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NLRP6 contributes to inflammation and brain injury following intracerebral haemorrhage by activating autophagy

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Abstract

Inflammation is a crucial factor contributing to secondary brain injury after intracerebral haemorrhage (ICH). NLRP6, a member of nod-like receptors (NLRs) family, has been reported to participate in inflammation and host-defence in multiple diseases. Distinct from the other NLR family members, NLRP6 regulates inflammation in an inflammasome-dependent as well as an inflammasome-independent pathway. However, the role of NLRP6 in regulating signalling pathways during ICH is poorly understood. In the present study, we demonstrated that NLRP6 expression was upregulated after ICH, both in humans and in rats. Subsequently, we developed a rat model of ICH and found that NLRP6 knockdown reduced brain injury, alleviated inflammation, and suppressed autophagy following ICH. Further, results indicated that autophagy involved in NLRP6 mediated inflammation after ICH. Moreover, we found that NLRP6 mediated regulation of autophagy and inflammation was inflammasome-dependent. This study revealed the underlying molecular mechanism of NLRP6 in inflammation and highlights the therapeutic potential of targeting NLRP6 in secondary brain injury after ICH.

Key messages

• NLRP6 was upregulated following ICH in humans and rats.

• NLRP6 knockdown reduced brain injury, alleviated inflammation, and suppressed autophagy following ICH.

• NLRP6 aggravated inflammation after ICH by activating autophagy.

• NLRP6 regulated inflammation and autophagy after ICH by activating inflammasome pathway.

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Acknowledgements

The authors are grateful to Prof. Jingxian Wu and Prof. Lingyu Li for technical assistance.

Funding

National Key Research and Development Program of China (No. 2016YFE0203900), National Natural Science Foundation of China (No. 81971217), and Natural Science Foundation of Chongqing Science and Technology Committee, China (No. cstc2015jcyjBX0144) supported this work.

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Authors and Affiliations

  1. Department of Neurosurgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Han Xiao, Hui Chen, Li Zhang, Lu Wang, Hui Gan, Xuan Zhai & Ping Liang

  2. Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Chongqing, China

    Han Xiao, Hui Chen, Li Zhang, Lu Wang, Hui Gan, Xuan Zhai & Ping Liang

  3. Institute of Neuroscience, Chongqing Medical University, Chongqing, China

    Han Xiao, Hui Chen, Li Zhang, Lu Wang, Hui Gan, Ning Jiang, Jing Zhao, Xuan Zhai & Ping Liang

  4. Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China

    Rong Jiang

  5. Department of Pathophysiology, Chongqing Medical University, Chongqing, China

    Hui Gan & Jing Zhao

  6. Department of Pathology, Chongqing Medical University, Chongqing, China

    Ning Jiang

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  1. Han Xiao
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  2. Hui Chen
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Correspondence to Ping Liang.

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All human studies have been approved by Ethics Committee of Children’s Hospital Affiliated to Chongqing Medical University. Prior written informed consent was obtained from participants or their legal representatives (in case of diseased). Animal experimentation conforms to protocols approved by the Institutional Ethics Committee of Chongqing Medical University.

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Xiao, H., Chen, H., Jiang, R. et al. NLRP6 contributes to inflammation and brain injury following intracerebral haemorrhage by activating autophagy. J Mol Med 98, 1319–1331 (2020). https://doi.org/10.1007/s00109-020-01962-3

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