Jourdan Tony, Szanda Gergő, Cinar Resat, Godlewski Grzegorz, Holovac David J, Park Joshua K, Nicoloro Sarah, Shen Yuefei, Liu Jie, Rosenberg Avi Z, Liu Ziyi, Czech Michael P, Kunos George
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
Diabetes. 2017 Apr;66(4):994-1007. doi: 10.2337/db16-1199. Epub 2017 Jan 12.
Islet inflammation promotes β-cell loss and type 2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CBR)-induced proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CBR signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CBR are protected from β-cell loss, hyperglycemia, and nephropathy that are present in ZDF littermates. Adoptive transfer of CBR bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia but not nephropathy. ZDF islets contain elevated levels of CBR, interleukin-1β, tumor necrosis factor-α, the chemokine CCL2, and interferon regulatory factor-5 (IRF5), a marker of inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CBR activation increased expression, whereas knockdown of blunted CBR-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown of protected ZDF rats from β-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CBR signaling in macrophages and a potential therapeutic target.
胰岛炎症会促进β细胞丢失和2型糖尿病（T2D），这一过程在Zucker糖尿病肥胖（ZDF）大鼠中也会出现，其中β细胞丢失与浸润胰腺胰岛的巨噬细胞中大麻素1受体（CBR）诱导的促炎信号有关。在此，我们分析了巨噬细胞中的CBR信号及其在T2D中的发育作用。CBR全球缺失的ZDF大鼠可免受ZDF同窝仔鼠所出现的β细胞丢失、高血糖和肾病的影响。将CBR骨髓过继转移至ZDF大鼠也可预防β细胞丢失和高血糖，但不能预防肾病。ZDF胰岛中CBR、白细胞介素-1β、肿瘤坏死因子-α、趋化因子CCL2和干扰素调节因子-5（IRF5，炎症性巨噬细胞极化的标志物）水平升高。在原代培养的啮齿动物和人类巨噬细胞中，CBR激活会增加 的表达，而敲低 会减弱CBR诱导的炎性细胞因子分泌，但不影响CCL2的表达，CCL2的表达依赖于p38MAPKα。巨噬细胞特异性体内敲低 可保护ZDF大鼠免受β细胞丢失和高血糖的影响。因此，IRF5是巨噬细胞中致糖尿病CBR信号的关键下游介质和潜在治疗靶点。
