AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.
AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.
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DOI：
10.1038/s41598-021-90573-0
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发表时间：
2021-06-11
影响因子：
4.6
通讯作者：
Zmijewski JW
中科院分区：
文献类型：
--
作者：
Bone NB;Becker EJ Jr;Husain M;Jiang S;Zmijewska AA;Park DW;Chacko B;Darley-Usmar V;Grégoire M;Tadie JM;Thannickal VJ;Zmijewski JW
免疫细胞的代谢和生物能可塑性对于对细菌感染的最佳反应至关重要。众所周知，AMPK 和 Parkin 泛素连接酶可调节线粒体质量控制线粒体自噬，从而防止不必要的炎症反应。然而，尚不清楚这种进化上保守的机制是否已被宿主免疫防御所利用，以根除细菌病原体并影响脓毒症后的免疫抑制。在脓毒症幸存者的人类白细胞以及野生型和 Park2−/− 鼠巨噬细胞中研究了 Parkin、AMPK 水平以及 AMPK 激活剂的作用。在体内，AMPK 和 Parkin 的影响是在遭受多种微生物腹内败血症和继发性肺部细菌感染的小鼠中确定的。在建立免疫抑制期间用二甲双胍治疗小鼠。我们表明，细菌和线粒体具有由哨兵事件触发的自噬杀伤/清除机制，这些哨兵事件涉及线粒体去极化和巨噬细胞中 Parkin 的募集。 Parkin 缺陷的小鼠/巨噬细胞无法形成吞噬溶酶体并杀死细菌。这种宿主防御的损害可以在脓毒症引起的免疫抑制和 Parkin 水平降低的背景下观察到。 AMPK 激活剂（包括二甲双胍）可刺激休克后患者的白细胞和脓毒症免疫抑制小鼠的肺部的 Parkin 依赖性自噬和细菌杀灭。我们的结果支持 Parkin 和 AMPK 在清除功能失调的线粒体和杀死病原菌方面的双重作用，并解释了与 Parkin 和 AMPK 缺陷相关的免疫抑制表型。 AMPK 激活似乎是巨噬细胞免疫抑制表型的重要治疗靶点，并可减轻继发性细菌性肺部感染和呼吸衰竭的严重程度。
Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
DOI：
10.1038/nri3552
发表时间：
2013-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Guigas, Bruno;Taleux, Nellie;Hue, Louis
通讯作者：
Hue, Louis
影响因子：
3.7
作者：
Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
通讯作者：
Darley-Usmar VM