First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Diabetologia. 2013 Jun;56(6):1403-12. doi: 10.1007/s00125-013-2885-1. Epub 2013 Mar 15.
AIMS/HYPOTHESIS: As obesity progresses, adipose tissue exhibits a hypoxic and inflammatory phenotype characterised by the infiltration of adipose tissue macrophages (ATMs). In this study, we examined how adipose tissue hypoxia is involved in the induction of the inflammatory M1 and anti-inflammatory M2 polarities of ATMs.
The hypoxic characteristics of ATMs were evaluated using flow cytometry after the injection of pimonidazole, a hypoxia probe, in normal-chow-fed or high-fat-fed mice. The expression of hypoxia-related and inflammation-related genes was then examined in M1/M2 ATMs and cultured macrophages.
Pimonidazole uptake was greater in M1 ATMs than in M2 ATMs. This uptake was paralleled by the levels of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β. The expression level of hypoxia-related genes, as well as inflammation-related genes, was also higher in M1 ATMs than in M2 ATMs. The expression of Il6, Il1β and Nos2 in cultured macrophages was increased by exposure to hypoxia in vitro but was markedly decreased by the gene deletion of Hif1a. In contrast, the expression of Tnf, another inflammatory cytokine gene, was neither increased by exposure to hypoxia nor affected by Hif1a deficiency. These results suggest that hypoxia induces the inflammatory phenotypes of macrophages via Hif1a-dependent and -independent mechanisms. On the other hand, the expression of inflammatory genes in cultured M2 macrophages treated with IL-4 responded poorly to hypoxia.
CONCLUSIONS/INTERPRETATION: Adipose tissue hypoxia induces an inflammatory phenotype via Hif1a-dependent and Hif1a-independent mechanisms in M1 ATMs but not in M2 ATMs.
目的/假设：随着肥胖的进展，脂肪组织表现出一种缺氧和炎症表型，其特征是脂肪组织巨噬细胞（ATMs）的浸润。在这项研究中，我们研究了脂肪组织缺氧如何参与诱导 ATMs 的炎症 M1 和抗炎 M2 极性。
在正常饮食喂养或高脂肪饮食喂养的小鼠中注射缺氧探针 pimonidazole 后，使用流式细胞术评估 ATMs 的缺氧特征。然后，在 M1/M2 ATMs 和培养的巨噬细胞中检查与缺氧相关和炎症相关的基因表达。
M1 ATMs 摄取 pimonidazole 的量大于 M2 ATMs。这种摄取与 TNF-α、IL-6 和 IL-1β 等炎症细胞因子的水平平行。缺氧相关基因以及炎症相关基因的表达水平在 M1 ATMs 中也高于 M2 ATMs。在体外缺氧暴露下，培养的巨噬细胞中 Il6、Il1β 和 Nos2 的表达增加，但 Hif1a 基因缺失则显著降低。相比之下，另一种炎症细胞因子基因 Tnf 的表达既不受缺氧的影响，也不受 Hif1a 缺乏的影响。这些结果表明，缺氧通过 Hif1a 依赖性和非依赖性机制诱导巨噬细胞的炎症表型。另一方面，用 IL-4 处理的培养的 M2 巨噬细胞中炎症基因的表达对缺氧反应不佳。
结论/解释：脂肪组织缺氧通过 Hif1a 依赖性和非依赖性机制在 M1 ATMs 中诱导炎症表型，但不在 M2 ATMs 中诱导。
