Abstract
Sodium can accumulate in the interstitium and promote inflammation through poorly defined mechanisms. Here we describe a novel pathway by which dendritic cells (DCs) are activated by increased extracellular sodium (190 mM). We show that sodium entry through the epithelial sodium channel (ENaC) and the sodium hydrogen exchanger (NHE) leads to calcium influx via the sodium calcium exchanger, activation of protein kinase C (PKC), phosphorylation of p47phox and association of p47phox with gp91phox. The assembled NADPH oxidase produces superoxide with subsequent formation of immunogenic isolevuglandin (IsoLG)-protein adducts. DCs activated by excess sodium produce increased interleukin 1β (IL-1β) and promote T cell production of cytokines IL-17A and interferon gamma (IFN-γ). When adoptively transferred into naive mice, these DCs prime hypertension in response to a sub-pressor dose of angiotensin II. These findings provide a mechanistic link between salt, inflammation and hypertension involving increased oxidative stress and IsoLG production in DCs.
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