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Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage

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Abstract

Intracerebral hemorrhage (ICH) is characterized by poor prognosis and high mortality rates. To date, satisfactory therapeutic approaches for ICH remain limited, so it is urgently needed to develop a safer and more effective prescription. Secondary inflammatory response has been acknowledged as an aggravating factor to neurological deterioration after ICH. As a component of inflammasome sensors, absent in melanoma 2 (AIM2) plays an important role in the neuroinflammation process. Here, ozanimod, a novel selective sphingosine 1-phosphate receptor modulator, has gained much attention, which alleviates the resultant neuroinflammation and improves functional recovery derived from ICH. In this study, ozanimod improved neurological functions of ICH mice via reduction of hematoma size. Furthermore, both microglial and AIM2 inflammasome activations were reversed by ozanimod, which are confirmed by the downregulation of related inflammatory proteins and cytokines (IL-1β, IL-6, and TNF-α), coupled with the upregulation of SIRT3, by leveraging the Western blot and enzyme-linked immunosorbent assay. Additionally, we find that ozanimod decreases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. Notably, in vitro cell experiments induced by lipopolysaccharide confirms that the anti-inflammatory effect of ozanimod could be abolished by the SIRT3 inhibitor. In conclusion, these results indicate that ozanimod mitigates ICH-induced secondary inflammatory responses by modulating AIM2 inflammasome mediated by SIRT3/NF-κB/AIM2 pathway. This demonstrates ozanimod orchestrates ICH-induced neuroinflammation and could be a targeted therapy for improving prognosis of ICH.

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Data Availability

All datasets in this manuscript are available from the corresponding author upon reasonable request.

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Acknowledgements

We appreciate the technical support of Dr. Wang ZY from the Institute of Health Science, China Medical University.

Funding

This work was sponsored by the National Natural Science Foundation of China (81971125, 82001234).

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Authors and Affiliations

  1. Department of Geriatrics, the First Hospital of China Medical University, Shenyang, 110001, China

    Xiaoxi Li

  2. Department of Neurology, the First Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, 510080, China

    Heyu Zhang

  3. Department of Geriatrics, Dalian Friendship Hospital, Dalian, 116100, China

    Wenxu Zheng

  4. Department of Neurosurgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China

    Jizhou Sun

  5. Department of Neurology, the First Hospital of China Medical University, Shenyang, 110001, China

    Liyuan Wang & Zhiyi He

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Contributions

XL and ZH conceived and designed the experiment; JS, HZ, and LW implemented the molecular biology experiment and neurobehavioral tests; XL processed the data and composed the draft manuscript. ZH, JS, and WZ revised the manuscript. All authors discussed the results and approved the submitted version.

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Correspondence to Jizhou Sun, Liyuan Wang or Zhiyi He.

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Li, X., Zhang, H., Zheng, W. et al. Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage. Mol Neurobiol 60, 1117–1131 (2023). https://doi.org/10.1007/s12035-022-03137-2

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