IL-11 ameliorates oxidative stress damage in neurons after spinal cord injury by activating the JAK/STAT signaling pathway

Yang Sun; Xue Song; Zhijun Geng; Yibo Xu; Linyu Xiao; Yue Chen; Bohan Li; Jinran Shi; Lian Wang; Yueyue Wang; Xiaofeng Zhang; Lugen Zuo; Jing Li; Hezuo Lü; Jianguo Hu

doi:10.1016/j.intimp.2023.111367

IL-11 ameliorates oxidative stress damage in neurons after spinal cord injury by activating the JAK/STAT signaling pathway

Int Immunopharmacol. 2024 Jan 25:127:111367. doi: 10.1016/j.intimp.2023.111367. Epub 2023 Dec 30.

Authors

Yang Sun¹, Xue Song², Zhijun Geng², Yibo Xu³, Linyu Xiao⁴, Yue Chen⁴, Bohan Li³, Jinran Shi³, Lian Wang⁵, Yueyue Wang⁶, Xiaofeng Zhang², Lugen Zuo⁵, Jing Li⁶, Hezuo Lü⁷, Jianguo Hu⁸

Affiliations

¹ Department of rehabilitation medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
² Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China.
³ Bengbu Medical University, Bengbu, China.
⁴ Department of rehabilitation medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China; Bengbu Medical University, Bengbu, China.
⁵ Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
⁶ Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
⁷ Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China. Electronic address: lhz233003@163.com.
⁸ Inflammatory Bowel Disease Research Center, First Affiliated Hospital of Bengbu Medical University, Bengbu, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases, Bengbu, China; Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu, China. Electronic address: jghu9200@163.com.

PMID: 38160564
DOI: 10.1016/j.intimp.2023.111367

Abstract

Objective: Excess reactive oxygen species (ROS) generated by oxidative stress is a crucial factor affecting neuronal dysfunction after spinal cord injury (SCI). IL-11 has been reported to have antioxidative stress capacity. In the present study, we investigated the protective effect and mechanism of IL-11 against neuronal cell damage caused by oxidative imbalance.

Methods: We established a H₂O₂-induced oxidative stress injury model in PC12 cells and observed the effects of IL-11 on cellular activity, morphology, oxidase and antioxidant enzymes, and ROS release. Furthermore, the effect of IL-11 on apoptosis of PC12 cells was assessed by flow cytometry, a TUNEL assay and Western blotting. Transcriptome analysis and rescue experiments revealed the mechanism by which IL-11 protects neurons from oxidative stress damage. For the in vivo investigation, an adenovirus-mediated IL-11 overexpression SCI rat model was constructed to validate the beneficial effect of IL-11 against SCI.

Results: IL-11 significantly improved the viability and enhanced the antioxidant activity of H₂O₂-treated PC12 cells while reducing ROS release. In addition, IL-11 reduced H₂O₂-induced PC12 cell apoptosis. Transcriptome analysis revealed that the JAK/STAT pathway may be related to the antioxidant activity of IL-11. Treatment with a JAK/STAT inhibitor (Stattic) exacerbated the oxidative damage induced by H₂O₂ and attenuated the protective effects of IL-11. The results of in vivo studies showed that IL-11 prevented neuronal apoptosis due to oxidative imbalance and promoted the restoration of motor function in SCI rats by activating the JAK/STAT signaling pathway.

Conclusion: IL-11 inhibited oxidative stress-induced neuronal apoptosis at least in part by activating the JAK/STAT signaling pathway and further promoted the recovery of motor function. These findings suggest that IL-11 may be an effective target for the treatment for SCI.

Keywords: Apoptosis; Interleukin 11; JAK/STAT; Neuron; Oxidative damage; Spinal cord injury.

MeSH terms

Animals
Antioxidants / metabolism
Antioxidants / pharmacology
Antioxidants / therapeutic use
Apoptosis
Hydrogen Peroxide / metabolism
Interleukin-11 / metabolism
Interleukin-11 / therapeutic use
Janus Kinases / metabolism
Neurons
Oxidative Stress
Rats
Reactive Oxygen Species / metabolism
STAT Transcription Factors / metabolism
Signal Transduction*
Spinal Cord / metabolism
Spinal Cord Injuries* / drug therapy
Spinal Cord Injuries* / metabolism

Substances

Janus Kinases
Antioxidants
Interleukin-11
Hydrogen Peroxide
Reactive Oxygen Species
STAT Transcription Factors