Abstract
Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt (i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNβ production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNβ signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses.
Highlights
Type I IFN production and signaling in macrophages play critical roles in innate immune responses
Recent studies have highlighted the important regulatory roles of high salt in macrophages, the impact of high salt on type I interferon production and signaling have not been explored in these cells
We demonstrated that high salt promoted the production of IFN and expression of interferon-stimulated genes (ISGs) in macrophages
Summary
Salt condition mounts inflammation [17, 18] and enhances bacterial killing [19] through shifting macrophage activation into the classically activated phenotype (M1). A recent study has demonstrated that high-salt formulation of aluminum-based adjuvant strongly promotes cancer vaccineinduced immune responses and antitumor effects due to the improvement of antigen cross-presentation in dendritic cells [24]. Despite the close relationships between high salt and immune responses, it remains unknown whether high salt regulates type I interferon production and signaling in macrophages. In this study we investigated the impact of high salt on type I interferon production and signaling as well as on host defense against viral infections. We identified interferon  (IFN) as the mediator of the effects of high salt on ISGs. We explored the influence of high salt on immune sensing and signaling of mouse macrophages responding to viruses or viral nucleic acids. We further uncovered the molecular mechanisms by which high salt regulated type I interferon production and signaling in macrophages. We studied the roles of high salt in resistance to vesicular stomatitis virus (VSV) infection both in vitro and in vivo
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