2. Academic Validation
  3. Interleukin-18 accelerates cardiac inflammation and dysfunction during ischemia/reperfusion injury by transcriptional activation of CXCL16

Interleukin-18 accelerates cardiac inflammation and dysfunction during ischemia/reperfusion injury by transcriptional activation of CXCL16

  • Cell Signal. 2021 Nov;87:110141. doi: 10.1016/j.cellsig.2021.110141.
Gang Zhao 1,  Hongqiang Zhang 2,  Shijie Zhu 2,  Shijun Wang 3,  Kai Zhu 2,  Yun Zhao 2,  Lei Xu 4,  Ping Zhang 5,  Jing Xie 5,  Aijun Sun 3,  Yunzeng Zou 4,  Junbo Ge 6
Affiliations

Affiliations

  • 1 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Department of Cardiology, Kashgar Prefecture Second People's Hospital, Kashi, China.
  • 2 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 4 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 5 Department of Cardiology, Kashgar Prefecture Second People's Hospital, Kashi, China.
  • 6 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China. Electronic address: jbge@zs-hospital.sh.cn.
PMID: 34487815 DOI: 10.1016/j.cellsig.2021.110141
Abstract

Myocardial ischemia/reperfusion(I/R) injury elicits an inflammatory response that drives tissue damage and cardiac remodeling. The trafficking and recruitment of inflammatory cells are controlled by C-X-C motif chemokine ligands and their receptors. CXCL16, a hallmark of acute coronary syndromes, is responsible for the recruitment of macrophages, monocytes and T lymphocytes. However, its role in cardiac I/R injury remains poorly characterized. Here we reported that CXCL16-mediated cardiac infiltration of CD11b+Ly6C+ cells played a crucial role in IL-18-induced myocardial inflammation, Apoptosis and left ventricular(LV) dysfunction during I/R. Treatment with CXCL16 shRNA attenuated I/R-induced cardiac injury, LV remodeling and cardiac inflammation by reducing the recruitment of inflammatory cells and the release of TNFα, IL-17 and IFN-γ in the heart. We found that I/R-mediated NLRP3/IL-18 signaling pathway triggered CXCL16 transcription in cardiac vascular endothelial cells(VECs). Two binding sites of FOXO3 were found at the promoter region of CXCL16. By luciferase report assay and ChIP analysis, we confirmed that FOXO3 was responsible for endothelial CXCL16 transcription. A pronounced reduction of CXCL16 was observed in FOXO3 siRNA pretreated-VECs. Further experiments revealed that IL-18 activated FOXO3 by promoting the phosphorylation of STAT3 but not STAT4. An interaction between FOXO3 and STAT3 enhanced the transcription of CXCL16 induced by FOXO3. Treatment with Anakinra or Stattic either effectively inhibited IL-18-mediated nuclear import of FOXO3 and CXCL16 transcription. Our findings suggested that IL-18 accelerated I/R-induced cardiac damage and dysfunction through activating CXCL-16 and CXCL16-mediated cardiac infiltration of the CD11b+Ly6C+ cells. CXCL16 might be a novel therapeutic target for the treatment of I/R-related ischemic heart diseases.

Keywords

CXCL16; FOXO3; IL-18; Ischemia/reperfusion; NLRP3.

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