The influence of a high salt diet on haematopoietic stem cell mobilisation via TH17/IL-17 signalling pathway.

A high salt diet (HSD) has been linked to an increase in atherosclerotic cardiovascular disease (CVD), which remains the leading cause of death worldwide. The link between salt and CVD has been associated with hypertension, however, this has recently become controversial. Preliminary data from our laboratory has shown that a HSD increases atherosclerosis via an immune cell dependent pathway. A HSD increased TH17 cells in the bone marrow (BM) which promoted haematopoietic stem and progenitor cell (HSPC) migration out of the BM and into the spleen. In the spleen, HSPCs differentiated into monocytes that contributed to atherosclerotic plaque formation. However, the mechanism as to how TH17 cells promote HSPC mobilisation in the setting of a HSD remains unknown. Studies have shown that BM niche cells can regulate the movement of HSPCs in the BM. Thus, we aimed to determine how TH17 cells may be causing HSPC mobilisation via BM niche remodelling in the setting of a HSD.Wild type (WT) mice were placed on a HSD for 6 weeks and BM niche cells were measured via flow cytometry and single cell RNA sequencing. CD4cre/+Ranklfl/fl or Leprcre/+Il17rfl/fl mice were also placed on a HSD for 6 weeks before flow cytometry was used to measure TH17 cell and HSPC abundance in the blood and BM along with niche cells.Our results showed that a HSD increases TH17 cells in blood and BM while causing HSPC mobilisation out of the BM. We showed that key BM niche cells such as LepR+ MSCs, cells and BM endothelial cells (ECs) decreased with a HSD. Analyses of BM niche cells revealed that IL17 receptor (R) was present in LepR+ MSCs. Furthermore, a HSD downregulated genes associated with vascular/ EC maintenance pathways in LepR+ MSCs. Deleting IL17R from LepR+ MSCs prevented HSD-induced HSPC mobilisation. This indicates that TH17 cells in the BM signals4through LepR+ MSCs to possibly reduce EC maintenance, which allowed HSPCs to exit out of the BM.