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.
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Institute of Clinical Microbiology and Hygiene, Universitätsklinikum Regensburg and Universität Regensburg, Regensburg, Germany. Electronic address: Jonathan.Jantsch@ukr.de.
Jonathan
J
Jantsch
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Institute of Clinical Microbiology and Hygiene, Universitätsklinikum Regensburg and Universität Regensburg, Regensburg, Germany.
Valentin
V
Schatz
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Diana
D
Friedrich
Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Agnes
A
Schröder
Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Christoph
C
Kopp
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Isabel
I
Siegert
Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Andreas
A
Maronna
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
David
D
Wendelborn
Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Peter
P
Linz
Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin Germany.
Katrina J
KJ
Binger
Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin Germany.
Matthias
M
Gebhardt
Max-Delbrück Center for Molecular Medicine, Berlin Germany; Department of Computational Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Matthias
M
Heinig
Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Patrick
P
Neubert
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Fabian
F
Fischer
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany; Institute for Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Stefan
S
Teufel
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany; Institute for Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jean-Pierre
JP
David
Department of Internal Medicine 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg.
Clemens
C
Neufert
Department of Radiology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Alexander
A
Cavallaro
Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
Natalia
N
Rakova
Department of Physiology, Ludwig-Maximilians-Universität München, Munich, Germany.
Christoph
C
Küper
Department of Physiology, Ludwig-Maximilians-Universität München, Munich, Germany.
Franz-Xaver
FX
Beck
V. Medical Clinic, University Hospital Mannheim, Mannheim, Germany.
Wolfgang
W
Neuhofer
Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany; Max-Delbrück Center for Molecular Medicine, Berlin Germany.
Dominik N
DN
Muller
Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Gerold
G
Schuler
Department of Radiology, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany.
Michael
M
Uder
Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Christian
C
Bogdan
Experimental and Clinical Research Center (ECRC), an institutional cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany; Divison of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Friedrich C
FC
Luft
Interdisciplinary Center for Clinical Research and Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Germany; Divison of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Jens
J
Titze
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D018320:Leishmania major / Q000187:drug effects; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000890:Anti-Infective Agents; D050778:NFATC Transcription Factors; D009569:Nitric Oxide; D012964:Sodium; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases