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Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis
- Source :
- Frontiers in Immunology, Vol 11 (2020), Frontiers in Immunology
- Publication Year :
- 2020
- Publisher :
- Frontiers Media SA, 2020.
-
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.
- Subjects :
- Male
lcsh:Immunologic diseases. Allergy
0301 basic medicine
Angiogenesis
medicine.medical_treatment
Immunology
Neovascularization, Physiologic
Cell Line
Extracellular matrix
angiogenesis
03 medical and health sciences
Apolipoproteins E
0302 clinical medicine
Downregulation and upregulation
Cell Movement
Ischemia
Extracellular
medicine
Animals
Humans
Immunology and Allergy
ischemia and hypoxia
Original Research
Mice, Knockout
Tube formation
Neovascularization, Pathologic
Chemistry
Interleukins
IL-12Rβ2
Receptors, Interleukin-12
Interleukin
endothelial cells
Extracellular Matrix
Hindlimb
Cell biology
Mice, Inbred C57BL
030104 developmental biology
Cytokine
IL-35
Interleukin 35
Reactive Oxygen Species
lcsh:RC581-607
030215 immunology
Subjects
Details
- ISSN :
- 16643224
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.doi.dedup.....c7b804c379de83bb29a3a6a93eeae75f