5-Hydroxymethylfurfural Enhances the Antiviral Immune Response in Macrophages through the Modulation of RIG-I-Mediated Interferon Production and the JAK/STAT Signaling Pathway

Abstract

5-Hydroxymethylfurfural (5-HMF) exists in a wide range of sugar-rich foods and traditional Chinese medicines. The role of 5-HMF in antiviral innate immunity and its mechanism have not been reported previously. In this study, we reveal for the first time that 5-HMF upregulates the production of retinoic acid-inducible gene I (RIG-I)-mediated type I interferon (IFN) as a response to viral infection. IFN-β and IFN-stimulated chemokine gene expressions induced by the vesicular stomatitis virus (VSV) are upregulated in RAW264.7 cells and primary peritoneal macrophages after treatment with 5-HMF, a natural product that appears to inhibit the efficiency of viral replication. Meanwhile, 5-HMF-pretreated mice show enhanced innate antiviral immunity, increased serum levels of IFN-β, and reduced morbidity and viral loads upon infection with VSV. Thus, 5-HMF can be seen to have a positive effect on enhancing type I IFN production. Mechanistically, 5-HMF upregulates the expression of RIG-I in macrophages, resulting in an acceleration of the RIG-I signaling pathway activation. Additionally, STAT1 and STAT2 phosphorylations, along with the expression of IFN-stimulated chemokine genes induced by IFN-α/β, were also enhanced in macrophages cotreated with 5-HMF. In summary, these findings indicate that 5-HMF not only can induce type I IFN production but also can enhance IFN-JAK/STAT signaling, leading to a novel immunomodulatory mechanism against viral infection. In conclusion, our study reveals a previously unrecognized effect of 5-HMF in the antiviral innate immune response and suggests new potential of utilizing 5-HMF for controlling viral infection.

Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia: Based on serum pharmacochemistry and network pharmacology

“…It also enhanced innate antiviral immunity in mice, resulting in elevated serum IFN‐β levels and decreased morbidity and viral load after infection with vesicular stomatitis virus (VSV). It has also been shown that 5‐HMF establishes a novel immunomodulatory mechanism against viral infections by enhancing IFN‐JAK/STAT signaling and increasing the production of type I interferon (IFN) through retinoic acid‐inducible gene I (RIG‐I) 23 . PCA, a natural phenolic acid, has many beneficial properties, including antioxidant, anti‐inflammatory, neuroprotective, antibacterial, antiviral, anticancer, anti‐osteoporosis, analgesic, antiaging, metabolism regulation, hepatoprotective, and protective effects on the renal, digestive and reproductive systems 24 .…”

“…It has also been shown that 5‐HMF establishes a novel immunomodulatory mechanism against viral infections by enhancing IFN‐JAK/STAT signaling and increasing the production of type I interferon (IFN) through retinoic acid‐inducible gene I (RIG‐I). 23 PCA, a natural phenolic acid, has many beneficial properties, including antioxidant, anti‐inflammatory, neuroprotective, antibacterial, antiviral, anticancer, anti‐osteoporosis, analgesic, antiaging, metabolism regulation, hepatoprotective, and protective effects on the renal, digestive and reproductive systems. 24 PCA administration to H1N1‐infected mice prevented weight loss and mortality and reduced lung index, viral titer, immune cell infectivity, and cytokine levels.…”

5-Hydroxymethylfurfural Alleviates Inflammatory Lung Injury by Inhibiting Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation

“…Thus, it is crucial to identify novel anti-inflammatory compounds for the prevention and treatment of inflammation-relevant lung injury. 5-HMF is an active compound commonly found in sugar-rich heat-processed foods, including honey, coffee, dried fruit and fruit juices ( Shapla et al, 2018 ; Zou et al, 2021 ). Studies show that 5-HMF exerts anti-inflammatory or anti-allergic effects ( Zhao et al, 2013 ; Alizadeh et al, 2017 ), and can inhibit ROS production and the expression of inflammatory factors such as PGE2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW264.7 macrophages ( Zhao et al, 2013 ).…”

The Golgi Apparatus: A Key Player in Innate Immunity

“…This interaction initiates the assembly of complexes between TBK1 and OPTN, leading to transautophosphorylation and activation of TBK1 [83]. Subsequently, TBK1 phosphorylates interferon regulatory factor 3 (IRF3) [85], a key step in promoting type I IFN production and triggering an effective antiviral response [86].…”