Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Front Endocrinol (Lausanne). 2023 Mar 9;14:1142988. doi: 10.3389/fendo.2023.1142988. eCollection 2023.
Immune cells were recently shown to support β-cells and insulin secretion. However, little is known about how islet immune cells are regulated to maintain glucose homeostasis. Administration of various cytokines, including Interleukin-33 (IL-33), was shown to influence β-cell function. However, the role of endogenous, locally produced IL-33 in pancreatic function remains unknown. Here, we show that IL-33, produced by pancreatic pericytes, is required for glucose homeostasis.
To characterize pancreatic IL-33 production, we employed gene expression, flow cytometry, and immunofluorescence analyses. To define the role of this cytokine, we employed transgenic mouse systems to delete the gene selectively in pancreatic pericytes, in combination with the administration of recombinant IL-33. Glucose response was measured and , and morphometric and molecular analyses were used to measure β-cell mass and gene expression. Immune cells were analyzed by flow cytometry.
Our results show that pericytes are the primary source of IL-33 in the pancreas. Mice lacking pericytic IL-33 were glucose intolerant due to impaired insulin secretion. Selective loss of pericytic IL-33 was further associated with reduced T and dendritic cell numbers in the islets and lower retinoic acid production by islet macrophages.
Our study demonstrates the importance of local, pericytic IL-33 production for glucose regulation. Additionally, it proposes that pericytes regulate islet immune cells to support β-cell function in an IL-33-dependent manner. Our study reveals an intricate cellular network within the islet niche.
最近有研究表明免疫细胞可以支持β细胞和胰岛素的分泌。然而，人们对于胰岛免疫细胞如何被调节以维持葡萄糖稳态知之甚少。多种细胞因子（包括白细胞介素 33，IL-33）的给药被证明可以影响β细胞的功能。然而，内源性、局部产生的 IL-33 在胰腺功能中的作用仍然未知。在这里，我们表明，胰岛周细胞产生的 IL-33 是葡萄糖稳态所必需的。
为了描述胰岛中 IL-33 的产生，我们采用了基因表达、流式细胞术和免疫荧光分析。为了定义这种细胞因子的作用，我们采用了转基因小鼠系统，选择性地在胰岛周细胞中删除 基因，并与重组 IL-33 的给药相结合。通过测量葡萄糖反应 和 ，以及形态和分子分析来测量β细胞的质量和基因表达，来评估胰岛周细胞缺失 IL-33 对β细胞功能的影响。通过流式细胞术分析免疫细胞。
我们的结果表明，周细胞是胰腺中 IL-33 的主要来源。缺乏周细胞 IL-33 的小鼠由于胰岛素分泌受损而出现葡萄糖不耐受。选择性地缺失周细胞 IL-33 与胰岛中 T 细胞和树突状细胞数量减少以及胰岛巨噬细胞中视黄酸产生减少有关。
我们的研究表明了局部周细胞产生的 IL-33 对葡萄糖调节的重要性。此外，它还提出了周细胞通过依赖于 IL-33 的方式调节胰岛免疫细胞来支持β细胞功能。我们的研究揭示了胰岛微环境中一个复杂的细胞网络。
