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 CaMKKβ-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.

从早期过度炎症过渡到长期免疫抑制已逐渐认识到败血症的进展，其特征是先天免疫细胞的反应性降低，称为脂多糖（LPS）耐受性。在这项研究中，我们调查了抗疟药青蒿琥酯逆转LPS耐受性的能力，并探讨了潜在的机制。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以及LPS耐受巨噬细胞对细菌清除的损害。然后我们证明了青蒿琥酯通过诱导自噬恢复了细胞因子的产生并增强了细菌清除率。此外，青蒿琥酯比自噬激活激酶1（ULK1）引起的Unc-51激活磷酸化抑制作用更大，通过抑制过度的AMP激活的蛋白激酶（AMPK）激活来启动自噬所必需的激酶。通过抑制钙可以达到这种效果²⁺ /钙调蛋白依赖性蛋白激酶II（CaMKII）磷酸化，导致肌醇1,4,5-三磷酸受体（IP3R）依赖性Ca ²⁺从内质网（ER）释放并抑制过度活跃的CaMKKβ-AMPK级联。青蒿琥酯的给药还上调了自噬并逆转了LPS耐受小鼠的耐受状态。总之，我们的发现揭示了青蒿琥酯通过恢复自噬逆转LPS耐受性的新的免疫药理作用。我们的结果也可能表明自噬诱导对于治疗败血症中的免疫抑制的重要性。