristic of caspase-independent signaling. This study also demonstrated that tumor necrosis factor, alpha-induced protein 3 (TNFAIP3, also known as A20) was indispensable for regulating and controlling necroptosis and inflammation after CCI. We found that a lack of A20 in a CCI model led to aggressive necroptosis and attenuated the anti-necroptotic effects of necrostatin-1 and melatonin.

Highlights

Traumatic brain injury (TBI) causes high fatality and disability rates worldwide, especially among young people (McDonald et al, 2016)
We collected 13 human brain tissues, including four Normal brain tissues (NBT) from cerebrovascular-malformation patients and nine TBI tissues from patients with brain injury caused during accidents
Mitigation of necroptosis by Nec-1 and melatonin attenuated these increases, and associated virus (AAV)-shA20 treatment reversed these effects. These results indicate that attenuated necroptosis by Nec-1 and melatonin reduces cortical impact (CCI)-induced levels of neuroinflammation, which was inhibited by silencing A20

Summary

Introduction

Traumatic brain injury (TBI) causes high fatality and disability rates worldwide, especially among young people (McDonald et al, 2016). TBI is a complex condition initiated by mechanical tissue disruption, which is followed by a secondary injury phase During this phase, a variety of types of programmed cell death lead to neuronal loss (Dusick et al, 2012; Hinson et al, 2015). A variety of types of programmed cell death lead to neuronal loss (Dusick et al, 2012; Hinson et al, 2015) These events are sometimes accompanied by cognitive and neurological deficits in human TBI and in rat Abbreviations: TBI, Traumatic brain injury; HMGB1, High-mobility group box-1; CCI, Controlled cortical impact; NBT, Normal brain tissues; IL-6, Interleukin-6; IL-1β, Interleukin-1; TUNEL, TdT-mediated dUTP Nick-End Labeling; AAV, Adeno-associated virus; MWM, Morris water maze; BBB, Blood-brain barrier. Blockade of biochemical and cellular events of secondary injury—such as inflammation, autophagy, and apoptosis—is key to improving neurological outcomes (Wu et al, 2016; Cui et al, 2017)

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Conclusion