巨噬细胞功能新发现：分化关键蛋白Trib1

巨噬细胞至少有两个亚类，即M1型和M2型。人类全基因组关联研究表明TRIB1参与脂质代谢。现在大阪大学WPI免疫前沿研究中心等处的研究人员发现TRIB1通过控制M2类巨噬细胞的分化，在脂肪组织维持和脂质代谢紊乱上发挥关键作用。

巨噬细胞至少有两个亚类，即M1型和M2型。M1型巨噬细胞参与促炎反应，且在宿主防御细菌和病毒感染中发挥核心作用。M2巨噬细胞与抗炎反应、寄生虫感染、组织重构、纤维化以及肿瘤疾病发展相关。 Trib1是个衔接蛋白，与泛素连接酶COP1相互作用参与蛋白降解。人类全基因组关联研究表明TRIB1参与脂质代谢。

现在，大阪大学WPI免疫前沿研究中心等处的研究人员，发现Trib1对F4/80 + MR +组织内在巨噬细胞的分化至关重要，且这些巨噬细胞和M2巨噬细胞、酸性粒细胞具有共同的特性（称之为M2类巨噬细胞）。但是，Trib1在M1髓系细胞就不会发挥这种作用。相关研究论文于2013年3月20日发表在Nature杂志上。

Trib1缺陷导致各种器官中M2类巨噬细胞急剧减少，如骨髓、脾脏、肺以及脂肪组织。在Trib1缺失的骨髓细胞中，C / EBP α的异常表达要为巨噬细胞分化缺陷负责。没有想到的是，造血细胞缺乏 Trib1的小鼠，减少了脂肪组织块，并伴随着脂肪分解增加，即使是在正常饮食条件下。

M2类巨噬细胞的补充可缓解这种病理学现象。这表明，这类巨噬细胞的缺乏是引发脂肪分解的原因。为了应对高脂肪饮食，造血细胞缺乏 Trib1的小鼠发育中会呈现高甘油三酯血症、胰岛素抗性，同时增加促炎细胞基因诱导。

总之，这些结果表明Trib1在脂肪组织维持和脂质代谢紊乱上发挥关键作用，而其作用是通过控制组织内在M2类巨噬细胞的分化实现的。

原文摘要：

Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages

Macrophages consist of at least two subgroups, M1 and M2 （refs 1, 2, 3）. Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections4, 5, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression6. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase7. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism8, 9, 10. Here we show that Trib1 is critical for the differentiation of F4/80+MR+ tissue-resident macrophages—that share characteristics with M2 macrophages （which we term M2-like macrophages）—and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.