NCX1 represents an ionic Na+ sensing mechanism in macrophages

Inflammation and infection can trigger local tissue Na(+)accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (M phi s) and their antimicrobial activity. Enhanced Na+-driven M phi function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na(+)sensing in M phi s remained unclear. High extracellular Na(+)levels (high salt [HS]) trigger a substantial Na(+)influx and Ca(2+)loss. Here, we show that the Na+/Ca(2+)exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na(+)influx, concomitant Ca(2+)efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na(+)and is required for amplifying inflammatory and antimicrobial M phi responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate M phi function

Cutaneous Na(+) storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense

Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection