IL-6 trans-signaling: an overlooked driver of retinal neovascularization?

IF 11.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2025-12-19 DOI:10.1007/s10456-025-10022-8

Malte Jung, Jan N. Ness, Melanie E. Schwämmle, Julian Rapp, Stefaniya Boneva, Olaf Groß, Julia Mitschke, Günther Schlunck, Hansjürgen Agostini, Luciana Hannibal, Felicitas Bucher

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引用次数: 0

Abstract

Background

Vascular endothelial growth factor (VEGF) is regarded as the essential promoter of vitreoretinal vascular diseases that threaten eyesight, such as proliferative diabetic retinopathy (PDR). Therefore, VEGF is the primary therapeutic target in these diseases, but not all patients respond adequately to VEGF inhibition. This raises the question if other factors contribute to disease modulation. PDR evolves in an interplay of pathological processes including inflammation, barrier integrity loss, aberrant angiogenesis, and metabolic dysregulation. Interleukin-6 (IL-6), recognized for its pro-inflammatory properties, was the focus of this study.

Aim

Investigate IL-6 mediated angiogenic potential and disease-relevant mechanisms in the context of VEGF driven vitreoretinal disorder.

Methods

Levels of IL-6 and soluble IL-6 receptor (sIL-6R) were quantified in patient samples using ELISA. In vitro, the functional effect and downstream signaling patterns of IL-6, sIL-6R and VEGF on vascular endothelial cells were analyzed with western blot, spheroid sprouting-, migration-, seahorse assays and LC–MS/MS.

Results

Vitreous samples from PDR patients showed elevated levels of IL-6 and its corresponding soluble IL-6 receptor (sIL-6R) compared to clinical control groups. In vitro, IL-6 trans-signaling (IL-6 + sIL-6R) leads to a pro angiogenic phenotype in human vascular endothelial cells demonstrated in migration and spheroid sprouting assays, mirroring the effects of VEGF. Interestingly, IL-6 trans- and VEGF-signaling differ in their effects on barrier integrity and metabolic profile. IL-6 trans-signaling disrupts endothelial barrier function and shows an increased mitochondrial oxygen consumption rate in the Seahorse assay, as well as lower produced lactate levels compared to VEGF. Tocilizumab, an IL-6R antibody, showed additive treatment effects to anti-VEGF therapeutics regarding angiogenesis and VEGF induced metabolic drive in vitro.

Conclusion

IL-6 trans-signaling functions as an independent promoter of vitreoretinal vascular disease and therapeutic targeting of its pathway could beneficially complement current anti-VEGF treatment protocols.

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IL-6反式信号：视网膜新生的一个被忽视的驱动因素？

血管内皮生长因子（VEGF）被认为是危及视力的玻璃体视网膜血管疾病的重要促进因子，如增殖性糖尿病视网膜病变（PDR）。因此，VEGF是这些疾病的主要治疗靶点，但并非所有患者对VEGF抑制都有充分的反应。这就提出了一个问题，即是否有其他因素有助于疾病调节。PDR在炎症、屏障完整性丧失、异常血管生成和代谢失调等病理过程的相互作用中发展。白细胞介素-6 （IL-6）因其促炎特性而被认为是本研究的重点。目的探讨在VEGF驱动的玻璃体视网膜疾病中IL-6介导的血管生成潜能和疾病相关机制。方法采用ELISA法测定患者血清中IL-6及可溶性IL-6受体（sIL-6R）水平。在体外，采用western blot、球样发芽-、迁移-、海马实验和LC-MS /MS分析IL-6、sIL-6R和VEGF对血管内皮细胞的功能作用及其下游信号通路。结果与临床对照组相比，PDR患者玻璃体样品中IL-6及其相应的可溶性IL-6受体（sIL-6R）水平升高。在体外，IL-6反式信号（IL-6 + sIL-6R）导致人血管内皮细胞的促血管生成表型，在迁移和球形发芽实验中得到证实，反映了VEGF的作用。有趣的是，IL-6反式和vegf信号对屏障完整性和代谢谱的影响不同。在海马实验中，IL-6反式信号破坏内皮屏障功能，显示线粒体耗氧量增加，与VEGF相比，产生的乳酸水平更低。Tocilizumab是一种IL-6R抗体，在血管生成和VEGF诱导的体外代谢驱动方面显示出抗VEGF治疗的附加治疗作用。结论il -6反式信号通路是玻璃体视网膜血管疾病的独立启动子，靶向治疗可有效补充目前的抗vegf治疗方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.