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Fu H , Sun Y , Shao Y , Saredy J , Cueto R , Liu L , Drummer Cth , Johnson C , Xu K , Lu Y , Li X , Meng S , Xue ER , Tan J , Jhala NC , Yu D , Zhou Y , Bayless KJ , Yu J , Rogers TJ , Hu W , Snyder NW , Sun J , Qin X , Jiang X , Wang H , Yang X
Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis
Front Immunol. 2020 ;11 :595813
PMID: 33154757 PMCID: PMC7591706 URL: https://www.ncbi.nlm.nih.gov/pubmed/33154757
AbstractInterleukin (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.
Notes1664-3224 Fu, Hangfei Sun, Yu Shao, Ying Saredy, Jason Cueto, Ramon Liu, Lu Drummer, Charles 4th 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 Journal Article Front Immunol. 2020 Oct 14;11:595813. doi: 10.3389/fimmu.2020.595813. eCollection 2020.