AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

Abstract 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 ev...

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Autores principales:	Nathaniel B. Bone, Eugene J. Becker, Maroof Husain, Shaoning Jiang, Anna A. Zmijewska, Dae-Won Park, Balu Chacko, Victor Darley-Usmar, Murielle Grégoire, Jean-Marc Tadie, Victor J. Thannickal, Jaroslaw W. Zmijewski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/721d2c15ada041d197bf848bf5d4bb98
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spelling	oai:doaj.org-article:721d2c15ada041d197bf848bf5d4bb982021-12-02T17:52:31ZAMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections10.1038/s41598-021-90573-02045-2322https://doaj.org/article/721d2c15ada041d197bf848bf5d4bb982021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90573-0https://doaj.org/toc/2045-2322Abstract 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.Nathaniel B. BoneEugene J. BeckerMaroof HusainShaoning JiangAnna A. ZmijewskaDae-Won ParkBalu ChackoVictor Darley-UsmarMurielle GrégoireJean-Marc TadieVictor J. ThannickalJaroslaw W. ZmijewskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nathaniel B. Bone Eugene J. Becker Maroof Husain Shaoning Jiang Anna A. Zmijewska Dae-Won Park Balu Chacko Victor Darley-Usmar Murielle Grégoire Jean-Marc Tadie Victor J. Thannickal Jaroslaw W. Zmijewski AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
description	Abstract 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.
format	article
author	Nathaniel B. Bone Eugene J. Becker Maroof Husain Shaoning Jiang Anna A. Zmijewska Dae-Won Park Balu Chacko Victor Darley-Usmar Murielle Grégoire Jean-Marc Tadie Victor J. Thannickal Jaroslaw W. Zmijewski
author_facet	Nathaniel B. Bone Eugene J. Becker Maroof Husain Shaoning Jiang Anna A. Zmijewska Dae-Won Park Balu Chacko Victor Darley-Usmar Murielle Grégoire Jean-Marc Tadie Victor J. Thannickal Jaroslaw W. Zmijewski
author_sort	Nathaniel B. Bone
title	AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
title_short	AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
title_full	AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
title_fullStr	AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
title_full_unstemmed	AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
title_sort	ampk activates parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/721d2c15ada041d197bf848bf5d4bb98
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_version_	1718379174192742400

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

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