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IFNγ binding to extracellular matrix prevents fatal systemic toxicity
Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding do...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977683/ https://www.ncbi.nlm.nih.gov/pubmed/36732425 http://dx.doi.org/10.1038/s41590-023-01420-5 |
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author | Kemna, Josephine Gout, Evelyne Daniau, Leon Lao, Jessica Weißert, Kristoffer Ammann, Sandra Kühn, Ralf Richter, Matthias Molenda, Christine Sporbert, Anje Zocholl, Dario Klopfleisch, Robert Lortat-Jacob, Hugues Aichele, Peter Kammertoens, Thomas Blankenstein, Thomas |
author_facet | Kemna, Josephine Gout, Evelyne Daniau, Leon Lao, Jessica Weißert, Kristoffer Ammann, Sandra Kühn, Ralf Richter, Matthias Molenda, Christine Sporbert, Anje Zocholl, Dario Klopfleisch, Robert Lortat-Jacob, Hugues Aichele, Peter Kammertoens, Thomas Blankenstein, Thomas |
author_sort | Kemna, Josephine |
collection | PubMed |
description | Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ(ΔKRKR)) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ(ΔKRKR) in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ(ΔKRKR) mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ(ΔKRKR) levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation. |
format | Online Article Text |
id | pubmed-9977683 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-99776832023-03-03 IFNγ binding to extracellular matrix prevents fatal systemic toxicity Kemna, Josephine Gout, Evelyne Daniau, Leon Lao, Jessica Weißert, Kristoffer Ammann, Sandra Kühn, Ralf Richter, Matthias Molenda, Christine Sporbert, Anje Zocholl, Dario Klopfleisch, Robert Lortat-Jacob, Hugues Aichele, Peter Kammertoens, Thomas Blankenstein, Thomas Nat Immunol Article Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ(ΔKRKR)) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ(ΔKRKR) in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ(ΔKRKR) mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ(ΔKRKR) levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation. Nature Publishing Group US 2023-02-02 2023 /pmc/articles/PMC9977683/ /pubmed/36732425 http://dx.doi.org/10.1038/s41590-023-01420-5 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kemna, Josephine Gout, Evelyne Daniau, Leon Lao, Jessica Weißert, Kristoffer Ammann, Sandra Kühn, Ralf Richter, Matthias Molenda, Christine Sporbert, Anje Zocholl, Dario Klopfleisch, Robert Lortat-Jacob, Hugues Aichele, Peter Kammertoens, Thomas Blankenstein, Thomas IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title | IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title_full | IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title_fullStr | IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title_full_unstemmed | IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title_short | IFNγ binding to extracellular matrix prevents fatal systemic toxicity |
title_sort | ifnγ binding to extracellular matrix prevents fatal systemic toxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977683/ https://www.ncbi.nlm.nih.gov/pubmed/36732425 http://dx.doi.org/10.1038/s41590-023-01420-5 |
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