Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation
Nrf2-SHP Cascade-Mediated STAT3 Inactivation Contributes to AMPK-Driven Protection Against Endotoxic Inflammation
复制标题
Nrf2-SHP 级联介导的 STAT3 失活有助于 AMPK 驱动的内毒素炎症保护
DOI：
10.3389/fimmu.2020.00414
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发表时间：
2020-03-10
影响因子：
7.3
通讯作者：
Xiao, Hengyi
中科院分区：
文献类型：
--
作者：
Gong, Hui;Tai, Haoran;Xiao, Hengyi
信号转导和转录激活因子3(STAT3)参与炎症过程，但其调节机制大多局限于Janus激酶(JAK)介导的磷酸化。虽然AMP活化蛋白激酶(AMPK)介导的STAT3失活已有报道，但STAT3失活与AMPK抗炎作用之间的分子信号转导机制还远未建立。在本研究中，我们探讨了AMPK和STAT3之间的相互作用，并揭示了STAT3失活在AMPK在内毒素应激巨噬细胞和小鼠的抗炎功能中的重要作用。首先，我们发现药物抑制STAT3可以提高AMPK在野生型小鼠体内的抗炎作用，并且在小鼠巨噬细胞中表达STAT3是AMPK抗炎作用的前提。关于连接AMPK和STAT3的分子信号级联，我们发现AMPK不仅通过减弱JAK信号途径抑制STAT3，还通过激活氧化还原调节转录因子Nrf2来抑制STAT3的转录，从而增加小分子异源二聚体蛋白(SHP)的表达，从而抑制STAT3的转录活性。综上所述，本研究提供了一组独特的证据表明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。这些发现扩大了我们对促炎和抗炎信号通路之间相互作用的理解，并有助于脓毒症治疗的发展。
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.