IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Autor: Josephine Kemna, Evelyne Gout, Leon Daniau, Jessica Lao, Kristoffer Weißert, Sandra Ammann, Ralf Kühn, Matthias Richter, Christine Molenda, Anje Sporbert, Dario Zocholl, Robert Klopfleisch, Hugues Lortat-Jacob, Peter Aichele, Thomas Kammertoens, Thomas Blankenstein
Přispěvatelé: Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany, Institute for Immunodeficiency, Fakultät für Biologie = Faculty of Biology [Freiburg], Albert-Ludwigs-Universität Freiburg, Center of Chronic Immunodeficiency, University Medical Center and University of Freiburg, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute of Veterinary Pathology
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Nature Immunology
Nature Immunology, 2023, ⟨10.1038/s41590-023-01420-5⟩
Nature Immunology, 2023, 24 (3), pp.414-422. ⟨10.1038/s41590-023-01420-5⟩
ISSN: 1529-2908
1529-2916
DOI: 10.1038/s41590-023-01420-5⟩
Popis: 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 (IFNγΔKRKR) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγΔKRKR 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 IFNγΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγΔKRKR 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.
Databáze: OpenAIRE
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