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Spata2 Knockdown Exacerbates Brain Inflammation via NF-κB/P38MAPK Signaling and NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Rats

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Abstract

Brain inflammation induced by ischemic stroke is an important cause of secondary brain injury. The nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and NLRP3 inflammasome signaling are believed to drive the progression of brain inflammation. Spermatogenesis-associated protein2 (SPATA2) functions as a partner protein that recruits CYLD, a negative regulator of NF-κB signaling, to signaling complexes. However, the role of SPATA2 in the central nervous system remains unclear and whether it is involved in regulating inflammatory responses remains controversial. Rats were subjected to transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R) surgery. The expression and localization of SPATA2 in the brain were investigated. The lentivirus-mediated shRNA was employed to inhibit SPATA2 expression. The inflammatory responses and outcomes of Spata2 knockdown were investigated. SPATA2 was co-localized with CYLD in neurons. SPATA2 expression was reduced in tMCAO/R rats. Spata2 knockdown resulted in increased microglia, increased expression of Tnfa, Il-1β, and Il-18, decreased Garcia score, and increased infarct volume. Spata2 knockdown resulted in the activation of P38MAPK and NLRP3 inflammasome and the increased activation of NF-κB signaling. These results suggest that SPATA2 plays a protective role against brain inflammation induced by ischemia/reperfusion injury. Therefore, SPATA2 could be a potential therapeutic target for treating ischemic stroke.

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Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 30470606) and the Natural Science Foundation of Chongqing, Grand No. cstc2019jcyj-msxmX0630, to JJ.

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  1. Yikun Ren and Jin Jiang have contributed equally to this work

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Yikun Ren, Jin Jiang, Wenxia Jiang, Xueling Zhou, Wenhao Lu, Jingwen Wang & Yong Luo

  2. Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Yikun Ren, Jin Jiang, Wenxia Jiang, Xueling Zhou, Wenhao Lu, Jingwen Wang & Yong Luo

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  1. Yikun Ren
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Contributions

Conceptualization, YR and JJ; methodology, YR, JJ, and WJ; software, XZ and WL; validation, YR, JJ, and JW; investigation, YR, JJ, and XZ; data curation, YR, JJ, and WJ; writing—original draft preparation, YR; writing—review and editing, JJ; supervision, YL; project administration, YL; funding acquisition, YL All authors have read and agreed to the published version of the manuscript.

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Correspondence to Yong Luo.

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The study was conducted according to the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the Ethics Committee for Animal Experimentation of Chongqing Medical University (number SCXK (Yu) 2018–0003). All efforts were made to minimize the number of rats sacrificed and their suffering.

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Ren, Y., Jiang, J., Jiang, W. et al. Spata2 Knockdown Exacerbates Brain Inflammation via NF-κB/P38MAPK Signaling and NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Rats. Neurochem Res 46, 2262–2275 (2021). https://doi.org/10.1007/s11064-021-03360-8

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