Krautter Franziska, Hussain Mohammed T, Zhi Zhaogong, Lezama Danielle R, Manning Julia E, Brown Emily, Marigliano Noemi, Raucci Federica, Recio Carlota, Chimen Myriam, Maione Francesco, Tiwari Alok, McGettrick Helen M, Cooper Dianne, Fisher Edward A, Iqbal Asif J
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
Atherosclerosis. 2022 Dec;363:57-68. doi: 10.1016/j.atherosclerosis.2022.11.014. Epub 2022 Nov 19.
Atherosclerosis is widely accepted to be an inflammatory disease driven by lipid accumulation and leukocyte recruitment. More recently, galectins, a family of β-galactoside binding proteins, have been shown to play a role in leukocyte recruitment among other immunomodulatory functions. Galectin (Gal) -9, a tandem repeat type galectin expressed by the endothelium in inflammatory environments, has been proposed to promote leukocyte recruitment. However, the role of Gal-9 in the context of monocyte recruitment remains elusive.
Here, we characterise the immunomodulatory role of Gal-9 in context of atherosclerosis. We show that ApoEGal-9 mice have a significantly reduced aortic plaque burden compared to their ApoE littermate controls after 12 weeks of high fat diet. RNA sequencing data from two independent studies reveal Lgals9 expression in leukocyte clusters isolated from murine atherosclerotic plaques. Additionally, soluble Gal-9 protein induces monocyte activation and a pro-inflammatory phenotype in macrophages. Furthermore, we show that immobilised recombinant Gal-9 acts as capture and adhesion molecule for CD14 monocytes in a β2-integrin and glycan dependent manner, while adhesion of monocytes to stimulated endothelium is reduced when Gal-9 is knocked down. Gal-9 also facilitates enhanced recruitment of leukocytes from peripheral arterial disease (PAD) patients compared to healthy young and aged controls. We further characterise the endothelium as source of circulating Gal-9, which is increased in plasma of PAD patients compared to healthy controls.
These results highlight a pathological role for Gal-9 as promoter of monocyte recruitment and atherosclerotic plaque progression, making it a novel target in the prevention of plaque formation and progression.
动脉粥样硬化被广泛认为是一种由脂质积聚和白细胞募集驱动的炎症性疾病。最近，半乳糖凝集素家族（一类β-半乳糖苷结合蛋白）已被证明在白细胞募集中发挥作用，以及其他免疫调节功能。半乳糖凝集素（Gal）-9是一种在炎症环境中由内皮细胞表达的串联重复型半乳糖凝集素，已被认为可促进白细胞募集。然而，Gal-9在单核细胞募集中的作用仍不清楚。
在此，我们描述了Gal-9在动脉粥样硬化背景下的免疫调节作用。我们发现，在高脂饮食12周后，与同窝对照的载脂蛋白E（ApoE）小鼠相比，ApoE Gal-9小鼠的主动脉斑块负担显著降低。来自两项独立研究的RNA测序数据显示，在从小鼠动脉粥样硬化斑块中分离出的白细胞簇中有Lgals9表达。此外，可溶性Gal-9蛋白可诱导巨噬细胞中单核细胞活化和促炎表型。此外，我们表明，固定化的重组Gal-9以β2整合素和聚糖依赖性方式作为CD14单核细胞的捕获和黏附分子，而当Gal-9被敲低时，单核细胞与受刺激内皮细胞的黏附减少。与健康的年轻和老年对照相比，Gal-9还促进了外周动脉疾病（PAD）患者白细胞的增强募集。我们进一步将内皮细胞鉴定为循环Gal-9的来源，与健康对照相比，PAD患者血浆中的Gal-9增加。
这些结果突出了Gal-9作为单核细胞募集和动脉粥样硬化斑块进展促进因子的病理作用，使其成为预防斑块形成和进展的新靶点。
