Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization
Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization
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DOI：
10.1080/15548627.2015.1009787
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发表时间：
2015-02-01
期刊：
影响因子：
13.3
通讯作者：
Czaja, Mark J.
中科院分区：
文献类型：
--
作者：
Liu, Kun;Zhao, Enpeng;Czaja, Mark J.
最近的证据表明，过量的脂质积累可以降低细胞自噬水平，自噬调节免疫反应性，这表明受损的巨噬细胞自噬可能会促进先天免疫激活的增加，这是肥胖的基础。来自高脂饮食（HFD）喂养的小鼠的原代骨髓源性巨噬细胞（BMDM）和腹膜巨噬细胞具有降低的自噬通量水平，表明肥胖小鼠中巨噬细胞自噬的普遍损害。为了评估减少的巨噬细胞自噬对炎症的影响，给巨噬细胞中具有Lyz 2-Cre介导的Atg 5敲除的小鼠喂食HFD并用低剂量脂多糖（LPS）处理。用HFD喂养和LPS，敲除小鼠发展全身和肝脏炎症。这种效应是肝脏特异性的，因为基因敲除小鼠没有增加脂肪组织炎症。自噬丧失促进炎症的机制是通过调节巨噬细胞极化。基因敲除小鼠的BMDM和Kupffer细胞表现出极化异常，通过基因和蛋白质的测量测定，促炎性M1极化增加，抗炎性M2极化减少。在HFD喂养的LPS治疗的基因敲除小鼠中，肝脏炎症反应升高导致肝损伤，但不影响脂肪变性。这些发现表明，自噬在巨噬细胞极化中具有重要的调节功能，从而下调炎症。巨噬细胞自噬的缺陷可能是炎症性疾病状态的基础，例如肥胖导致的巨噬细胞自噬减少，导致肝脏炎症和肝损伤的进展。
Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.