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IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion
Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by a...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218203/ https://www.ncbi.nlm.nih.gov/pubmed/30355498 http://dx.doi.org/10.1016/j.celrep.2018.09.001 |
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author | Gkirtzimanaki, Katerina Kabrani, Eleni Nikoleri, Dimitra Polyzos, Alexander Blanas, Athanasios Sidiropoulos, Prodromos Makrigiannakis, Antonis Bertsias, George Boumpas, Dimitrios T. Verginis, Panayotis |
author_facet | Gkirtzimanaki, Katerina Kabrani, Eleni Nikoleri, Dimitra Polyzos, Alexander Blanas, Athanasios Sidiropoulos, Prodromos Makrigiannakis, Antonis Bertsias, George Boumpas, Dimitrios T. Verginis, Panayotis |
author_sort | Gkirtzimanaki, Katerina |
collection | PubMed |
description | Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology. IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive. Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs. Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance. Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies. |
format | Online Article Text |
id | pubmed-6218203 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62182032018-11-09 IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion Gkirtzimanaki, Katerina Kabrani, Eleni Nikoleri, Dimitra Polyzos, Alexander Blanas, Athanasios Sidiropoulos, Prodromos Makrigiannakis, Antonis Bertsias, George Boumpas, Dimitrios T. Verginis, Panayotis Cell Rep Article Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology. IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive. Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs. Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance. Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies. Cell Press 2018-10-23 /pmc/articles/PMC6218203/ /pubmed/30355498 http://dx.doi.org/10.1016/j.celrep.2018.09.001 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Gkirtzimanaki, Katerina Kabrani, Eleni Nikoleri, Dimitra Polyzos, Alexander Blanas, Athanasios Sidiropoulos, Prodromos Makrigiannakis, Antonis Bertsias, George Boumpas, Dimitrios T. Verginis, Panayotis IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title | IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title_full | IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title_fullStr | IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title_full_unstemmed | IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title_short | IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion |
title_sort | ifnα impairs autophagic degradation of mtdna promoting autoreactivity of sle monocytes in a sting-dependent fashion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218203/ https://www.ncbi.nlm.nih.gov/pubmed/30355498 http://dx.doi.org/10.1016/j.celrep.2018.09.001 |
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