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RBM3 Promotes Anti-inflammatory Responses in Microglia and Serves as a Neuroprotective Target of Ischemic Stroke

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Abstract

Ischemic stroke is a major cause of death and disability in adults. Hypothermic treatment is successful in treating neonatal cerebral ischemia, but its application is restricted in adult patients due to complex management strategies and severe adverse effects. Two homologous RNA-binding proteins, RBM3 and CIRP, are the only known cold-inducible proteins in vertebrates, and their expression levels are robustly elevated by mild to moderate hypothermia. In previous studies, we and others have demonstrated that both RBM3 and CIRP mediate the neuroprotective and neurogenic effects of hypothermia in cell and animal models. However, CIRP can also be detrimental to neurons by triggering neuroinflammatory responses, complicating its post-stroke functions. In this study, we compared the properties of the two cold-inducible RNA-binding proteins after ischemic stroke. Our results indicated that RBM3 expression was stimulated in the ischemic brain of stroke patients, while CIRP expression was not. In an experimental model, RBM3 can ameliorate ischemic-like insult by promoting neuronal survival and eliciting anti-inflammatory responses in activated microglia, while the impact of CIRP was intriguing. Collectively, our data supported the notion that RBM3 may be a more promising therapeutic target than CIRP for treating ischemic stroke. We further demonstrated that zr17-2, a small molecule initially identified to target CIRP, can specifically target RBM3 but not CIRP in microglia. zr17-2 demonstrated anti-inflammatory and neuroprotective effects after ischemic stroke both in vitro and in vivo, suggesting its potential therapeutic value.

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Acknowledgements

The authors thank Dr. Xianyuan Xiang (Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences) for scientific discussion.

Funding

This study was supported by the National Natural Science Foundation of China (No. 32100774), Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases (No. ZDSYS20220304163558001) and the Foundation of Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (No. NSY889021031).

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  1. Junyi Zhao, Siyu Liu, and Kunyu Li contribute equally.

Authors and Affiliations

  1. The Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, China

    Junyi Zhao, Siyu Liu, Kunyu Li, Yulu Yang, Yue Zhao & Xinzhou Zhu

  2. Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases, Shenzhen, China

    Junyi Zhao, Siyu Liu, Yue Zhao & Xinzhou Zhu

  3. School of Life Sciences, University of Science and Technology of China, Hefei, China

    Yulu Yang

  4. Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China

    Xinzhou Zhu

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Contributions

XZ designed the study, performed experiments, analyzed data, and wrote the manuscript. JZ, KL, YY, and YZ performed in vitro experiments and assisted with data analysis. SL and KL performed in vivo experiments and assisted with data analysis. All authors approved for the final version of manuscript.

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Correspondence to Xinzhou Zhu.

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All animal experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) in Shenzhen Institute of Advanced Technology (SIAT) with the license number SIAT-IACUC-20210909-NS-NTPZX-ZXZ-A1231-08.

The omics data from patients were collected from the Gene Expression Omnibus (GEO) public database. Institutional Review Board in SIAT confirmed that no ethical approval was required.

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Zhao, J., Liu, S., Li, K. et al. RBM3 Promotes Anti-inflammatory Responses in Microglia and Serves as a Neuroprotective Target of Ischemic Stroke. Mol Neurobiol 61, 7384–7402 (2024). https://doi.org/10.1007/s12035-024-04052-4

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