Zhao Ying-Zheng, Huang Zhi-Wei, Zhai Yuan-Yuan, Shi Yannan, Du Chu-Chu, Zhai Jiaoyuan, Xu He-Lin, Xiao Jian, Kou Longfa, Yao Qing
Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Acta Biomater. 2021 Mar 1;122:172-185. doi: 10.1016/j.actbio.2020.12.047. Epub 2020 Dec 31.
Macrophage polarization is one of the main factors contributing to the proinflammatory milieu of transplanted islets. It causes significant islet loss. Bilirubin exhibits protective effects during the islet transplantation process, but the mode of delivering drugs along with the islet graft has not yet been developed. In addition, it remains unclear whether bilirubin or its derivatives can modulate macrophage polarization during islet transplantation. Therefore, this study aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and to explore its macrophage modulation activities. In in vitro studies, the PLL-BR was shown to tightly adhere to the islet surface. It also exhibited enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2-type macrophage polarization. In in vivo studies, the PLL-BR-protected islets successfully prolonged the euglycemia period in diabetic mice and accelerated the blood glucose clearance rate by maintaining the insulin secretion function. Compared to the untreated islets, the PLL-BR-encapsulated islets induced anti-inflammatory responses that were characterized by elevated levels of M2 macrophage markers and local vascularization. In conclusion, PLL-BR can be used as a tool for reprograming macrophage polarization while providing a more efficient immune protection for transplanted islets. STATEMENT OF SIGNIFICANCE: Macrophage polarization is one main factor that caused significant loss of transplanted islets. Bilirubin possesses protective effects toward pancreatic islet, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivatives could modulate macrophage polarization during the host rejections has also not been answered. In this study, we developed an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets and explore its role in macrophage modulation activities. PLL-BR could attach to the surface of islets and exerted high oxidation resistance and anti-inflammatory effect. For the first time, we demonstrate that bilirubin and its derivatives effectively promoted the M2-type macrophage polarization, and optimize the immune microenvironment for islets survival and function.
巨噬细胞极化是导致移植胰岛促炎环境的主要因素之一。它会导致胰岛大量损失。胆红素在胰岛移植过程中具有保护作用，但尚未开发出与胰岛移植物一起给药的方式。此外，胆红素或其衍生物在胰岛移植过程中是否能调节巨噬细胞极化仍不清楚。因此，本研究旨在开发一种ε-聚赖氨酸-胆红素共轭物（PLL-BR）来包裹胰岛以提供保护，并探索其巨噬细胞调节活性。在体外研究中，PLL-BR被证明能紧密附着于胰岛表面。它还通过促进M2型巨噬细胞极化，对氧化和炎症条件表现出增强的细胞保护作用。在体内研究中，PLL-BR保护的胰岛成功延长了糖尿病小鼠的正常血糖期，并通过维持胰岛素分泌功能加快了血糖清除率。与未处理的胰岛相比，PLL-BR包裹的胰岛诱导了抗炎反应，其特征是M2巨噬细胞标志物水平升高和局部血管生成。总之，PLL-BR可作为一种工具，用于重新编程巨噬细胞极化，同时为移植胰岛提供更有效的免疫保护。重要性声明：巨噬细胞极化是导致移植胰岛大量损失的一个主要因素。胆红素对胰岛具有保护作用，但如何与胰岛移植物一起给药尚未得到解决。更重要的是，胆红素或其衍生物在宿主排斥反应期间是否能调节巨噬细胞极化也尚未得到解答。在本研究中，我们开发了一种ε-聚赖氨酸-胆红素共轭物（PLL-BR）来包裹胰岛，并探索其在巨噬细胞调节活性中的作用。PLL-BR可以附着在胰岛表面，并发挥高抗氧化和抗炎作用。我们首次证明，胆红素及其衍生物有效地促进了M2型巨噬细胞极化，并优化了胰岛存活和功能的免疫微环境。
