Artesunate reverses LPS tolerance by promoting ULK1-mediated autophagy through interference with the CaMKII-IP3R-CaMKKβ pathway
Artesunate reverses LPS tolerance by promoting ULK1-mediated autophagy through interference with the CaMKII-IP3R-CaMKKβ pathway
复制标题
青蒿琥酯通过干扰 CaMKII-IP3R-CaMKK beta 途径促进 ULK1 介导的自噬来逆转 LPS 耐受
DOI：
10.1016/j.intimp.2020.106863
复制
发表时间：
2020-10-01
影响因子：
5.6
通讯作者：
Zheng, Jiang
中科院分区：
文献类型：
--
作者：
Liu, Xin;Wu, Jiaqi;Zheng, Jiang
脓毒症的进展越来越多地被认为是从早期炎症过度到长期免疫抑制的转变，其特征在于先天免疫细胞中的反应性降低，称为脂多糖（LPS）耐受。在这项研究中，我们研究了抗疟疾药物青蒿琥酯逆转LPS耐受的能力，并探讨了其潜在的机制。最初，我们检测到自噬的急剧下降，伴随着细胞因子产生的减少和LPS耐受性巨噬细胞的细菌清除受损。然后，我们证明青蒿琥酯通过诱导自噬恢复细胞因子的产生并增强细菌清除。此外，青蒿琥酯对Unc-51的抑制性磷酸化的抑制作用大于对Unc-51的激活性磷酸化的抑制作用，例如自噬激活激酶1（ULK 1），这是一种通过抑制过度的AMP激活蛋白激酶（AMPK）激活来启动自噬所必需的激酶。该效应通过抑制Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）磷酸化来实现，导致肌醇1，4，5-三磷酸受体（IP 3R）依赖性Ca 2+从内质网（ER）释放减少，并抑制过度活跃的CaMKK β-AMPK级联反应。青蒿琥酯的管理也上调自噬和逆转LPS耐受小鼠的耐受状态。总之，我们的研究结果揭示了青蒿琥酯通过恢复自噬逆转LPS耐受的新的免疫药理学作用。我们的研究结果也可能表明自噬诱导治疗脓毒症免疫抑制的意义。
The progress of sepsis is increasingly recognized by the transition from early hyperinflammation to long term immunosuppression, which is characterized in innate immune cells by diminished responsiveness termed as lipopolysaccharide (LPS) tolerance. In this study, we investigated the ability of the antimalarial drug artesunate to reverse LPS tolerance and explored the underlying mechanisms. Initially, we detected a dramatic decline in autophagy accompanied by decreased cytokine production and impaired bacterial clearance by LPS tolerant macrophages. Then we demonstrated that artesunate restored cytokine production and enhanced bacterial clearance by inducing autophagy. Moreover, artesunate caused greater suppression of inhibitory phosphorylation than of activating phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1), a kinase that is essential for initiating autophagy through the inhibition of excessive AMP-activated protein kinase (AMPK) activation. This effect was shown to be achieved by suppression of Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, resulting in reduction of the inositol 1,4,5-triphate receptor (IP3R) dependent Ca2+ release from the endoplasmic reticulum (ER) and inhibiting the overactive CaMKK beta-AMPK cascade. Administration of artesunate also upregulated autophagy and reversed the tolerant status in LPS tolerant mice. In summary, our findings reveal a novel immunopharmacological action of artesunate to reverse LPS tolerance by restoring autophagy. Our results may also indicate the significance of autophagy induction for treating immunosuppression in sepsis.