Artesunate interacts with the vitamin D receptor to reverse sepsis-induced immunosuppression in a mouse model via enhancing autophagy
Artesunate interacts with the vitamin D receptor to reverse sepsis-induced immunosuppression in a mouse model via enhancing autophagy
复制标题
青蒿琥酯与维生素 D 受体相互作用，通过增强自噬逆转小鼠模型中败血症诱导的免疫抑制
DOI：
10.1111/bph.15158
复制
发表时间：
2020-07-06
影响因子：
7.3
通讯作者：
Zhou, Hong
中科院分区：
文献类型：
--
作者：
Shang, Shenglan;Wu, Jiaqi;Zhou, Hong
背景和目的由于不能根除病原体，免疫抑制是脓毒症死亡的主要原因。临床上没有能够逆转免疫抑制的有效和特异性药物。有证据表明，维生素D受体（NR 1 I1）参与脓毒症诱导的免疫抑制。研究抗疟疾青蒿琥酯对脓毒症诱导的免疫抑制的作用。实验方法青蒿琥酯对脓毒症诱导的免疫抑制的作用在小鼠以及人和小鼠细胞系中进行了研究。生物信息学预测维生素D受体为青蒿琥酯的候选靶点，PCR和免疫印迹法鉴定该靶点，并对Vdr、Atg 16 l1和NF-κ B B p65进行修饰，研究青蒿琥酯对脓毒症诱导的免疫抑制中促炎细胞因子释放、细菌清除和自噬活性的影响。关键结果青蒿琥酯可显著降低铜绿假单胞菌感染的盲肠结扎穿孔（CLP）诱导的脓毒症免疫抑制小鼠的死亡率，增强促炎细胞因子的释放和细菌清除，逆转脓毒症诱导的免疫抑制，其机制是青蒿琥酯与维生素D受体相互作用，抑制其核转位，从而影响ATG 16 L1转录和随后的自噬活性。青蒿琥酯抑制LPS耐受巨噬细胞中维生素D受体与NF-κ B p65的物理相互作用，促进NF-κ B p65核转位，从而激活NF-κ B p65靶基因如促炎细胞因子的转录。结论和意义我们的研究结果提供了证据表明青蒿琥酯与维生素D受体相互作用，以自噬和NF-κ B依赖的方式逆转脓毒症诱导的免疫抑制，突出了脓毒症治疗的新方法和青蒿琥酯的药物再利用具有双向免疫调节剂。
Background and Purpose Immunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate pathogens. No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis-induced immunosuppression. The anti-malarial artesunate was investigated to determine action on sepsis-induced immunosuppression. Experimental Approach The effect of artesunate on sepsis-induced immunosuppression was investigated in mice and human and mice cell lines. Bioinformatics predicted vitamin D receptor as a candidate target for artesunate, which was then identified using PCR and immunoblotting.Vdr,Atg16l1andNF-kappa B p65were modified to investigate artesunate 's effect on pro-inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis-induced immunosuppression. Key Results Artesunate significantly reduced the mortality of caecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged withPseudomonas aeruginosaand enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppressionin vivoandin vitro.Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influencedATG16L1transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor andNF-kappa B p65in LPS-tolerant macrophages and then promoted the nuclear translocation ofNF-kappa B p65, which activated the transcription ofNF-kappa B p65target genes such as pro-inflammatory cytokines. Conclusion and Implications Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-kappa B-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.