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High dietary salt–induced DC activation underlies microbial dysbiosis-associated hypertension
Jane F. Ferguson, … , Muredach P. Reilly, Annet Kirabo
Jane F. Ferguson, … , Muredach P. Reilly, Annet Kirabo
Published June 4, 2019
Citation Information: JCI Insight. 2019;4(13):e126241. https://doi.org/10.1172/jci.insight.126241.
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Research Article Inflammation

High dietary salt–induced DC activation underlies microbial dysbiosis-associated hypertension

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Abstract

Excess dietary salt contributes to inflammation and hypertension via poorly understood mechanisms. Antigen-presenting cells including DCs play a key role in regulating intestinal immune homeostasis in part by surveying the gut epithelial surface for pathogens. Previously, we found that highly reactive γ-ketoaldehydes or isolevuglandins (IsoLGs) accumulate in DCs and act as neoantigens, promoting an autoimmune-like state and hypertension. We hypothesized that excess dietary salt alters the gut microbiome leading to hypertension and this is associated with increased immunogenic IsoLG adduct formation in myeloid antigen-presenting cells. To test this hypothesis, we performed fecal microbiome analysis and measured blood pressure of healthy human volunteers with salt intake above or below the American Heart Association recommendations. We also performed 16S rRNA analysis on cecal samples of mice fed normal or high-salt diets. In humans and mice, high-salt intake was associated with changes in the gut microbiome reflecting an increase in Firmicutes, Proteobacteria, and genus Prevotella bacteria. These alterations were associated with higher blood pressure in humans and predisposed mice to vascular inflammation and hypertension in response to a subpressor dose of angiotensin II. Mice fed a high-salt diet exhibited increased intestinal inflammation, including the mesenteric arterial arcade and aorta, with a marked increase in the B7 ligand CD86 and formation of IsoLG protein adducts in CD11c+ myeloid cells. Adoptive transfer of fecal material from conventionally housed high-salt diet–fed mice to germ-free mice predisposed them to increased inflammation and hypertension. These findings provide potentially novel insights into the mechanisms underlying inflammation and hypertension associated with excess dietary salt and may lead to interventions targeting the microbiome to prevent and treat this important disease.

Authors

Jane F. Ferguson, Luul A. Aden, Natalia R. Barbaro, Justin P. Van Beusecum, Liang Xiao, Alan J. Simmons, Cassandra Warden, Lejla Pasic, Lauren E. Himmel, Mary K. Washington, Frank L. Revetta, Shilin Zhao, Shivani Kumaresan, Matthew B. Scholz, Zhengzheng Tang, Guanhua Chen, Muredach P. Reilly, Annet Kirabo

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Figure 7

A high-salt diet increases formation of isolevuglandin adducts and inflammation in the mesentery and mesenteric lymph nodes of mice.

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A high-salt diet increases formation of isolevuglandin adducts and infla...
(A) Flow cytometry gating strategy to identify inflammatory cell subtypes. (B) Effect of a high-salt diet on mesenteric total CD45+ cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells. (C) Effect of high salt on CD11c+ cells, surface expression of B7 ligand CD86 and intracellular isolevuglandin formation in CD11c+ cells. (D) Flow cytometry gating strategy to identify effector memory T cell subtypes. (E) Representative flow cytometry dot plots for T cell and effector memory T cell subtypes. (F and G) Effect of high-salt feeding on total CD45+ cells, CD3+ T cells, CD4+ T cell, and CD8+ T cells and effector memory CD4+ and CD8+ T cells in the mesenteric lymph nodes (percentages and numbers are shown; *P < 0.05, **P < 0.001 using 2-tailed unpaired Student’s t tests or Mann-Whitney according to the distribution).

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