Immune cells control skin lymphatic electrolyte homeostasis and blood pressure
Helge Wiig, … , Kari Alitalo, Jens Titze
Helge Wiig, … , Kari Alitalo, Jens Titze
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):2803-2815. https://doi.org/10.1172/JCI60113.
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Research Article Immunology

Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

Abstract

The skin interstitium sequesters excess Na+ and Cl– in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl– accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl–, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure–regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3–mediated modification of cutaneous lymphatic capillary function.

Authors

Helge Wiig, Agnes Schröder, Wolfgang Neuhofer, Jonathan Jantsch, Christoph Kopp, Tine V. Karlsen, Michael Boschmann, Jennifer Goss, Maija Bry, Natalia Rakova, Anke Dahlmann, Sven Brenner, Olav Tenstad, Harri Nurmi, Eero Mervaala, Hubertus Wagner, Franz-Xaver Beck, Dominik N. Müller, Dontscho Kerjaschki, Friedrich C. Luft, David G. Harrison, Kari Alitalo, Jens Titze

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Figure 3

Relationship among Na+ and Cl– accumulation, water retention, MAP, and unmeasured anions in mice without and with mF4-31c1 treatment.

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Relationship among Na+ and Cl– accumulation, water retention, MAP, and u...
Relationship between (A) Cl– accumulation and (B) Na+ accumulation in the skin and MAP in control and in mF4-31c1–treated mice fed a HSD. Elevated blood pressure with anti-VEGFR3 treatment was paralleled by increased skin Cl– content but not with increased skin Na+ content. (C) Skin Na+ content, skin Cl– content, and Cl–-to-Na+ ratio in the mice. With HSD, blockade of cutaneous lymphatic capillary density by mF4-31c1 treatment selectively increased skin Cl– content. (D) Relationship between skin Na+ (orange) and Cl– (blue) accumulation and skin water content in control mice and in mF4-31c1–treated mice fed HSD. Increasing skin Na+ or Cl– content increased skin water. However, the skin Cl–-to-water ratio was shifted to the right with mF4-31c1 treatment (0.035 ± 0.006 mmol/ml [control HSD] versus 0.050 ± 0.010 mmol/ml [HSD plus mF4-31c1]; P < 0.05), indicating a reduction in the gap between skin Na+ and Cl– content, which represents unmeasured anionic osmolytes. rSKNa+, skin Na+ content relative to DW; rSKW, skin water content relative to DW. *P < 0.05 versus LSD WT; †P < 0.05 versus LSD plus mF4-31c1; ‡P < 0.05 versus HSD WT.