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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01122/full |
| _version_ | 1828317691668070400 |
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| author | Michele Ferrara Ginevra Chialli Ginevra Chialli Lorena Maria Ferreira Elena Ruggieri Elena Ruggieri Giorgia Careccia Giorgia Careccia Alessandro Preti Rosanna Piccirillo Marco Emilio Bianchi Marco Emilio Bianchi Giovanni Sitia Emilie Venereau |
| author_facet | Michele Ferrara Ginevra Chialli Ginevra Chialli Lorena Maria Ferreira Elena Ruggieri Elena Ruggieri Giorgia Careccia Giorgia Careccia Alessandro Preti Rosanna Piccirillo Marco Emilio Bianchi Marco Emilio Bianchi Giovanni Sitia Emilie Venereau |
| author_sort | Michele Ferrara |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T17:32:01Z |
| format | Article |
| id | doaj.art-162427c17b064142ab4f283b2f9df774 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T17:32:01Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-162427c17b064142ab4f283b2f9df7742022-12-22T02:37:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01122544164Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological ConditionsMichele Ferrara0Ginevra Chialli1Ginevra Chialli2Lorena Maria Ferreira3Elena Ruggieri4Elena Ruggieri5Giorgia Careccia6Giorgia Careccia7Alessandro Preti8Rosanna Piccirillo9Marco Emilio Bianchi10Marco Emilio Bianchi11Giovanni Sitia12Emilie Venereau13Division of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyDivision of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Immunology, Transplantation and Infectious Diseases, Experimental Hepatology Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyDivision of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyHMGBiotech srl, Milan, ItalyDepartment of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, Milan, ItalyDivision of Genetics and Cell Biology, Chromatin Dynamics Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Immunology, Transplantation and Infectious Diseases, Experimental Hepatology Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyAcute 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.01122/fullinflammationregenerationinjuryleukocytetumorcancer cachexia |
| spellingShingle | Michele Ferrara Ginevra Chialli Ginevra Chialli Lorena Maria Ferreira Elena Ruggieri Elena Ruggieri Giorgia Careccia Giorgia Careccia Alessandro Preti Rosanna Piccirillo Marco Emilio Bianchi Marco Emilio Bianchi Giovanni Sitia Emilie Venereau Oxidation of HMGB1 Is a Dynamically Regulated Process in Physiological and Pathological Conditions Frontiers in Immunology inflammation regeneration injury leukocyte tumor cancer cachexia |
| 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 | inflammation regeneration injury leukocyte tumor cancer cachexia |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01122/full |
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