The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, United States; Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH 43210, United States.
The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, United States; Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States.
Brain Behav Immun. 2021 Jul;95:477-488. doi: 10.1016/j.bbi.2021.05.005. Epub 2021 May 12.
Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.
物理和社会环境影响脂肪组织中的免疫稳态，但这些机制仍未得到明确界定。我们报告称，丰富的环境（EE）可以调节小鼠白色脂肪组织中的免疫细胞群体，包括自然杀伤（NK）细胞的丰度增加。EE 上调了 IL-15 及其受体 IL-15Rα 在成熟脂肪细胞中的表达。从机制上讲，我们表明下丘脑脑源性神经营养因子（BDNF）通过交感β-肾上腺素能信号转导上调脂肪细胞中 IL-15 的产生。通过重组腺相关病毒（rAAV）载体在下丘脑中转染过量表达的 BDNF 可扩增脂肪 NK 细胞。相反，通过基因转移显性负 TrkB 受体抑制下丘脑 BDNF 信号可抑制脂肪 NK 细胞。在白色脂肪组织中，使用脂肪细胞特异性 rAAV 载体过表达 IL-15 可刺激脂肪 NK 细胞并抑制皮下黑色素瘤的进展，而局部 IL-15 敲低可阻断 EE 效应。这些结果表明，生物行为因素通过下丘脑 BDNF-交感神经-脂肪细胞 IL-15 轴调节脂肪 NK 细胞。靶向该途径可能对癌症具有治疗意义。
