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VSIG4 Attenuates NLRP3 and Ameliorates Neuroinflammation via JAK2-STAT3-A20 Pathway after Intracerebral Hemorrhage in Mice

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Abstract

Intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease. Neuroinflammation plays an important pathological role in brain injury after ICH. NLRP3 contributes to the pathogenesis of ICH, but the underlying mechanisms regulating of NLRP3 remain elusive. V-set and immunoglobulin domain containing 4 (VSIG4), specifically expressed in resting tissue-resident macrophages, can deliver anti-inflammatory signals into various inflammatory diseases. However, the interaction between VSIG4 and NLRP3, as well as the underlying mechanisms after ICH have not been reported. C57BL/6 mice were subjected to the autologous blood injection ICH model. VSIG4 and NLRP3 levels of macrophages were detected following ICH. Ad-VSIG4 or controls were administered via intracerebroventricular (i.c.v) injection before ICH induction. STAT3 inhibitor (S31-201), JAK2 inhibitor (TG101348), or Ad-A20 RNAi was administered to investigate the role of JAK2-STAT3-A20 pathway in VSIG4-mediated neuroinflammation after ICH. Pro-inflammatory cytokine production, BBB disruption, brain water content, and neurological test were examined in ICH mice. VSIG4 levels were significantly decreased, and NLRP3 levels were significantly increased in the perihematomal brain tissues after ICH. Ad-VSIG4 attenuated NLRP3 levels and inhibited inflammation, as well as improved neurological function and reduced BBB disruption and brain water content. Furthermore, Ad-VSIG4 increased the protein levels of phosphorylated JAK2 and STAT3, and A20 levels at 24 h after ICH. STAT3 inhibitor, JAK2 inhibitor, and A20 RNAi abolished the beneficial effects of Ad-VSIG4 after ICH. In summary, these data suggested that VSIG4 attenuated NLRP3 and ameliorated neuroinflammation via JAK2-STAT3-A20 pathway after intracerebral hemorrhage in mice. VSIG4 might be an ideal therapeutic target for ICH patients.

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Availability of data and materials

The data used in the present study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (82060245) and ycstc-jckx20027.

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Author notes

  1. Na Ji and Lirong Wu contributed equally to this study and are regarded as co-first authors.

Authors and Affiliations

  1. Department of Anesthesia, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Na Ji

  2. Department of Neurology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China

    Lirong Wu

  3. Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160, China

    Hui Shi, Qianlu Li & Zhao Yang

  4. Emergency Department of Emergency, Affiliated Hospital of Zunyi Medical University, Guizhou, 563003, China

    Anyong Yu

Authors
  1. Na Ji
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  2. Lirong Wu
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  3. Hui Shi
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  4. Qianlu Li
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  5. Anyong Yu
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  6. Zhao Yang
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Contributions

NJ designed the research. LRW performed the research. AYY analyzed the data. ZY wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Anyong Yu or Zhao Yang.

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All experimental protocols for this study were approved by the Animal Ethics Committee of Chongqing Medical University in accordance with the National Institutes of Health guidelines for the care and use of experimental animals.

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The authors declare no competing interests.

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Ji, N., Wu, L., Shi, H. et al. VSIG4 Attenuates NLRP3 and Ameliorates Neuroinflammation via JAK2-STAT3-A20 Pathway after Intracerebral Hemorrhage in Mice. Neurotox Res 40, 78–88 (2022). https://doi.org/10.1007/s12640-021-00456-5

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  • DOI: https://doi.org/10.1007/s12640-021-00456-5

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