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
Not applicable.
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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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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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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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DOI: https://doi.org/10.1007/s11033-021-07099-x