Aberrant Trafficking of Intestinal Immune Cells in Salt-Sensitive Hypertension

Background: Essential hypertension is the leading risk factor for cardiovascular disease. In addition to elevated blood pressure, hypertension is characterized by an inflammatory immune response that precedes the clinical detection of organ-damage. Yet, the activation and origin of target-organ-infiltrating immune cells are not fully understood. This study takes a systems view on inflammation in hypertension and aims to investigate the extent to which the gut-associated immune cells contribute to the immune response in salt-sensitive hypertension. Methods: Immune cell trafficking from the intestine to hypertensive target-organs was analyzed using in vivo labelling of intestinal immune cells via targeted UV photoconversion in Kaede-transgenic mice. Salt-sensitive hypertension was induced in male mice by oral L-NAME pretreatment and two 3-week periods of high-salt feeding (HSD), separated by a 2-week normal-salt (NSD) wash-out phase. Hypertensive organ damage and trafficking of photolabelled cells was analyzed 5 days after photoconversion. Subsets of mice received additionally FTY720 or an oral antibiotic cocktail or Lactobacillus murinus during the second HSD-period. Results: HSD-fed mice displayed target organ damage assessed by mRNA-expression (qPCR and mRNAseq) of markers of kidney damage, inflammation and fibrosis. Intestinal immune cell trafficking was observed both in homeostasis (NSD) and disease (HSD). Infiltration of photolabelled intestinal immune cells was detected in various organs such as the spleen and kidney (flow cytometry and scRNAseq). B cells and T cells were among the major migrating populations. FTY720 strongly reduced photolabelled cells in target organs, indicating S1P-dependent immune cell trafficking. Salt-sensitive hypertension was characterized by a dysregulation of the intestinal-renal immune cell axis. Modulation of the microbiome via antibiotics or Lactobacillus murinus lead to a modulated immune cell trafficking. Conclusion: Immune cells originating from the intestine migrate and populate various organs via the S1P-axis, both in homeostasis and in an aberrant manner in salt-sensitive hypertension. Our findings provide insight into mechanisms underlying hypertension-induced organ damage and could argue for interventions targeting intestinal immune cells. Funding: Government Support – Non-U.S.