Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation
Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation
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DOI：
10.1172/jci79590
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发表时间：
2016-04-01
影响因子：
15.9
通讯作者：
Leitinger, Norbert
中科院分区：
文献类型：
--
作者：
Adamson, Samantha E.;Griffiths, Rachael;Leitinger, Norbert
急性和慢性组织损伤导致巨噬细胞通过改变其表型和功能来响应无数的环境线索。这种表型调节对于控制组织炎症和解决至关重要。在这里，我们已经确定了接头蛋白失能同源物2 （DAB2）作为巨噬细胞表型转换的调节因子。在小鼠和人分离的M2巨噬细胞中，Dab2的表达上调，而在M1巨噬细胞中，Dab2的表达被抑制，并且Dab2的基因缺失易使巨噬细胞采用促炎M1表型。在骨髓细胞特异性缺失Dab2（Dab2(fi/fi) Lysm-Cre）的小鼠中，用亚致死剂量的LPS治疗导致促炎基因表达和巨噬细胞活化增加。此外，与对照组相比，慢性高脂喂养加重了dab2缺陷动物的脂肪组织炎症、脂肪组织巨噬细胞M1极化和胰岛素抵抗的发生。突变分析显示，DAB2与TNF受体相关因子6 （TRAF6）相互作用，并减弱NF-kappa B p65反激活域中Ser536的依赖性（IKK依赖性）磷酸化。总之，这些发现揭示了DAB2在巨噬细胞表型极化过程中对控制炎症信号至关重要，并表明操纵DAB2的表达和功能可能具有治疗急性和慢性炎症性疾病的治疗潜力。
Acute and chronic tissue injury results in the generation of a myriad of environmental cues that macrophages respond to by changing their phenotype and function. This phenotypic regulation is critical for controlling tissue inflammation and resolution. Here, we have identified the adaptor protein disabled homolog 2 (DAB2) as a regulator of phenotypic switching in macrophages. Dab2 expression was upregulated in M2 macrophages and suppressed in M1 macrophages isolated from both mice and humans, and genetic deletion of Dab2 predisposed macrophages to adopt a proinflammatory M1 phenotype. In mice with myeloid cell-specific deletion of Dab2 (Dab2(fi/fi) Lysm-Cre), treatment with sublethal doses of LPS resulted in increased proinflammatory gene expression and macrophage activation. Moreover, chronic high-fat feeding exacerbated adipose tissue inflammation, M1 polarization of adipose tissue macrophages, and the development of insulin resistance in DAB2-deficient animals compared with controls. Mutational analyses revealed that DAB2 interacts with TNF receptor-associated factor 6 (TRAF6) and attenuates I kappa B kinase beta-dependent (IKK beta-dependent) phosphorylation of Ser536 in the transactivation domain of NF-kappa B p65. Together, these findings reveal that DAB2 is critical for controlling inflammatory signaling during phenotypic polarization of macrophages and suggest that manipulation of DAB2 expression and function may hold therapeutic potential for the treatment of acute and chronic inflammatory disorders.