Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension

• Published in: Cell reports (Cambridge) 2017-10, Vol.21 (4), p.1009-1020
• Main Authors: Barbaro, Natalia R., Foss, Jason D., Kryshtal, Dmytro O., Tsyba, Nikita, Kumaresan, Shivani, Xiao, Liang, Mernaugh, Raymond L., Itani, Hana A., Loperena, Roxana, Chen, Wei, Dikalov, Sergey, Titze, Jens M., Knollmann, Bjorn C., Harrison, David G., Kirabo, Annet
• Format: Article
• Language: English
• Subjects: amiloride; calcium; dendritic cells; ENaC; hypertension; isolevuglandins; NADPH oxidase; oxidative stress; sodium chloride
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.10.002

Sodium accumulates in the interstitium and promotes inflammation through poorly defined mechanisms. We describe a pathway by which sodium enters dendritic cells (DCs) through amiloride-sensitive channels including the alpha and gamma subunits of the epithelial sodium channel and the sodium hydrogen exchanger 1. This 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. [Display omitted] •Increased extracellular sodium is transported into DCs by amiloride-sensitive channels•Sodium is exchanged for calcium, activating O2·– formation by the NADPH oxidase•Enhanced O2·– in DCs leads to formation of isolevuglandin protein adducts•Salt-stimulated DCs produce pro-inflammatory cytokines and drive T cell activation Barbaro et al. describe a pathway by which increased extracellular sodium activates dendritic cells. This pathway potentially explains the link between excessive salt intake, inflammation, and high blood pressure.