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Sirt1-ROS-TRAF6 Signaling-Induced Pyroptosis Contributes to Early Injury in Ischemic Mice

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Abstract

Stroke is an acute cerebro-vascular disease with high incidence and poor prognosis, most commonly ischemic in nature. In recent years, increasing attention has been paid to inflammatory reactions as symptoms of a stroke. However, the role of inflammation in stroke and its underlying mechanisms require exploration. In this study, we evaluated the inflammatory reactions induced by acute ischemia and found that pyroptosis occurred after acute ischemia both in vivo and in vitro, as determined by interleukin-1β, apoptosis-associated speck-like protein, and caspase-1. The early inflammation resulted in irreversible ischemic injury, indicating that it deserves thorough investigation. Meanwhile, acute ischemia decreased the Sirtuin 1 (Sirt1) protein levels, and increased the TRAF6 (TNF receptor associated factor 6) protein and reactive oxygen species (ROS) levels. In further exploration, both Sirt1 suppression and TRAF6 activation were found to contribute to this pyroptosis. Reduced Sirt1 levels were responsible for the production of ROS and increased TRAF6 protein levels after ischemic exposure. Moreover, N-acetyl-L-cysteine, an ROS scavenger, suppressed the TRAF6 accumulation induced by oxygen-glucose deprivation via suppression of ROS bursts. These phenomena indicate that Sirt1 is upstream of ROS, and ROS bursts result in increased TRAF6 levels. Further, the activation of Sirt1 during the period of ischemia reduced ischemia-induced injury after 72 h of reperfusion in mice with middle cerebral artery occlusion. In sum, these results indicate that pyroptosis-dependent machinery contributes to the neural injury during acute ischemia via the Sirt1-ROS-TRAF6 signaling pathway. We propose that inflammatory reactions occur soon after oxidative stress and are detrimental to neuronal survival; this provides a promising therapeutic target against ischemic injuries such as a stroke.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31771292 and 31571162). We thank Professor Heping Cheng, Peking University, for kindly supporting the analytical methods for the fluorescence images.

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  1. Weijie Yan and Wei Sun have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Ministry of Education Key Laboratory for Neurodegenerative Disorders, Capital Medical University, Beijing, 100069, China

    Weijie Yan, Jiahui Fan, Song Han, Junfa Li & Yanling Yin

  2. Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Wei Sun & Haiqing Wang

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  1. Weijie Yan
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Yan, W., Sun, W., Fan, J. et al. Sirt1-ROS-TRAF6 Signaling-Induced Pyroptosis Contributes to Early Injury in Ischemic Mice. Neurosci. Bull. 36, 845–859 (2020). https://doi.org/10.1007/s12264-020-00489-4

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