Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis
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,...
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.595813/full |
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| author | 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. Rogers Wenhui Hu Nathaniel W. Snyder Jianxin Sun Xuebin Qin Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Hong Wang Xiaofeng Yang Xiaofeng Yang Xiaofeng Yang |
| author_facet | 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. Rogers Wenhui Hu Nathaniel W. Snyder Jianxin Sun Xuebin Qin Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Hong Wang Xiaofeng Yang Xiaofeng Yang Xiaofeng Yang |
| author_sort | Hangfei Fu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T23:20:03Z |
| format | Article |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-14T23:20:03Z |
| publishDate | 2020-10-01 |
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| spelling | doaj.art-df5786bc9d924b9887e995d7168595082022-12-21T22:44:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-10-011110.3389/fimmu.2020.595813595813Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative AngiogenesisHangfei Fu0Yu Sun1Ying Shao2Jason Saredy3Ramon Cueto4Lu Liu5Charles Drummer6Candice Johnson7Keman Xu8Yifan Lu9Xinyuan Li10Shu Meng11Eric R. Xue12Judy Tan13Nirag C. Jhala14Daohai Yu15Yan Zhou16Kayla J. Bayless17Jun Yu18Thomas J. Rogers19Wenhui Hu20Nathaniel W. Snyder21Jianxin Sun22Xuebin Qin23Xiaohua Jiang24Xiaohua Jiang25Xiaohua Jiang26Hong Wang27Xiaofeng Yang28Xiaofeng Yang29Xiaofeng Yang30Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenter for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesDepartment of Pathology & Laboratory Medicine Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesDepartment of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesBiostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United StatesDepartment of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenter for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenter for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States0National Primate Research Center, Tulane University, Covington, LA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenter for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenters for Metabolic Disease Research, Cardiovascular Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesCenter for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United StatesInterleukin (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.https://www.frontiersin.org/article/10.3389/fimmu.2020.595813/fullIL-35angiogenesisischemia and hypoxiaendothelial cellsIL-12Rβ2 |
| spellingShingle | 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. Rogers Wenhui Hu Nathaniel W. Snyder Jianxin Sun Xuebin Qin Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Hong Wang Xiaofeng Yang Xiaofeng Yang Xiaofeng Yang Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis Frontiers in Immunology IL-35 angiogenesis ischemia and hypoxia endothelial cells IL-12Rβ2 |
| title | Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis |
| title_full | Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis |
| title_fullStr | Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis |
| title_full_unstemmed | Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis |
| title_short | Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis |
| title_sort | interleukin 35 delays hindlimb ischemia induced angiogenesis through regulating ros extracellular matrix but spares later regenerative angiogenesis |
| topic | IL-35 angiogenesis ischemia and hypoxia endothelial cells IL-12Rβ2 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.595813/full |
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