Zhang W, Liu H, Liu W, Liu Y, Xu J
Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Key Laboratory of Glycoconjugate Research, Ministry of Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
Cell Death Differ. 2015 Feb;22(2):287-97. doi: 10.1038/cdd.2014.142. Epub 2014 Sep 12.
Serine/threonine kinase family members p21-activated kinases (PAKs) are important regulators of cytoskeletal remodeling and cell motility in mononuclear phagocytic system, but their role in macrophage differentiation and polarization remains obscure. We have shown here that inflammatory stimuli induced PAK1 overexpression in human and murine macrophages. Elevated expression of PAK1 contributed to macrophage M1 polarization and lipopolysaccharide (LPS)-induced endotoxin shock. We further observed that epigenetic loss of microRNA let-7c due to enhancer of zeste homolog 2 (EZH2) upregulation determined PAK1 elevation and inflammatory phenotype in M1 macrophages. EZH2/let-7c/PAK1 axis promotes macrophage M1 polarization via NIK-IKK-NF-κB signaling. Moreover, pharmacological and genetic ablation with EZH2/let-7c/PAK1 axis blunted inflammatory phenotype in M1 macrophages. Critically, either myeloid-restricted PAK1 deletion (PAK1(Lyz2cre)) or pharmacological and genetic ablation with EZH2/let-7c/PAK1 signal resulted in resistance to LPS-induced endotoxin shock via blunting macrophage M1 polarization. PAK1, therefore, is an essential controller of inflammatory macrophage polarization, regulating immune responses against pathogenic stimuli.
丝氨酸/苏氨酸激酶家族成员p21活化激酶（PAKs）是单核吞噬系统中细胞骨架重塑和细胞运动的重要调节因子，但其在巨噬细胞分化和极化中的作用仍不清楚。我们在此表明，炎症刺激可诱导人源和鼠源巨噬细胞中PAK1的过表达。PAK1表达的升高有助于巨噬细胞的M1极化和脂多糖（LPS）诱导的内毒素休克。我们进一步观察到，由于zeste同源物2（EZH2）上调导致的微小RNA let-7c的表观遗传缺失决定了M1巨噬细胞中PAK1的升高和炎症表型。EZH2/let-7c/PAK1轴通过NIK-IKK-NF-κB信号通路促进巨噬细胞的M1极化。此外，对EZH2/let-7c/PAK1轴进行药理学和基因敲除可减弱M1巨噬细胞的炎症表型。至关重要的是，髓系特异性PAK1缺失（PAK1(Lyz2cre)）或对EZH2/let-7c/PAK1信号进行药理学和基因敲除，均可通过减弱巨噬细胞的M1极化而导致对LPS诱导的内毒素休克产生抗性。因此，PAK1是炎症性巨噬细胞极化的关键调控因子，可调节针对致病刺激的免疫反应。
