Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, São Paulo, Brazil.
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Exerc Immunol Rev. 2020;26:10-22.
Moderate aerobic training may be therapeutic for chronic low-grade inflammatory diseases due to the associated anti-inflammatory response that is mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPARγ) regulates the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Against this background, the present study seeks to clarify whether the conditional deletion of PPARγ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic training. To test this hypothesis, two mice strains were used: PPARγ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary high-fat diet (HF) and 2) high-fat diet and moderate aerobic training (HFT) (n = 5-8 per group). The experimental protocol lasted for 12 weeks, comprising 4 weeks of HF diet only and 8 weeks of HF diet and aerobic training (5 times/week, 50-60 minutes/day at 60% of maximum speed). Metabolic analyses were carried out on the serum glucose homeostase, adipose tissue morphology and cytokine content, and macrophage cytokine production.Immunophenotyping and gene expression were also performed. KO male mice were more prone to hypertrophy in the subcutaneous adipose tissue, though only the IL-1β (p = 0.0049) was higher compared to the values observed in WT animals. Peritoneal macrophages from KO animals exhibited a marked inflammatory environment with an increase in TNF-α (p = 0.0008), IL- 1β (p = 0.0017), and IL-6 (p < 0.0001) after lipopolysaccharide stimulation. The moderate aerobic training protected both genotypes from weight gain and reduced the caloric intake in the KO animals. Despite the attenuation of the M2 marker CD206 (p < 0.001) in the absence of PPAR-γ, the aerobic training modulated cytokine production in LPS stimulated peritoneal macrophages from both genotypes, reducing proinflammatory cytokines such as TNF-α (p = 0.0002) and IL-6 (p < 0.0001). Overall, our findings demonstrate the essential role of PPARγ in macrophage immunophenotypes. However, the deletion of PPARγ did not inhibit the exercise-mediated anti-inflammatory effect, underscoring the important role of exercise in modulating inflammation.
适度的有氧运动可能对慢性低度炎症性疾病具有治疗作用，因为它会引起免疫细胞介导的抗炎反应。过氧化物酶体增殖物激活受体 γ（PPARγ）调节 M1（促炎）和 M2（抗炎）极化以及巨噬细胞的免疫代谢反应。在此背景下，本研究旨在阐明巨噬细胞中 PPARγ 的条件性缺失是否会对适度有氧运动的抗炎作用产生影响。为了验证这一假设，使用了两种小鼠品系：PPARγLyzCre+/+（KO）和同窝对照动物（WT）。每个基因型分为 1）久坐高脂饮食（HF）和 2）高脂饮食和适度有氧运动（HFT）（每组 5-8 只）。实验方案持续 12 周，包括 4 周的 HF 饮食和 8 周的 HF 饮食和有氧运动（每周 5 次，每天 60%最大速度运动 50-60 分钟）。对血清葡萄糖稳态、脂肪组织形态和细胞因子含量以及巨噬细胞细胞因子产生进行代谢分析。还进行了免疫表型和基因表达分析。雄性 KO 小鼠更容易出现皮下脂肪组织肥大，尽管与 WT 动物相比，只有白细胞介素-1β（p = 0.0049）更高。来自 KO 动物的腹腔巨噬细胞在脂多糖刺激后表现出明显的炎症环境，TNF-α（p = 0.0008）、白细胞介素-1β（p = 0.0017）和白细胞介素-6（p < 0.0001）增加。适度的有氧运动保护两种基因型免受体重增加，并减少 KO 动物的热量摄入。尽管在缺乏 PPAR-γ 的情况下，M2 标志物 CD206（p < 0.001）减弱，但有氧运动调节了两种基因型 LPS 刺激的腹腔巨噬细胞的细胞因子产生，减少了促炎细胞因子，如 TNF-α（p = 0.0002）和白细胞介素-6（p < 0.0001）。总的来说，我们的研究结果表明了 PPARγ 在巨噬细胞免疫表型中的重要作用。然而，PPARγ 的缺失并没有抑制运动介导的抗炎作用，这凸显了运动在调节炎症中的重要作用。
