Immune cells control skin lymphatic electrolyte homeostasis and blood pressure

Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Mueller DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J (2013)

Publication Type: Journal article

Publication year: 2013

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 123

Pages Range: 2803-15

Journal Issue: 7

DOI: 10.1172/JCI60113

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 with CRIS profile

Agnes Schröder Interdisziplinäres Zentrum für Klinische Forschung IZKF-Förderlinien Jens Titze Professur für Elektrolyt- und Kreislaufforschung

Involved external institutions

University of Bergen / Universitetet i Bergen NO Norway (NO) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Biomedicum Helsinki FI Finland (FI) Medizinische Universität Wien AT Austria (AT) Max-Rubner-Institut - Bundesforschungsinstitut für Ernährung und Lebensmittel DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Vanderbilt University US United States (USA) (US) Helsingin yliopisto / University of Helsinki FI Finland (FI)

How to cite

APA:

Wiig, H., Schröder, A., Neuhofer, W., Jantsch, J., Kopp, C., Karlsen, T.V.,... Titze, J. (2013). Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. Journal of Clinical Investigation, 123(7), 2803-15. https://dx.doi.org/10.1172/JCI60113

MLA:

Wiig, Helge, et al. "Immune cells control skin lymphatic electrolyte homeostasis and blood pressure." Journal of Clinical Investigation 123.7 (2013): 2803-15.

BibTeX: Download