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JAK2/STAT3 inhibition attenuates intestinal ischemia–reperfusion injury via promoting autophagy: in vitro and in vivo study

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Abstract

Background

Intestinal ischemia–reperfusion (I/R) causes severe injury to the intestine, leading to systemic inflammation and multiple organ failure. Autophagy is a stress-response mechanism that can protect against I/R injury by removing damaged organelles and toxic protein aggregates. Recent evidence has identified JAK-STAT signaling pathway as a new regulator of autophagy process, however, their regulatory relationship in intestinal I/R remains unknown.

Methods and results

We systematically analyzed intestinal transcriptome data and found that JAK-STAT pathway was largely activated in response to I/R with most significant upregulation observed for JAK2 and STAT3. ChIP-Seq and luciferase assays in an in vitro oxygen–glucose deprivation and reoxygenation model revealed that activated JAK2/STAT3 signaling directly inhibited the transcription of autophagy regulator Beclin-1, leading to the suppression of autophagy and the activation of intestinal cell death. These findings were further confirmed in an in vivo mouse model, in which, intestinal I/R injury was associated with the activation of JAK2/STAT3 pathway and the deactivation of Beclin-1-mediated autophagy, while inhibiting JAK2/STAT3 with AG490 reactivated autophagy and improved survival after intestinal I/R injury.

Conclusions

JAK2/STAT3 signaling suppresses autophagy process during intestinal I/R, while inhibiting JAK-STAT can be protective against intestinal I/R injury by activating autophagy. These findings expand our knowledge on intestinal I/R injury and provide therapeutic targets for clinical treatment.

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Data availability

Data will be made available on reasonable request.

Code availability

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Funding

This work was supported by Key R & D Project of Jiangxi Provincial Science and Technology Department of Jiangxi Province (20192BBG70024) and Science and Technology Research Project of Education Department of Jiangxi Province (GJJ190058).

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Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi Province, People’s Republic of China

    Zhen Liu, Ying-Jie Huang, Qian Hu, Wei Zeng, Yue Cao, Qin Xiao & Xue-Kang Zhang

  2. Department of Anesthesiology, Nanchang Hongdu Hospital of Traditional Chinese Medicine, Nanchang, 330008, Jiangxi Province, People’s Republic of China

    Kai Hu

  3. Department of Anesthesiology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People’s Republic of China

    Yue-Sheng Chen

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  1. Zhen Liu
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Contributions

ZL, KH, YSC, YJH and YC carried out the experiment; ZL, KH, QH and WZ analyzed the data; ZL, YC and XKZ wrote the manuscript; QX and XKZ conceived the original idea and supervised the project.

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Correspondence to Xue-Kang Zhang.

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Animal experiments were carried out in accordance with the guidelines approved by the Institutional Animal Care and Use Committee of First Affiliated Hospital of Nanchang University.

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Liu, Z., Hu, K., Chen, YS. et al. JAK2/STAT3 inhibition attenuates intestinal ischemia–reperfusion injury via promoting autophagy: in vitro and in vivo study. Mol Biol Rep 49, 2857–2867 (2022). https://doi.org/10.1007/s11033-021-07099-x

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