Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis. Academic Article uri icon


  • 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.

published proceedings

  • Front Immunol

altmetric score

  • 0.75

author list (cited authors)

  • Fu, H., Sun, Y. u., Shao, Y., Saredy, J., Cueto, R., Liu, L. u., ... Yang, X.

citation count

  • 10

complete list of authors

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

publication date

  • October 2020