Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion 71003, Crete, Greece.
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9517-22. doi: 10.1073/pnas.1119038109. Epub 2012 May 30.
Activated macrophages are described as classically activated or M1 type and alternatively activated or M2 type, depending on their response to proinflammatory stimuli and the expression of genetic markers including iNOS, arginase1, Ym1, and Fizz1. Here we report that Akt kinases differentially contribute to macrophage polarization, with Akt1 ablation giving rise to an M1 and Akt2 ablation resulting in an M2 phenotype. Accordingly, Akt2(-/-) mice were more resistant to LPS-induced endotoxin shock and to dextran sulfate sodium (DSS)-induced colitis than wild-type mice, whereas Akt1(-/-) mice were more sensitive. Cell depletion and reconstitution experiments in a DSS-induced colitis model confirmed that the effect was macrophage-dependent. Gene-silencing studies showed that the M2 phenotype of Akt2(-/-) macrophages was cell autonomous. The microRNA miR-155, whose expression was repressed in naive and in LPS-stimulated Akt2(-/-) macrophages, and its target C/EBPβ appear to play a key role in this process. C/EBPβ, a hallmark of M2 macrophages that regulates Arg1, was up-regulated upon Akt2 ablation or silencing. Overexpression or silencing of miR-155 confirmed its central role in Akt isoform-dependent M1/M2 polarization of macrophages.
激活的巨噬细胞根据其对促炎刺激的反应和基因标志物（包括 iNOS、arginase1、Ym1 和 Fizz1）的表达，被描述为经典激活或 M1 型和替代激活或 M2 型。在这里，我们报告 Akt 激酶对巨噬细胞极化有不同的贡献，Akt1 的缺失导致 M1 表型，而 Akt2 的缺失导致 M2 表型。相应地，与野生型小鼠相比，Akt2(-/-)小鼠对 LPS 诱导的内毒素休克和葡聚糖硫酸钠（DSS）诱导的结肠炎更具抵抗力，而 Akt1(-/-)小鼠则更敏感。在 DSS 诱导的结肠炎模型中的细胞耗竭和重建实验证实了这种作用是依赖于巨噬细胞的。基因沉默研究表明，Akt2(-/-)巨噬细胞的 M2 表型是细胞自主的。miR-155 的表达在幼稚和 LPS 刺激的 Akt2(-/-)巨噬细胞中受到抑制，其靶标 C/EBPβ似乎在这个过程中起着关键作用。C/EBPβ是 M2 巨噬细胞的一个标志，调节 Arg1，在 Akt2 缺失或沉默时上调。miR-155 的过表达或沉默证实了它在 Akt 同工型依赖性巨噬细胞 M1/M2 极化中的核心作用。
