Serum- and Glucocorticoid-Inducible Kinase 1 Promotes Alternative Macrophage Polarization and Restrains Inflammation through FoxO1 and STAT3 Signaling.
Serum- and Glucocorticoid-Inducible Kinase 1 Promotes Alternative Macrophage Polarization and Restrains Inflammation through FoxO1 and STAT3 Signaling.
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DOI：
10.4049/jimmunol.2001455
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Ren J;Han X;Lohner H;Liang R;Liang S;Wang H
血清和糖皮质激素诱导激酶1（SGK 1）的表达和活性与许多代谢和炎症性疾病相关。在这里，我们报告说，SGK 1促进替代巨噬细胞极化和抑制牙龈感染环境中的炎症。抑制SGK 1表达或活性可通过直接激活编码iNOS、IL-12 P40、TNFα、IL-6的基因转录并在信息和蛋白水平抑制IL-10，产生M1巨噬细胞特征性变化。此外，SGK 1抑制强烈降低M2巨噬细胞分子标志物的表达，包括β-淀粉酶-1，Ym-1，Fizz 1和Mgl 1。这些结果通过多种功能获得和丧失方法得到证实，包括siRNA、编码SGK 1的质粒和LysM-Cre介导的sgk 1基因敲除。进一步的机制分析表明，SGK 1缺陷分别在M2或M1巨噬细胞引发条件下降低STAT 3但增加FoxO 1表达。结合观察到的FoxO 1磷酸化降低和随后的细胞质易位抑制，SGK 1缺陷强烈增强FoxO 1活性并驱动巨噬细胞优先M1表型。此外，FoxO 1抑制废除M1表型和STAT 3过表达导致M2表型的显着增加，表明FoxO 1和STAT 3都参与SGK 1介导的巨噬细胞极化。此外，SGK 1差异调节M1和M2分子标志物的表达，包括CD 68和F4/F80，以及CD 163和CD 206，并在小鼠模型中保护牙龈卟啉单胞菌诱导的牙槽骨丢失。综上所述，我们已经证明SGK 1对巨噬细胞极化和牙周骨丢失至关重要，并且我们首次阐明了SGK 1促进替代的分叉信号通路，同时抑制炎症性巨噬细胞极化。
Expression and activity of serum- and glucocorticoid-inducible kinase 1 (SGK1) are associated with many metabolic and inflammatory diseases. Here, we report that SGK1 promotes alternative macrophage polarization and restrains inflammation in the infectious milieu of the gingiva. Inhibition of SGK1 expression or activity produces changes characteristic of M1 macrophages, by directly activating transcription of genes encoding iNOS, IL-12P40, TNFα, IL-6 and repressing IL-10 at message and protein levels. Moreover, SGK1 inhibition robustly reduces expression of M2 macrophage molecular markers including arginase-1, Ym-1, Fizz1, and Mgl1. These results were confirmed by multiple gain- and loss-of-function approaches including siRNA, a plasmid encoding SGK1, and LysM-Cre-mediated sgk1 gene knockout. Further mechanistic analysis showed that SGK1 deficiency decreases STAT3 but increases FoxO1 expression in macrophages under M2 or M1 macrophage-priming conditions, respectively. Combined with decreased FoxO1 phosphorylation and subsequent suppressed cytoplasmic translocation observed, SGK1 deficiency robustly enhances FoxO1 activity and drives macrophage to preferential M1 phenotypes. Furthermore, FoxO1 inhibition abrogates M1 phenotypes and STAT3 overexpression results in a significant increase of M2 phenotypes, indicating that both FoxO1 and STAT3 are involved in SGK1-mediated macrophage polarization. Additionally, SGK1 differentially regulates expression of M1 and M2 molecular markers, including CD68 and F4/F80, and CD163 and CD206, respectively, and protects against P. gingivalis-induced alveolar bone loss in a mouse model. Taken together, we have demonstrated that SGK1 is critical for macrophage polarization and periodontal bone loss, and for the first time, we elucidated a bifurcated signaling circuit by which SGK1 promotes alternative, while suppressing inflammatory, macrophage polarization.
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