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IFNγ binding to extracellular matrix prevents fatal systemic toxicity

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Item Type:Article
Title:IFNγ binding to extracellular matrix prevents fatal systemic toxicity
Creators Name:Kemna, J. and Gout, E. and Daniau, L. and Lao, J. and Weißert, K. and Ammann, S. and Kühn, R. and Richter, M. and Molenda, C. and Sporbert, A. and Zocholl, D. and Klopfleisch, R. and Lortat-Jacob, H. and Aichele, P. and Kammertoens, T. and Blankenstein, T.
Abstract: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.
Keywords:Cytokines, Extracellular Matrix, Interferon-gamma, Neoplasms, Signal Transduction, Animals, Mice
Source:Nature Immunology
Publisher:Nature Publishing Group
Page Range:414-422
Date:March 2023
Additional Information:Erratum in: Nat Immunol 24(3): 558
Official Publication:https://doi.org/10.1038/s41590-023-01420-5
PubMed:View item in PubMed

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