Martins Larissa M S, Perez Malena M, Pereira Camila A, Costa Frederico R C, Dias Murilo S, Tostes Rita C, Ramos Simone G, de Zoete Marcel R, Ryffel Bernhard, Silva João S, Carlos Daniela
Departments of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Immunology. 2018 May 2;154(4):624-36. doi: 10.1111/imm.12946.
We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice.
我们探讨了白细胞介素-23（IL-23）在高脂饮食（HFD）诱导的肥胖和代谢综合征进展过程中驱动肠道1型辅助性T细胞（Th17）反应的作用。饮食诱导的肥胖小鼠和瘦小鼠分别接受HFD或对照饮食（CTD）20周。在第9周和第20周检测营养、代谢和免疫参数。喂食HFD 9周的肥胖野生型小鼠（WT）回肠中IL-23p19和IL-23受体的基因和蛋白表达增加。缺乏IL-23并喂食HFD的小鼠体重增加更多、脂肪堆积更高、脂肪细胞肥大且肝脏脂肪变性。值得注意的是，这些小鼠有更多的葡萄糖不耐受、胰岛素抵抗以及相关的代谢改变，如高胰岛素血症和高脂血症。IL-23缺乏还显著降低了回肠中IL-17、CCL20和中性粒细胞弹性蛋白酶的蛋白水平，并减少了HFD小鼠肠系膜淋巴结中Th17细胞的扩增。重要的是，与喂食HFD的WT小鼠相比，IL-23缺陷小鼠的肠道通透性增加且血液细菌易位。最后，肠道微生物群的宏基因组学分析显示，HFD后IL-23缺陷小鼠粪便中拟杆菌门相对于厚壁菌门显著增多，拟杆菌属占优势。总之，IL-23似乎维持Th17反应和中性粒细胞向肠黏膜的迁移，使肠道生态失调最小化，并预防小鼠肥胖和代谢疾病的发生。
