Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis.
Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis.
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DOI：
10.3389/fimmu.2020.595813
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Fu H;Sun Y;Shao Y;Saredy J;Cueto R;Liu L;Drummer C 4th;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
白细胞介素（IL）-35是白细胞介素 - 12家族中一种新型的具有免疫抑制作用的异源二聚体细胞因子。在周围动脉疾病中，IL - 35是否以及如何调节缺血诱导的血管生成尚未明确。为填补这一重要的知识空白，我们采用了功能缺失、功能获得、组学数据分析、RNA测序以及体内外实验等方法，并取得了以下重要发现：i）在后肢缺血（HLI）后，肌肉中诱导产生IL - 35及其受体亚基IL - 12RB2，但不诱导IL - 6ST；ii）与野生型（WT）和载脂蛋白E基因敲除（ApoE−/−）对照组相比，Il12rb2−/−小鼠和ApoE−/−/Il12rb2−/−小鼠中HLI诱导的血管生成得到改善，其中高脂血症在体内外均会抑制血管生成；iii）作为一种功能获得性方法，注射IL - 35细胞因子会延迟HLI后第14天的血流灌注恢复；iv）在HLI后第14天之后的HLI恢复后期，IL - 35不影响再生性血管生成；v）对HLI后14天的内皮细胞（ECs）进行转录组分析发现，注射IL - 35的小鼠细胞外基质重组受到干扰；vi）IL - 35下调三种活性氧（ROS）启动子并上调一种ROS减弱因子，这可能在功能上介导了IL - 35对内皮细胞中抗血管生成细胞外基质蛋白的上调作用；vii）IL - 35主要通过上调抗血管生成的细胞外基质重塑蛋白，在体外抑制人微血管内皮细胞迁移和管腔形成。这些发现为IL - 35未来的治疗潜力提供了新的见解，即IL - 35在早期可抑制缺血/炎症引发的炎症性血管生成，而在后期不影响再生性血管生成。
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.
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影响因子：
16.6
作者：
Dambuza IM;He C;Choi JK;Yu CR;Wang R;Mattapallil MJ;Wingfield PT;Caspi RR;Egwuagu CE
通讯作者：
Egwuagu CE
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
白介素10可保护小鼠免受致命性内毒素血症的侵害。
影响因子：
15.3
作者：
Howard, M;Muchamuel, T;Andrade, S;Menon, S
通讯作者：
Menon, S
影响因子：
28.5
作者：
Fu H;Vadalia N;Xue ER;Johnson C;Wang L;Yang WY;Sanchez C;Nelson J;Chen Q;Choi ET;Ma JX;Yu J;Wang H;Yang X
通讯作者：
Yang X
DOI：
10.4049/jimmunol.1100315
发表时间：
2011-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chaturvedi V;Collison LW;Guy CS;Workman CJ;Vignali DA
通讯作者：
Vignali DA