{"doi":"10.3389/fimmu.2020.595813","title":"Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis","abstract":"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.","journal":"Frontiers in Immunology","year":2020,"id":71213,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":237312,"name":"Yu Sun","orcid":"0000-0002-0877-7186","position":1,"is_corresponding":false},{"id":237315,"name":"Ying Shao","orcid":"0000-0001-5879-0154","position":2,"is_corresponding":false},{"id":233131,"name":"Jason Saredy","orcid":"0000-0002-0738-5236","position":3,"is_corresponding":false},{"id":377728,"name":"Ramón Cueto","orcid":null,"position":4,"is_corresponding":false},{"id":376532,"name":"Lu Liu","orcid":"0000-0002-4173-9886","position":5,"is_corresponding":false},{"id":237314,"name":"Charles Drummer","orcid":"0000-0001-9059-1454","position":6,"is_corresponding":false},{"id":325175,"name":"Candice Johnson","orcid":"0000-0003-1622-7544","position":7,"is_corresponding":false},{"id":237316,"name":"Keman Xu","orcid":"0000-0002-0816-1760","position":8,"is_corresponding":false},{"id":237313,"name":"Yifan Lu","orcid":"0000-0003-4461-0698","position":9,"is_corresponding":false},{"id":320125,"name":"Xinyuan Li","orcid":"0000-0002-6746-8367","position":10,"is_corresponding":false},{"id":316743,"name":"Shu Meng","orcid":"0000-0002-1282-0706","position":11,"is_corresponding":false},{"id":376533,"name":"Eric Xue","orcid":"0009-0001-3977-8173","position":12,"is_corresponding":false},{"id":376534,"name":"Judy Y. 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