Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance

Abstract

Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt ( 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 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.

Osteoprotective action of low-salt diet requires myeloid cell–derived NFAT5

“…Increases in Na + have been demonstrated to help fight against the protozoan parasite Leishmania major (45) and against the bacterial pathogen E. coli (42,50). Recent evidence also suggests that elevation in Na + facilitates antiviral responses against vesicle stomatitis virus (51). In this report, we focused on the impact of this Na + microenvironment on the cessation of osteoclastogenesis.…”

High-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation

“…This phenomenon was consistent with the accumulation of salt found in tumour tissues. Previous studies have found that the p38/MAPK pathway regulates NFAT5 in response to high salt, further mediating cellular protective effects and activation of other signalling pathways including inflammatory responses 6,25,56 . In addition, NFAT5 has been implicated in the pathogenesis of autoimmune diseases, such as RA 27 , autoimmune type 1 diabetes (T1D) 57 and EAE 3 .…”

HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting

“…Of note, enhanced antimicrobial MΦ activity with high Na + is not restrained to anti-parasitic defenses but is also operative against E. coli [1,14]. Moreover, there is evidence that increased extracellular Na + helps in antigen degradation [15] and fighting viral infections [16,17]. In addition, elevated Na + levels prime malignant cells for apoptosis [18,19] and augment the cytotoxic potential of death receptors in cancer cells [20].…”