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Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions

Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (H...

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Autores principales: Ferrara, Michele, Chialli, Ginevra, Ferreira, Lorena Maria, Ruggieri, Elena, Careccia, Giorgia, Preti, Alessandro, Piccirillo, Rosanna, Bianchi, Marco Emilio, Sitia, Giovanni, Venereau, Emilie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326777/
https://www.ncbi.nlm.nih.gov/pubmed/32670275
http://dx.doi.org/10.3389/fimmu.2020.01122
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author Ferrara, Michele
Chialli, Ginevra
Ferreira, Lorena Maria
Ruggieri, Elena
Careccia, Giorgia
Preti, Alessandro
Piccirillo, Rosanna
Bianchi, Marco Emilio
Sitia, Giovanni
Venereau, Emilie
author_facet Ferrara, Michele
Chialli, Ginevra
Ferreira, Lorena Maria
Ruggieri, Elena
Careccia, Giorgia
Preti, Alessandro
Piccirillo, Rosanna
Bianchi, Marco Emilio
Sitia, Giovanni
Venereau, Emilie
author_sort Ferrara, Michele
collection PubMed
description Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (HMGB1) protein is a Damage-Associated Molecular Pattern (DAMP) molecule that orchestrates key events in inflammation by switching among mutually exclusive redox states. Fully reduced HMGB1 (frHMGB1) supports immune cell recruitment and tissue regeneration, while the isoform containing a disulphide bond (dsHMGB1) promotes secretion of inflammatory mediators by immune cells. Although it has been suggested that the tissue itself determines the redox state of the extracellular space and of released HMGB1, the dynamics of HMGB1 oxidation in health and disease are unknown. In the present work, we analyzed the expression of HMGB1 redox isoforms in different inflammatory conditions in skeletal muscle, from acute injury to muscle wasting, in tumor microenvironment, in spleen, and in liver after drug intoxication. Our results reveal that the redox modulation of HMGB1 is tissue-specific, with high expression of dsHMGB1 in normal spleen and liver and very low in muscle, where it appears after acute damage. Similarly, dsHMGB1 is highly expressed in the tumor microenvironment while it is absent in cachectic muscles from the same tumor-bearing mice. These findings emphasize the accurate and dynamic regulation of HMGB1 redox state, with the presence of dsHMGB1 tightly associated with leukocyte infiltration. Accordingly, we identified circulating, infiltrating, and resident leukocytes as reservoirs and transporters of dsHMGB1 in tissue and tumor microenvironment, demonstrating that the redox state of HMGB1 is controlled at both tissue and cell levels. Overall, our data point out that HMGB1 oxidation is a timely and spatially regulated process in physiological and pathological conditions. This precise modulation might play key roles to finetune inflammatory and regenerative processes.
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spelling pubmed-73267772020-07-14 Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions Ferrara, Michele Chialli, Ginevra Ferreira, Lorena Maria Ruggieri, Elena Careccia, Giorgia Preti, Alessandro Piccirillo, Rosanna Bianchi, Marco Emilio Sitia, Giovanni Venereau, Emilie Front Immunol Immunology Acute inflammation is a complex biological response of tissues to harmful stimuli, such as pathogens or cell damage, and is essential for immune defense and proper healing. However, unresolved inflammation can lead to chronic disorders, including cancer and fibrosis. The High Mobility Group Box 1 (HMGB1) protein is a Damage-Associated Molecular Pattern (DAMP) molecule that orchestrates key events in inflammation by switching among mutually exclusive redox states. Fully reduced HMGB1 (frHMGB1) supports immune cell recruitment and tissue regeneration, while the isoform containing a disulphide bond (dsHMGB1) promotes secretion of inflammatory mediators by immune cells. Although it has been suggested that the tissue itself determines the redox state of the extracellular space and of released HMGB1, the dynamics of HMGB1 oxidation in health and disease are unknown. In the present work, we analyzed the expression of HMGB1 redox isoforms in different inflammatory conditions in skeletal muscle, from acute injury to muscle wasting, in tumor microenvironment, in spleen, and in liver after drug intoxication. Our results reveal that the redox modulation of HMGB1 is tissue-specific, with high expression of dsHMGB1 in normal spleen and liver and very low in muscle, where it appears after acute damage. Similarly, dsHMGB1 is highly expressed in the tumor microenvironment while it is absent in cachectic muscles from the same tumor-bearing mice. These findings emphasize the accurate and dynamic regulation of HMGB1 redox state, with the presence of dsHMGB1 tightly associated with leukocyte infiltration. Accordingly, we identified circulating, infiltrating, and resident leukocytes as reservoirs and transporters of dsHMGB1 in tissue and tumor microenvironment, demonstrating that the redox state of HMGB1 is controlled at both tissue and cell levels. Overall, our data point out that HMGB1 oxidation is a timely and spatially regulated process in physiological and pathological conditions. This precise modulation might play key roles to finetune inflammatory and regenerative processes. Frontiers Media S.A. 2020-06-24 /pmc/articles/PMC7326777/ /pubmed/32670275 http://dx.doi.org/10.3389/fimmu.2020.01122 Text en Copyright © 2020 Ferrara, Chialli, Ferreira, Ruggieri, Careccia, Preti, Piccirillo, Bianchi, Sitia and Venereau. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ferrara, Michele
Chialli, Ginevra
Ferreira, Lorena Maria
Ruggieri, Elena
Careccia, Giorgia
Preti, Alessandro
Piccirillo, Rosanna
Bianchi, Marco Emilio
Sitia, Giovanni
Venereau, Emilie
Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title_full Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title_fullStr Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title_full_unstemmed Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title_short Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions
title_sort oxidation of hmgb1 is a dynamically regulated process in physiological and pathological conditions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326777/
https://www.ncbi.nlm.nih.gov/pubmed/32670275
http://dx.doi.org/10.3389/fimmu.2020.01122
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