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- W4313365814 abstract "Abstract Introduction High dietary salt intake is a risk factor for hypertension and autoimmune diseases. Recent studies show high salt intake can result in high-concentration interstitial salt accumulation. In macrophages, similar concentrations induce pro-inflammatory gene expression and amplify activation by LPS. African Americans, a notably salt-sensitive population, have an exclusively high frequency (~23%) for a missense single nucleotide polymorphism (SNP) in cytochrome b5 reductase 3 (CYB5R3), an enzyme important for oxidative stress resistance. We have shown this SNP, T117S, decreases enzymatic activity. Given macrophages’ sizable productive capacity for reactive oxygen species (ROS), we hypothesize T117S expression amplifies salt-mediated pro-inflammatory gene expression and ROS production. Results Culture of bone marrow-derived macrophages (BMDMs) from WT or T117S-expressing mice in high salt medium (+51mM NaCl) increased expression of pro-inflammatory genes iNOS, IL-6, and IL-1β. However, the increase was significantly greater in T117S BMDMs. High salt also increased hydrogen peroxide (H2O2) production in both groups, but more so in T117S BMDMs. Of note, pretreatment with inhibitors targeting p38, a MAP kinase involved in the inflammatory response, or NOX2, the major macrophage superoxide source, ablated salt-mediated H2O2 production in both groups. Conclusions We show presence of loss-of-function variant T117S CYB5R3 in macrophages enhances salt-mediated pro-inflammatory gene expression and ROS production in a p38 and NOX2-dependent manner. This suggests CYB5R3 may be involved in the response to high salt and raises the possibility that T117S carriers may have an exacerbated response to high salt intake." @default.
- W4313365814 created "2023-01-06" @default.
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- W4313365814 date "2019-05-01" @default.
- W4313365814 modified "2023-09-26" @default.
- W4313365814 title "A loss-of-function single nucleotide polymorphism in cytochrome b5 reductase 3 amplifies the response of bone marrow-derived macrophages to high salt" @default.
- W4313365814 doi "https://doi.org/10.4049/jimmunol.202.supp.59.7" @default.
- W4313365814 hasPublicationYear "2019" @default.
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