Hoxa5 alleviates obesity-induced chronic inflammation by reducing ER stress and promoting M2 macrophage polarization in mouse adipose tissue
Hoxa5 alleviates obesity-induced chronic inflammation by reducing ER stress and promoting M2 macrophage polarization in mouse adipose tissue
复制标题
Hoxa5 通过降低小鼠脂肪组织中的内质网应激和促进 M2 巨噬细胞极化来减轻肥胖引起的慢性炎症
DOI：
10.1111/jcmm.14600
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发表时间：
2019-10-01
影响因子：
5.3
通讯作者：
Sun, Chao
中科院分区：
文献类型：
--
作者：
Cao, Weina;Zhang, Tiantian;Sun, Chao
肥胖引起的慢性炎症与脂肪细胞内质网应激（ERS）以及脂肪组织巨噬细胞（ATMs）数量和表型的变化有关。此外，ERS增强巨噬细胞活化。迄今为止，人们对Hoxa5在肥胖引起的慢性炎症中的作用知之甚少。在此，我们证明了转录因子Hoxa5在决定脂肪组织巨噬细胞（ATM）极性和ERS中的重要性。Hoxa5降低高脂饮食（HFD）小鼠的体重，减少炎症细胞因子分泌，并与脂肪组织中M2巨噬细胞数量增加相对应。转录组测序数据显示，脂肪细胞中Hoxa5的过表达改变了内质网（ER）蛋白加工相关基因的表达。基于转录组测序数据和生物信息学预测，我们已经提出Hoxa5通过抑制ERS和激活小鼠脂肪组织中的PPAR γ通路来减轻炎症反应。Hoxa5通过抑制脂肪细胞中的eIF2 α /PERK信号通路减轻ERS和炎症反应。Hoxa5还通过促进M2巨噬细胞极化来抑制脂肪细胞的慢性炎症。此外，Hoxa5转录激活PPAR γ通路，促进M2巨噬细胞极化，从而减轻脂肪细胞的慢性炎症。综上所述，这些结果揭示了hoxa5依赖性抑制肥胖诱导的慢性炎症的机制，通过减少ERS和促进M2巨噬细胞的极化。这些结果表明Hoxa5可能是肥胖和其他代谢综合征的潜在治疗靶点。
Obesity-induced chronic inflammation is associated with endoplasmic reticulum stress (ERS) in adipocytes and changes in both the number and phenotype of adipose tissue macrophages (ATMs). In addition, ERS enhances macrophage activation. So far, the function of Hoxa5 in obesity-induced chronic inflammation has been poorly understood. Herein, we demonstrate the importance of the transcription factor, Hoxa5, in determining adipose tissue macrophage (ATM) polarity and ERS. Hoxa5 decreased bodyweight, reduced inflammatory cytokine secretion and corresponded with an increased number of M2 macrophages in the adipose tissue of high-fat diet (HFD) mice. Transcriptome sequencing data showed that overexpression of Hoxa5 in adipocytes changed expression of endoplasmic reticulum (ER) protein processing-related genes. Based on transcriptome sequencing data and bioinformatics prediction, we have been suggested that Hoxa5 alleviated inflammatory responses by inhibiting ERS and by activating PPAR gamma pathway in mouse adipose tissue. Hoxa5 alleviated ERS and inflammatory responses by inhibiting the eIF2 alpha/PERK signalling pathway in adipocytes. Hoxa5 also inhibited chronic inflammation of adipocytes by promoting M2 macrophage polarization. In addition, Hoxa5 transcriptionally activated the PPAR gamma pathway to promote polarization of M2 macrophages, which in turn alleviated chronic inflammation of adipocytes. Taken together, these results shed light on the mechanisms underlying Hoxa5-dependent inhibition of obesity-induced chronic inflammation by reducing ERS and promoting polarization of M2 macrophages. These results suggest that Hoxa5 may be a potential therapeutic target for obesity and other metabolic syndromes.