Sodium chloride exacerbates dextran sulfate sodium-induced colitis by tuning proinflammatory and antiinflammatory lamina propria mononuclear cells through p38/MAPK pathway in mice

ARTICLE HIGHLIGHTS

Research background

At present, most diets are characterized by high salt content. Extant studies have shown that high salt intake contributes to inflammatory bowel disease (IBD) incidence and pathogenesis. However, the mechanism underlying these effects remains unclear.

Research motivation

NaCl mediates the inflammatory effects of immune cells. Both innate and adaptive immune proinflammatory cells play important roles in IBD. Studies have shown the high salt intake promotes the activation of Th17 cells in lamina propria (LP) and exacerbates experimental colitis in mice. However, the influence of high salt content in diet on other immune cells is still unclear. The present study explored the influence of high NaCl concentration on immune cell subsets and the underlying mechanisms.

Research objectives

The aim of the present study was to determine the impact of high NaCl concentration on dextran sulfate sodium (DSS)-induced colitis in mice and explore its influence on other immune cells, such as T helper 1 cells, regulatory T cells and macrophages, while attempting to elucidate the mechanism underlying this effect.

Research methods

DSS and NaCl were used to establish a proinflammatory animal model. The immune cell subsets were detected by flow cytometry in order to determine the target cells of NaCl. Cytokines secreted by intestinal tissue were detected. In the present study, clodronate liposomes treatment was used to deplete macrophages to further delineate their vital role in the promotion of DSS-induced colitis in mice by NaCl. In cell experiments, NaCl at different concentrations acted directly on lamina propria mononuclear cells (LPMCs) and macrophages. mRNA levels of inflammation genes and p38/MAPK proteins were determined by RT-PCR and western blot, respectively.

Research results

High NaCl concentration exacerbated the DSS-induced colitis. Intestinal CD4⁺IFN-γ⁺IL-17⁺ T cells and macrophages both play crucial roles in the promotion of inflammation by NaCl in mice with colitis. NaCl promotes M1 proinflammatory gene expression in lipopolysaccharide (LPS)-activated peritoneal macrophages. High NaCl concentrations promote the up-regulation of the p38/MAPK axis in the LPS and IFN-γ-activated LPMCs.

Research conclusions

NaCl evokes both innate and adaptive immune proinflammatory cell activation in mice affected by colitis. Colitis may be promoted by high NaCl levels, by NaCl initially by acting on macrophages, pushing them towards M1 polarization. Then, M1 polarization shifts the T cell response toward proinflammatory CD4⁺IFN-γ⁺IL-17⁺ T cells. Inflammation promotion by NaCl in LPS- and IFN-γ-activated LPMCs relies on the up-regulation of the p38/MAPK axis.

Research perspectives

Although results in this study indicate that high NaCl intake can promote the inflammation in mice with DSS-induced colitis, the causality of high-salt diet and IBD still needs to be confirmed by further investigations. More clinical and experimental studies are inspired to fully clarify the role of salt in IBD.