Department of Surgery, Faculty of Medicine, The University of British Columbia, Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada, V5Z 4H4.
Diabetologia. 2014 Aug;57(8):1645-54. doi: 10.1007/s00125-014-3249-1. Epub 2014 May 12.
AIMS/HYPOTHESIS: Inflammation contributes to pancreatic beta cell dysfunction in type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in recently diagnosed type 2 diabetes patients, and TLR2- and TLR4-deficient mice are protected from the metabolic consequences of a high-fat diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated effects on islet inflammation and beta cell function.
Genetic and pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 ligands on mouse islets, human islets and purified rat beta cells. Islet macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function were assessed.
Macrophages contributed to TLR2/6- and TLR4-induced islet Il1a/IL1A and Il1b/IL1B mRNA expression in mouse and human islets and IL-1β secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing Ins1, Ins2, and Pdx1 mRNA expression. Antagonism of the IL-1 receptor and neutralisation of IL-6 completely reversed the effects of activated macrophages on beta cell gene expression.
CONCLUSIONS/INTERPRETATION: We conclude that islet macrophages are major contributors to islet IL-1β secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1β- and IL-6-mediated decreased insulin gene expression.
目的/假设：炎症导致 2 型糖尿病患者胰岛β细胞功能障碍。在新诊断的 2 型糖尿病患者中，Toll 样受体（TLR）-2 和 -4 配体在系统中增加，TLR2 和 TLR4 缺陷小鼠可免受高脂肪饮食引起的代谢后果的影响。在这里，我们研究了巨噬细胞在 TLR2/6 和 TLR4 介导的对胰岛炎症和β细胞功能的影响中的作用。
使用遗传和药理学方法来确定 TLR2/6 和 TLR4 配体对小鼠胰岛、人胰岛和纯化的大鼠β细胞的影响。通过流式细胞术耗尽和分选胰岛巨噬细胞，并评估 TLR2/6 和 TLR4 激活的骨髓来源巨噬细胞（BMDM）对β细胞功能的影响。
巨噬细胞有助于 TLR2/6 和 TLR4 诱导的小鼠和人胰岛中的 Il1a/IL1A 和 Il1b/IL1B mRNA 表达以及人胰岛中的 IL-1β 分泌。TLR2/6 和 TLR4 配体也降低了胰岛素基因表达；然而，这是在非β细胞自主的方式下发生的。TLR2/6 和 TLR4 激活的 BMDM 通过降低 Ins1、Ins2 和 Pdx1 mRNA 表达部分减少β细胞胰岛素分泌。IL-1 受体拮抗剂和 IL-6 中和完全逆转了激活的巨噬细胞对β细胞基因表达的影响。
结论/解释：我们得出结论，胰岛巨噬细胞是 TLR2/6 和 TLR4 配体引起的胰岛 IL-1β 分泌的主要贡献者。用 TLR2/6 和 TLR4 配体刺激的 BMDM 部分通过 IL-1β 和 IL-6 介导的胰岛素基因表达减少而减少胰腺β细胞的胰岛素分泌。
