Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Hangfei Fu, Yu Sun, Ying Shao, Jason Saredy, Ramon Cueto, Lu Liu, Charles Drummer, Candice Johnson, Keman Xu, Yifan Lu, Xinyuan Li, Shu Meng, Eric R. Xue, Judy Tan, Nirag C. Jhala, Daohai Yu, Yan Zhou, Kayla J. Bayless, Jun Yu, Thomas J. RogersWenhui Hu, Nathaniel W. Snyder, Jianxin Sun, Xuebin Qin, Xiaohua Jiang, Hong Wang, Xiaofeng Yang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii) HLI-induced angiogenesis is improved in Il12rb2−/− mice, in ApoE−/−/Il12rb2−/− mice compared to WT and ApoE−/− controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase.

Original languageEnglish (US)
Article number595813
JournalFrontiers in immunology
StatePublished - Oct 14 2020


  • IL-12Rβ2
  • IL-35
  • angiogenesis
  • endothelial cells
  • ischemia and hypoxia

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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