Lab for Aging Research, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Development and Regeneration Key Lab of Sichuan Province, Department of Anatomy and Histology and Embryology, Chengdu Medical College, Chengdu, China.
Front Immunol. 2020 Mar 10;11:414. doi: 10.3389/fimmu.2020.00414. eCollection 2020.
Signal transducer and activator of transcription 3 (STAT3) is implicated in inflammation processing, but the mechanism of its regulation mostly remains limited to Janus kinase (JAK)-mediated phosphorylation. Although AMP-activated protein kinase (AMPK)-mediated STAT3 inactivation has got documented, the molecular signaling cascade connecting STAT3 inactivation and the anti-inflammatory role of AMPK is far from established. In the present study, we addressed the interplay between AMPK and STAT3, and revealed the important role of STAT3 inactivation in the anti-inflammatory function of AMPK in lipopolysaccharide-stressed macrophages and mice. Firstly, we found that pharmacological inhibition of STAT3 can improve the anti-inflammatory effect of AMPK in wild-type mice, and the expression of STAT3 in macrophage of mice is a prerequisite for the anti-inflammatory effect of AMPK. As to the molecular signaling cascade linking AMPK to STAT3, we disclosed that AMPK suppressed STAT3 not only by attenuating JAK signaling but also by activating nuclear factor erythroid-2-related factor-2 (Nrf2), a redox-regulating transcription factor, which consequently increased the expression of small heterodimer protein (SHP), thus repressing the transcriptional activity of STAT3. In summary, this study provided a unique set of evidence showing the relationship between AMPK and STAT3 signaling and explored a new mechanism of AMPK-driven STAT3 inactivation that involves Nrf2-SHP signaling cascade. These findings expand our understanding of the interplay between pro- and anti-inflammatory signaling pathways and are beneficial for the therapeutic development of sepsis treatments.
信号转导子和转录激活子 3（STAT3）参与炎症处理，但调节其的机制主要限于 Janus 激酶（JAK）介导的磷酸化。虽然已经有文献证明 AMP 激活的蛋白激酶（AMPK）介导的 STAT3 失活，但连接 STAT3 失活和 AMPK 的抗炎作用的分子信号级联仍远未确定。在本研究中，我们研究了 AMPK 和 STAT3 之间的相互作用，并揭示了 STAT3 失活在 LPS 应激巨噬细胞和小鼠中 AMPK 的抗炎功能中的重要作用。首先，我们发现抑制 STAT3 的药理作用可以提高 AMPK 在野生型小鼠中的抗炎作用，而 STAT3 在小鼠巨噬细胞中的表达是 AMPK 抗炎作用的前提。至于连接 AMPK 和 STAT3 的分子信号级联，我们揭示 AMPK 不仅通过减弱 JAK 信号通路来抑制 STAT3，还通过激活核因子红细胞 2 相关因子 2（Nrf2），一种氧化还原调节转录因子，从而增加小异二聚体蛋白（SHP）的表达，从而抑制 STAT3 的转录活性。总之，本研究提供了一组独特的证据，显示了 AMPK 和 STAT3 信号之间的关系，并探索了 AMPK 驱动的 STAT3 失活的新机制，涉及 Nrf2-SHP 信号级联。这些发现扩展了我们对促炎和抗炎信号通路之间相互作用的理解，有利于脓毒症治疗的治疗开发。
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