Cutaneous Na+ Storage Strengthens the Antimicrobial Barrier Function of the Skin and Boosts Macrophage-Driven Host Defense

• DOI: 10.1016/j.cmet.2015.02.003
• Publication Date: 2015-03-03T16:45:19Z
• Authors: Jonathan Jantsch; Valentin Schatz; Diana Friedrich; Agnes Schröder; Christoph Kopp; Isabel Siegert; Andreas Maronna; David Wendelborn; Peter Linz; Katrina J. Binger; Matthias Gebhardt; Matthias Heinig; Patrick Neubert; Fabian Fischer; Stefan Teufel; Jean-Pierre David; Clemens Neufert; Alexander Cavallaro; Natalia Rakova; Christoph Küper; Franz-Xaver Beck; Wolfgang Neuhofer; Dominik N. Muller; Gerold Schuler; Michael Uder; Christian Bogdan; Friedrich C. Luft; Jens Titze
• Keywords: 0303 health sciences; NFATC Transcription Factors; Physiology; Macrophages; Sodium; Leishmaniasis, Cutaneous; Nitric Oxide Synthase Type II; Cell Biology; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Enzyme Activation; Mice; 03 medical and health sciences; Anti-Infective Agents; Animals; Humans; Molecular Biology; Leishmania major; Skin

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.