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Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1

BACKGROUND: Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy...

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Autores principales: Peng, Jialing, Pan, Jingrui, Wang, Hongxuan, Mo, Jingjing, Lan, Lihuan, Peng, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006625/
https://www.ncbi.nlm.nih.gov/pubmed/35414088
http://dx.doi.org/10.1186/s12974-022-02453-7
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author Peng, Jialing
Pan, Jingrui
Wang, Hongxuan
Mo, Jingjing
Lan, Lihuan
Peng, Ying
author_facet Peng, Jialing
Pan, Jingrui
Wang, Hongxuan
Mo, Jingjing
Lan, Lihuan
Peng, Ying
author_sort Peng, Jialing
collection PubMed
description BACKGROUND: Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy is linked with morphine-induced immunosuppression in the brain remains unknown. NLRX1 is the only mitochondrially localized NOD family receptor protein which serves as a critical regulator in immunity and mitophagy activation, but it remains an enigma how NLRX1 functions in the crosstalk between microglial inflammatory defense and mitophagy in the presence of morphine. METHODS: Primary microglia and astrocytes, BV2 and MA cell lines were utilized. Mice were stimulated with repeated morphine treatment to mimic chronic morphine exposure, and activation of mitophagy, lysosomal functions, and inflammation were assayed in specific brain regions and immune organs with or without NLRX1-silencing. RESULTS: Morphine induced microglial mitophagy in a LC3 (microtubule-associated proteins light chain 3)-dependent manner, which was mediated by NLRX1. Contrastingly, morphine impaired lysosomal functions, including generation, acidification and mitophagosome–lysosome fusion, thus leading to insufficient mitophagy activation in microglia. NLRX1-silencing inhibited mitophagy activity and rescued lysosomal functions including generation and acidification in microglia. The NLRX1-mediated incomplete mitophagy in microglial cells contributed to immunosuppression and vulnerability towards pathogenic challenge after morphine treatment. In vivo, NLRX1-mediated microglial mitophagy activation by morphine was mainly located in the murine brain cortex, striatum, and cerebellum, where NLRX1 functioned as a negative immune regulator and facilitated septic shock. Collectively, microglial immune responses to septic shock were amenable to NLRX1 silencing in the brain with morphine treatment. CONCLUSION: Morphine activated insufficient mitophagy in microglia which was regulated by NLRX1, ultimately leading to host immunosuppression and susceptible conditions in the brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02453-7.
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spelling pubmed-90066252022-04-14 Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1 Peng, Jialing Pan, Jingrui Wang, Hongxuan Mo, Jingjing Lan, Lihuan Peng, Ying J Neuroinflammation Research BACKGROUND: Chronic morphine exposure induces immunosuppression in the peripheral and central nervous system, resulting in susceptibility of patients to invading pathogens. Mitophagy is a crucial regulator of inflammation, and dysregulated mitophagy may cause immunosuppression, but whether mitophagy is linked with morphine-induced immunosuppression in the brain remains unknown. NLRX1 is the only mitochondrially localized NOD family receptor protein which serves as a critical regulator in immunity and mitophagy activation, but it remains an enigma how NLRX1 functions in the crosstalk between microglial inflammatory defense and mitophagy in the presence of morphine. METHODS: Primary microglia and astrocytes, BV2 and MA cell lines were utilized. Mice were stimulated with repeated morphine treatment to mimic chronic morphine exposure, and activation of mitophagy, lysosomal functions, and inflammation were assayed in specific brain regions and immune organs with or without NLRX1-silencing. RESULTS: Morphine induced microglial mitophagy in a LC3 (microtubule-associated proteins light chain 3)-dependent manner, which was mediated by NLRX1. Contrastingly, morphine impaired lysosomal functions, including generation, acidification and mitophagosome–lysosome fusion, thus leading to insufficient mitophagy activation in microglia. NLRX1-silencing inhibited mitophagy activity and rescued lysosomal functions including generation and acidification in microglia. The NLRX1-mediated incomplete mitophagy in microglial cells contributed to immunosuppression and vulnerability towards pathogenic challenge after morphine treatment. In vivo, NLRX1-mediated microglial mitophagy activation by morphine was mainly located in the murine brain cortex, striatum, and cerebellum, where NLRX1 functioned as a negative immune regulator and facilitated septic shock. Collectively, microglial immune responses to septic shock were amenable to NLRX1 silencing in the brain with morphine treatment. CONCLUSION: Morphine activated insufficient mitophagy in microglia which was regulated by NLRX1, ultimately leading to host immunosuppression and susceptible conditions in the brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02453-7. BioMed Central 2022-04-12 /pmc/articles/PMC9006625/ /pubmed/35414088 http://dx.doi.org/10.1186/s12974-022-02453-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Peng, Jialing
Pan, Jingrui
Wang, Hongxuan
Mo, Jingjing
Lan, Lihuan
Peng, Ying
Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title_full Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title_fullStr Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title_full_unstemmed Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title_short Morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by NLRX1
title_sort morphine-induced microglial immunosuppression via activation of insufficient mitophagy regulated by nlrx1
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006625/
https://www.ncbi.nlm.nih.gov/pubmed/35414088
http://dx.doi.org/10.1186/s12974-022-02453-7
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