3057 – HIGH SALT DIETS PROMOTE A TH17 CELL DRIVEN GUT-BONE AXIS TO REGULATE HAEMATOPOIESIS AND ATHEROSCLEROSIS

Abstract

Salt intake is often associated with increased risk of cardiovascular disease through its relationship with hypertension. However, a high salt diet (HSD) can directly modulate immune cells. We found that a HSD increases IL-17A-producing T helper (TH17) cells in the bone marrow (BM), which promotes hematopoietic stem and progenitor cells (HSPCs) mobilization into the spleen, expanding the population of atherogenic monocytes to impact atherosclerosis. Next, we wanted to explore how a HSD increases TH17 cells in the BM. As salt is first sensed in the gut, we questioned if TH¬17 cells arose from the gut to influence the BM. We placed WT mice on a normal salt diet (NSD) or a HSD for 6 weeks and discovered that a HSD promotes gut permeability, increases gut TH17 cells and causes microbial dysbiosis. To explore how the HSD-induced effects in the gut influences HSPC mobilization, we first blocked TH17 cell migration from the gut with anti-CCL20. This resulted in a reduction in TH17 cells in the BM and HSPC mobilization. We then blocked intestinal permeability using AT-1001, demonstrating that dampening permeability prevented HSD-induced HSPC mobilization. Moreover, restoring the microbiome with prebiotics increased microbial diversity, decreased gut permeability and TH17 cell abundance, which was associated with a reduction in BM TH17 cells and HSPC mobilization. Finally, to determine how dampening gut inflammation influences HSD-induced atherosclerosis, we placed Apoe-/- mice on a NSD or HSD with or without prebiotics for 12 weeks. We found that supplementing HSD-fed mice with prebiotics not only decreased TH17 cells in the gut, blood, and BM, but also prevented HSPC mobilization from the BM to the blood and spleen, thereby reducing myelopoiesis and atherosclerosis. This suggests that targeting the gut using prebiotics can reduce TH17-driven myelopoiesis and atherosclerosis. Salt intake is often associated with increased risk of cardiovascular disease through its relationship with hypertension. However, a high salt diet (HSD) can directly modulate immune cells. We found that a HSD increases IL-17A-producing T helper (TH17) cells in the bone marrow (BM), which promotes hematopoietic stem and progenitor cells (HSPCs) mobilization into the spleen, expanding the population of atherogenic monocytes to impact atherosclerosis. Next, we wanted to explore how a HSD increases TH17 cells in the BM. As salt is first sensed in the gut, we questioned if TH¬17 cells arose from the gut to influence the BM. We placed WT mice on a normal salt diet (NSD) or a HSD for 6 weeks and discovered that a HSD promotes gut permeability, increases gut TH17 cells and causes microbial dysbiosis. To explore how the HSD-induced effects in the gut influences HSPC mobilization, we first blocked TH17 cell migration from the gut with anti-CCL20. This resulted in a reduction in TH17 cells in the BM and HSPC mobilization. We then blocked intestinal permeability using AT-1001, demonstrating that dampening permeability prevented HSD-induced HSPC mobilization. Moreover, restoring the microbiome with prebiotics increased microbial diversity, decreased gut permeability and TH17 cell abundance, which was associated with a reduction in BM TH17 cells and HSPC mobilization. Finally, to determine how dampening gut inflammation influences HSD-induced atherosclerosis, we placed Apoe-/- mice on a NSD or HSD with or without prebiotics for 12 weeks. We found that supplementing HSD-fed mice with prebiotics not only decreased TH17 cells in the gut, blood, and BM, but also prevented HSPC mobilization from the BM to the blood and spleen, thereby reducing myelopoiesis and atherosclerosis. This suggests that targeting the gut using prebiotics can reduce TH17-driven myelopoiesis and atherosclerosis.