抗菌肽cathelicidin对beta细胞功能的免疫调节作用及机理研究

Beta cell dysfunction and the resultant insulin insufficiency or resistance are the key pathological event in type 1 and 2 diabetes. Innate immunity and its components are increasingly recognized to be intrinsically linked to this process. Pleiotropic antimicrobial peptides cathelicidins possess intrinsic broad-spectrum microbicidal activities. Besides, they are immune-modulatory and important in functional regulation of various mammalian cells including epithelial, endothelial and immune cells, and host defense processes such as wound healing and autophagy. This study aims to describe for the first time that a cathelicidin peptide is involved in beta cell function and immune defense by modulating the inflammatory milieu within pancreatic islets/beta cells. Our preliminary results have demonstrated that in cultured rat beta cells, expression of the rat cathelicidin-related antimicrobial peptide (rCRAMP) are induced upon stimulation with the known transcriptional inducer of cathelicidins, butyrate. When pretreated with rCRAMP, rat islets showed EGFR-mediated hyper-responsiveness to high glucose stimulation by secreting insulin at a magnitude comparable to the incretin glucagon-like peptide 1 (GLP-1). In vivo relevance of these data was demonstrated. Compared to wild-type mice, cathelicidin-deficient mice (Cnlp-/-) exhibited an early onset of streptozotocin-induced diabetes. Future study will investigate in vitro, ex vivo and in vivo, the modulatory effects of cathelicidins on beta cell function and immune defense and multiple mechanisms by which cathelicidins act to protect the local islet milieu from external inflammatory stimuli. This study will shed lights on cathelicidins and their inducers to be considered as novel molecular targets in diabetes prevention.

Beta细胞功能障碍所导致的胰岛素分泌不足或功能缺失是1、2型糖尿病发病的核心病理变化。先天免疫系统组成的细胞与介质在其中起着重要的作用。抗菌肽cathelicidins是具有广谱抗微生物活性以及免疫调节作用的内源性多功能肽，对上皮、内皮以及免疫细胞等多种哺乳动物细胞具有重要的调节作用。Cathelicidins对beta细胞功能调节作用尚未有报道。我们的初步研究发现cathelicidins在beta细胞微环境的存在，cathelicidins可促进beta细胞在高糖刺激下胰岛素的分泌，并初步揭示表皮生长因子受体在这一效果中的作用。Cathelicidin缺失型小鼠与野生型相比更早发生自身免疫型糖尿病。本课题将进一步从细胞、组织及动物水平系统地探究cathelicidins对beta细胞功能及免疫防御能力的调节及机理，为抗菌肽及其食源诱导剂在糖尿病防治中的应用提供理论基础和方向。

胰岛Beta细胞功能障碍所导致的胰岛素分泌不足或功能缺失是1、2型糖尿病发病的核心病理变化。先天免疫系统组成的细胞与介质在其中起着重要的作用。抗菌肽cathelicidins是具有广谱抗微生物活性以及免疫调节作用的内源性多功能肽，对上皮细胞、内皮细胞以及免疫细胞等多种哺乳动物细胞具有重要的调节作用。但抗菌肽Cathelicidins对胰岛Beta细胞的功能调节作用尚未有报道。在本基金的支持下，通过研究我们得到如下重要结果：1) 发现防止1型糖尿病新方法，即揭示通过维持肠道菌群稳态调控胰岛内源活性物质抗菌肽水平，维持胰岛区域免疫稳态，防止1型糖尿病发病；2) 揭示内源活性物质对免疫及胰腺β细胞的调控及机制，阐明了抗菌肽维持胰岛β细胞功能稳态及机制；3）阐明菊粉、丁酸梭菌等在肠道发酵产生短链脂肪酸，进而诱导内源性抗菌肽cathelicidin分泌，从而防止1型糖尿病的分子机制。在本基金的支持下，我们在Immunity，Front Immunol，FASEB J，Mol Nutr Food Res等期刊发表SCI论文12篇，总影响因子超过70。同时，项目负责人兼任SCI杂志Front Immunol 副主编。本课题从细胞、组织及动物水平系统地探究了cathelicidins对beta细胞功能及免疫防御能力的调节及机理，为抗菌肽及其食源诱导剂在糖尿病防治中的应用提供了理论基础和方向。