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Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice

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Abstract

Major depressive disorder is characterized by the deficiencies of monoamine neurotransmitters, neurotrophic factors and persistent neuroinflammation. Microglial activation has been associated with neuroinflammation-related mental diseases, accompanied by NLR family pyrin domain containing 3 (NLRP3) inflammasome. Here, we investigated the effect of NLRP3 inhibition by its small molecular inhibitor MCC950 on inflammatory activity and depressive-like mice induced by chronic unpredictable mild stress (CUMS), followed by the behavioral tests including sucrose preference test and forced swimming test. NLRP3/caspase-1/IL-1β signaling and microglial morphology in the prefrontal cortex were measured. The results showed that CUMS caused a decrease in sucrose preference and an increase in immobility time, which were reversed by NLRP3 inhibitor MCC950. In addition, NLRP3 inhibition decreased the number of microglia and changed the activated state of microglia to a resting state by morphology 3D reconstruction. Moreover, NLRP3 inhibition inactivated NLRP3/caspase-1/IL-1β signaling in the prefrontal cortex. The results from immunofluorescence demonstrated that NLRP3 and IL-1β expression was decreased in microglia in response to MCC950 treatment. Accordingly, proinflammatory cytokines were also decreased by NLRP3 inhibition. In conclusion, this study demonstrates that microglial NLRP3 inhibition prevents stress-induced neuroinflammation in the prefrontal cortex and suggests that microglial NLRP3 could be one of the potential therapeutic targets for depression treatment.

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Acknowledgments

This work was supported by the Science Research Foundation of ministry of Health & United Fujian Provincial Health and Education Project for Tacking the Key Research [2019-WJ-38]. We would like to thank Instrumental Analysis Center of Huaqiao University for the help of confocal testing.

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Authors and Affiliations

  1. Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Fujian province, Xiamen, 361021, PR China

    Qing Liu, Man-Man Zhang, Jie Cheng, Shi-Le Wang & Li-Tao Yi

  2. Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Jiangxi province, Nanchang, 330004, PR China

    Min-Xia Guo, Na-Zhi Li & Ji-Xiao Zhu

  3. Xiamen Hospital of Traditional Chinese Medicine, Fujian province, Xiamen, 361009, PR China

    Qiu-Ping Zhang & Cheng-Fu Li

  4. Xiamen Medicine Research Institute, Fujian province, Xiamen, 361008, PR China

    Guang-Hui Xu

  5. Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen, 361021, PR China

    Li-Tao Yi

  6. Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen, 361021, PR China

    Li-Tao Yi

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  1. Qing Liu
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Contributions

L.Y., J.Z. and C.L. designed the study. Q.L., M.Z., M.G., Q.Z., N.L., J.C., S.W. and G.X. performed the behavioral and biochemical experiments. L.Y. did molecular docking. L.Y., C.L. and J.Z. analyzed the data. L.Y., Q.L. and J.Z. wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ji-Xiao Zhu or Li-Tao Yi.

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All animal procedure was approved by Huaqiao University (A2019018) and in accordance with the published guidelines of the China Council on Animal Care.

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The authors declare that they have no conflicts of interest.

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Liu, Q., Zhang, MM., Guo, MX. et al. Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice. J Neuroimmune Pharmacol 17, 503–514 (2022). https://doi.org/10.1007/s11481-021-10037-0

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