T Cell-Derived IL-22 Amplifies IL-1β-Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes
T Cell-Derived IL-22 Amplifies IL-1β-Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes
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DOI：
10.2337/db13-1511
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发表时间：
2014-06-01
期刊：
影响因子：
7.7
通讯作者：
Guerre-Millo, Michele
中科院分区：
文献类型：
--
作者：
Dalmas, Elise;Venteclef, Nicolas;Guerre-Millo, Michele
促炎细胞因子在脂肪组织生物学改变中起着关键作用，导致肥胖症患者葡萄糖稳态的恶化。在这里，我们显示了2型糖尿病肥胖患者脂肪组织巨噬细胞的显著促炎特征，主要由NLRP 3依赖性白细胞介素（11）-1 β产生增加驱动。IL-1 β的释放随着血糖恶化而增加，在胃旁路手术后减少。在2型糖尿病肥胖患者的脂肪组织中发现了产生IL-17和IL-22的CD 4 + T细胞的特异性富集。共培养实验鉴定了巨噬细胞来源的IL-1 β促进人脂肪组织CDC 4 + T细胞产生IL-22和IL-17的作用。反过来，脂肪组织巨噬细胞表达IL-17和IL-22受体，使它们对IL-17和IL-22敏感。IL-22通过激活巨噬细胞中的C-Jun途径诱导IL-1 β前体转录来增加IL-1 β的释放。总之，这些人类数据确定IL-1 β和T细胞细胞因子IL-22是以前在脂肪组织中未鉴定的旁分泌炎症途径的关键参与者，与肥胖诱导的2型糖尿病具有病理学相关性。这些结果为靶向肥胖相关的2型糖尿病中的IL-1 β提供了额外的理论基础，并且可能对人类肥胖症中新型抗IL-1 β和抗IL-22联合免疫疗法的概念具有重要意义。
Proinflammatory cytokines are critically involved in the alteration of adipose tissue biology leading to deterioration of glucose homeostasis in obesity. Here we show a pronounced proinflammatory signature of adipose tissue macrophages in type 2 diabetic obese patients, mainly driven by increased NLRP3-dependent interleukin (11)-1 beta production. IL-1 beta release increased with glycemic deterioration and decreased after gastric bypass surgery. A specific enrichment of IL-17-and IL-22-producing CD4+ T cells was found in adipose tissue of type 2 diabetic obese patients. Coculture experiments identified the effect of macrophage-derived IL-1 beta to promote IL-22 and IL-17 production by human adipose tissue CDC4+ T cells. Reciprocally, adipose tissue macrophages express IL-17 and IL-22 receptors, making them sensitive to IL-17 and IL-22. IL-22 increased IL-1 beta release by inducing pro-IL-1 beta transcription through activation of C-Jun pathways in macrophages. In sum, these human data identified IL-1 beta and the T-cell cytokine IL-22 as key players of a paracrine inflammatory pathway previously unidentified in adipose tissue, with a pathological relevance to obesity-induced type 2 diabetes. These results provide an additional rationale for targeting IL-1 beta in obesity-linked type 2 diabetes and may have important implications for the conception of novel combined anti-IL-1 beta and anti-IL-22 immunotherapy in human obesity.