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(Journal Article) |
Cell metabolism 21 (3): 493-501 (2015)
Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense.
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
ABSTRACT
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.