Polylysine-Bilirubin Conjugates Maintain Functional Islets and Promote M2 Macrophage Polarization

Abstract

Macrophage polarization has been considered as one main factor that contributes to the pro-inflammatory milieu of the transplanted islets and caused significant islet loss. Bilirubin possesses protective effects in islet transplantation, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivates could modulate macrophage polarization during the host rejections has also not been answered. To this end, we aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and explore its macrophage modulation activities. In vitro studies indicated that PLL-BR tightly adheres to the islet surface, and achieved enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2 type macrophage polarization. In vivo data demonstrated that PLL-BR protected islets successfully prolonged the period of euglycemia in diabetic mice and accelerated the clearance rate of blood glucose by maximumly maintain the insulin secretion function. The PLL-BR encapsulated islets elicited anti-inflammatory response characterized by the elevated proportion of M2 macrophage markers and local vascularization compared to untreated islets. Hence PLL-BR might serve as a useful tool for reprograming the macrophage polarization and providing a more efficient immune protection for transplanted islets and improve the outcomes.