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    Fever-range hyperthermia promotes cGAS-STING pathway and synergizes DMXAA-induced antiviral immunity

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    Author
    Khan, Inam Ullah
    Brooks, Gabriel
    Guo, Nina Ni
    Chen, Junsong
    Guo, Fang
    Date
    2021-01-14
    Journal
    International Journal of Hyperthermia : the Official Journal of European Society for Hyperthermic Oncology
    Publisher
    Taylor and Francis Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1080/02656736.2020.1868582
    Abstract
    Background: Fever-range hyperthermia or fever-range temperature (hereafter FRT) improves survival and shortens disease duration in microbial infections. However, the mechanisms of these beneficial effects still remain elusive. We hypothesized that FRT might enhance cell responsiveness to infections by promoting cGAS-STING signaling to cause enhanced production of IFN-β. Objective: To investigate the effect fever-range hyperthermia on cGAS-STING pathway. Methods: RAW 264.7 and cGAS-/- RAW 264.7 cells, stimulated with 5μg/ml herring testis DNA (htDNA), were heated to 39.5°C and analyzed for the expression of cGAS, STING, IFN-β, and the synthesis of cGAMP and IRF3 phosphorylation. In vivo, wild type C57BL/6J mice were subjected to whole body hyperthermia (WBH) at 39.5°C. The mice were then challenged with influenza virus and analyzed for antiviral response in term of IFN-β expression, body weight and survival. Results: We found that 39.5°C FRT upregulated the expression of cGAS and STING, and induced the synthesis of cGAMP and production of IFN-β in htDNA-transfected RAW 264.7 cells more potently as compared to 37°C. Moreover, FRT+DMXAA-treated cells were better protected from vesicular stomatitis virus (VSV)-induced cytotoxicity in vitro in contrast to the nonprotected control (no FRT and DMXAA) or DMXAA treatment alone. In vivo, FRT at 39.5°C, co-administered with DMXAA, significantly induced the expression of IFN-β, showed reduced weight loss mice and exhibited 25% more survival over the course of 14 days as compared to DMXAA treated mice 37°C. Conclusion: We conclude that fever-range hyperthermia promotes cGAS-STING pathway to cause increased expression of IFN-β and mediate its antiviral effects.
    Keyword
    DXMAA
    Fever-range hyperthermia
    IFN-β
    antiviral immunity
    cGAS-STING
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14489
    ae974a485f413a2113503eed53cd6c53
    10.1080/02656736.2020.1868582
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