Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Amsterdam University Medical Centers, location AMC, Amsterdam Cardiovascular Sciences (ACS), University of Amsterdam, Amsterdam, The Netherlands.
Department of Pathology and Department of Molecular Genetics, CARIM, University of Maastricht, Maastricht, The Netherlands.
Sci Rep. 2019 Oct 11;9(1):14702. doi: 10.1038/s41598-019-50976-6.
The co-stimulatory CD40-CD40L dyad plays a central role in fine-tuning immune reactions, including obesity-induced inflammation. Genetic ablation of CD40L reduced adipose tissue inflammation, while absence of CD40 resulted in aggravated metabolic dysfunction in mice. During obesity, CD40 expressing CD11c dendritic cells (DC) and macrophages accumulate in adipose tissue and liver. We investigated the role of CD40CD11c cells in the metabolic syndrome and nonalcoholic steatohepatitis (NASH). DC-CD40-ko mice (CD40CD11c) mice were subjected to obesity or NASH. Obesity and insulin resistance were induced by feeding mice a 54% high fat diet (HFD). NASH was induced by feeding mice a diet containing 40% fat, 20% fructose and 2% cholesterol. CD40CD11c mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40CD11c mice had higher plasma and hepatic cholesterol levels and developed profound liver steatosis. Overall, regulatory T cell numbers were decreased in these mice. In NASH, absence of CD40 on CD11c cells slightly decreased liver inflammation but did not affect liver lipid accumulation. Our experiments suggest that CD40 expressing CD11c cells can act as a double-edged sword: CD40 expressing CD11c cells contribute to liver inflammation during NASH but are protective against the metabolic syndrome via induction of regulatory T cells.
共刺激分子 CD40-CD40L 二聚体在微调免疫反应中起着核心作用，包括肥胖引起的炎症。CD40L 的基因缺失减少了脂肪组织炎症，而 CD40 的缺失导致小鼠代谢功能障碍加重。在肥胖期间，表达 CD40 的 CD11c 树突状细胞 (DC) 和巨噬细胞在脂肪组织和肝脏中积累。我们研究了 CD40CD11c 细胞在代谢综合征和非酒精性脂肪性肝炎 (NASH) 中的作用。将 CD40CD11c 缺失小鼠 (CD40CD11c) 暴露于肥胖或 NASH 中。通过给小鼠喂食 54%高脂肪饮食 (HFD) 诱导肥胖和胰岛素抵抗。通过给小鼠喂食含有 40%脂肪、20%果糖和 2%胆固醇的饮食来诱导 NASH。喂食 HFD 的 CD40CD11c 小鼠体重增加、脂肪细胞增大和胰岛素抵抗加重。此外，CD40CD11c 小鼠的血浆和肝胆固醇水平升高，并发生严重的肝脂肪变性。总的来说，这些小鼠中的调节性 T 细胞数量减少。在 NASH 中，CD11c 细胞上的 CD40 缺失略微减少了肝炎症，但对肝脂质积累没有影响。我们的实验表明，表达 CD40 的 CD11c 细胞可以起到双刃剑的作用：表达 CD40 的 CD11c 细胞在 NASH 期间有助于肝炎症，但通过诱导调节性 T 细胞对代谢综合征具有保护作用。
