Abstract
Infection and inflammation can augment local Na+ abundance. These increases in local Na+ levels boost proinflammatory and antimicrobial macrophage activity and can favor polarization of T cells towards a proinflammatory Th17 phenotype. Although neutrophils play an important role in fighting intruding invaders, the impact of increased Na+ on the antimicrobial activity of neutrophils remains elusive. Here we show that, in neutrophils, increases in Na+ (high salt, HS) impair the ability of human and murine neutrophils to eliminate Escherichia coli and Staphylococcus aureus. High salt caused reduced spontaneous movement, degranulation and impaired production of reactive oxygen species (ROS) while leaving neutrophil viability unchanged. High salt enhanced the activity of the p38 mitogen-activated protein kinase (p38/MAPK) and increased the interleukin (IL)-8 release in a p38/MAPK-dependent manner. Whereas inhibition of p38/MAPK did not result in improved neutrophil defense, pharmacological blockade of the phagocyte oxidase (PHOX) or its genetic ablation mimicked the impaired antimicrobial activity detected under high salt conditions. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) overcame high salt-induced impairment in ROS production and restored antimicrobial activity of neutrophils. Hence, we conclude that high salt-impaired PHOX activity results in diminished antimicrobial activity. Our findings suggest that increases in local Na+ represent an ionic checkpoint that prevents excessive ROS production of neutrophils, which decreases their antimicrobial potential and could potentially curtail ROS-mediated tissue damage.
Highlights
High salt diets [1, 2], renal impairment [3,4,5,6], inflammation, and infection [7,8,9,10,11] can induce Na+ accumulation in skin tissues that can be simulated by addition of approximately 40 mM NaCl to standard cell culture media (= high salt condition, HS) [2, 8, 12, 13]
HS boosted antimicrobial activity of murine peritoneal macrophages and diminished the bactericidal activity of murine peritoneal elicited neutrophils. In accordance with these findings obtained from murine cells, HS augmented the antibacterial activity of human peripheral blood mononuclear cells (PBMC; Figure 1E) and, again, decreased the antibacterial activity of human polymorphonuclear leukocytes (PMN) isolated from peripheral blood (Figure 1F)
We demonstrate that a Na+-rich environment curtails the expression of activation markers, spontaneous movement, and reactive oxygen species (ROS) production of PMN upon exposure to bacteria and bacterial products which leads to diminished antimicrobial capacities of PMN
Summary
High salt diets [1, 2], renal impairment [3,4,5,6], inflammation, and infection [7,8,9,10,11] can induce Na+ accumulation in skin tissues that can be simulated by addition of approximately 40 mM NaCl to standard cell culture media (= high salt condition, HS) [2, 8, 12, 13]. HS in combination with inflammatory stimuli leads to enhanced proinflammatory activation and increased antimicrobial capacity [8, 12, 13, 24, 25], while limiting their regulatory features [26,27,28,29] This HS-boosted proinflammatory macrophage activation requires osmoprotective signaling involving the mitogenactivated protein kinase (MAPK) p38 and the transcription factor ‘nuclear factor of activated T cells 5’ (NFAT5/TonEBP), an emerging modulator in immunity [reviewed in: [30, 31]]. This signaling circuit is crucial in renal defenses against uropathogenic Escherichia coli [UPEC, [32]] under regular diet conditions as well as in cutaneous macrophage-driven antimicrobial responses against the protozoan parasite Leishmania major under experimental HS diet [8]
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