Variation in Dietary Salt Intake Induces Coordinated Dynamics of Monocyte Subsets and Monocyte-Platelet Aggregates in Humans: Implications in End Organ Inflammation

Abstract

BackgroundMonocyte activation and tissue infiltration are quantitatively associated with high-salt intake induced target organ inflammation. We hypothesized that high-salt challenge would induce the expansion of CD14++CD16+ monocytes, one of the three monocyte subsets with a pro-inflammatory phenotype, that is associated with target organ inflammation in humans.Methodology/Principal FindingsA dietary intervention study was performed in 20 healthy volunteers, starting with a 3-day usual diet and followed with a 7-day high-salt diet (≥15 g NaCl/day), and a 7-day low-salt diet (≤5 g NaCl/day). The amounts of three monocyte subsets (“classical” CD14++CD16-, “intermediate” CD14++CD16+ and “non-classical” CD14+CD16++) and their associations with monocyte-platelet aggregates (MPAs) were measured by flow cytometry. Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) was used to evaluate renal hypoxia. Switching to a high-salt diet resulted in CD14++ monocyte activation and a rapid expansion of CD14++CD16+ subset and MPAs, with a reciprocal decrease in the percentages of CD14++CD16- and CD14+CD16++ subsets. In vitro study using purified CD14++ monocytes revealed that elevation in extracellular [Na+] could lead to CD14++CD16+ expansion via a ROS dependent manner. In addition, high-salt intake was associated with progressive hypoxia in the renal medulla (increased R2* signal) and enhanced urinary monocyte chemoattractant protein-1 (MCP-1) excretion, indicating a temporal and spatial correlation between CD14++CD16+ subset and renal inflammation. The above changes could be completely reversed by a low-salt diet, whereas blood pressure levels remained unchanged during dietary intervention.Conclusions/SignificanceThe present work demonstrates that short-term increases in dietary salt intake could induce the expansion of CD14++CD16+ monocytes, as well as an elevation of MPAs, which might be the underlying cellular basis of high-salt induced end organ inflammation and potential thromboembolic risk. In addition, this process seems largely unrelated to changes in blood pressure levels. This finding provides novel links between dietary salt intake, innate immunity and end organ inflammation.

Inflammation is associated to volume status in peritoneal dialysis patients

“…dietary salt intake can induce inflammation. 16 Recently, Telini et al have reported that dietary sodium restriction is associated with the attenuation of the inflammatory process, without changes in blood pressure and ECW, suggesting inhibition of a salt-induced inflammatory process. 17 Similarly, the same group has observed that dialysate sodium reduction give rise to similar results.…”

High-salt intake induced visceral adipose tissue hypoxia and its association with circulating monocyte subsets in humans

“…Moreover, our recent work also demonstrated that a high-salt diet can induce circulating monocyte pro-inflammatory activation and is associated with end-organ inflammation (14). The role of monocyte/macrophage infiltration in initiating AT hypoxia and altered insulin sensitivity has been suggested as a key pathophysiological process during obesity (2).…”

“…Flow cytometry analysis of circulating monocyte subsets was performed using a CD14-, CD16-and CD86-based protocol according to our previous work (14). Detailed methods and gating strategies are presented in Supporting Information sFigure 1.…”

“…Among the 23 participants, a total of 21 participants finished serial magnetic resonance imaging on days 3, 10, and 17 using a Phillips Intera 3.0 Tesla whole body magnetic resonance system (Philips Medical Systems, the Netherlands) with a six-channel flexible matrix coil to receive the MR signal, according to previously described methods (8,14,16,17). Coronal, axial T2*-weighted images were acquired to cover the psoas major muscle and liver.…”

“…BOLD-MRI images were analyzed based on a modified protocol from previously published work (14,18). We selected 18 consecutive center slices from the 20 slices, and at each slice position, the image stack acquired at all echo times was loaded in the ImageJ software (NIH, Bethesda, MD).…”