Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice
Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice
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DOI：
10.1007/s00125-013-2885-1
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发表时间：
2013-06-01
期刊：
影响因子：
8.2
通讯作者：
Tobe, K.
中科院分区：
文献类型：
--
作者：
Fujisaka, S.;Usui, I.;Tobe, K.
随着肥胖的进展，脂肪组织表现出缺氧和炎症表型，其特征在于脂肪组织巨噬细胞（ATM）的浸润。在这项研究中，我们研究了脂肪组织缺氧是如何参与诱导的炎性M1和抗炎M2极性的ATM。ATM的缺氧特性进行了评估后，使用流式细胞仪注射哌莫硝唑，缺氧探针，在正常的食物喂养或高脂肪喂养的小鼠。然后在M1/M2 ATM和培养的巨噬细胞中检测缺氧相关和炎症相关基因的表达。这种摄取受到炎性细胞因子如TNF-α、IL-6和IL-1 β水平的影响。缺氧相关基因以及炎症相关基因的表达水平在M1 ATM中也高于M2 ATM。体外培养的巨噬细胞在低氧条件下IL 6、IL 1 β和Nos 2的表达增加，而HIF 1a基因缺失则使IL 6、IL 1 β和Nos 2的表达显著降低。相反，另一种炎性细胞因子基因Tnf的表达既不因缺氧而增加，也不受Hif 1a缺乏的影响。这些结果表明，缺氧诱导的炎症表型的巨噬细胞通过HIF 1a依赖和非依赖的机制。另一方面，在培养的M2巨噬细胞中，用IL-4处理的炎症基因的表达对缺氧的反应较差。脂肪组织缺氧通过HIF 1a依赖性和HIF 1a非依赖性机制在M1 ATM中诱导炎症表型，但在M2 ATM中不诱导。
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-alpha, IL-6 and IL-1 beta. 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, Il1 beta 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.Adipose tissue hypoxia induces an inflammatory phenotype via Hif1a-dependent and Hif1a-independent mechanisms in M1 ATMs but not in M2 ATMs.