Sodium Chloride Is an Ionic Checkpoint for Human TH2 Cells and Shapes the Atopic Skin Microenvironment

Julia Matthias1,2,3, Julia Maul4, Rebecca Noster3, Hanna Meinl 1,2,5, Ying-Yin Chao 1,2,5, Heiko Gerstenberg 6, Florian Jeschke 6, Gilles Gasparoni7, Anna Welle7, Jörn Walter7, Karl Nordström7, Klaus Eberhardt 8, Dennis Renisch8, Sainitin Donakonda2,9, Percy Knolle2,9, Dominik Soll1,2, Stephan Grabbe10, Natalie Garzorz-Stark11, Kilian Eyerich11, Tilo Biedermann11, Dirk Baumjohann4, Christina E Zielinski 12,2,3,5

  1. Institute of Virology, Technical University of Munich, 81675 Munich, Germany.
  2. German Center for Infection Research, Partner Site Munich, Munich, Germany.
  3. Department of Dermatology, Unit Cellular Immunoregulation, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
  4. Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
  5. TranslaTUM, Technical University of Munich, 81675 Munich, Germany.
  6. ZWE FRM II, Technical University of Munich, 85748 Garching, Germany.
  7. Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
  8. Institute for Nuclear Chemistry, Johannes Gutenberg-Universität Mainz and Helmholtz Institute Mainz, 55252 Mainz, Germany.
  9. Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, 81675 Munich, Germany.
  10. Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
  11. Department of Dermatology and Allergology, Technical University of Munich; Clinical Unit Allergology (EKA), Helmholtz Zentrum München; German Research Centre for Environmental Health GmbH, 80802 Munich, Germany.
  12. Institute of Virology, Technical University of Munich, 81675 Munich, Germany. christina.zielinski@tum.de. 

Abstract

The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (TH17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes TH2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-γ (IFN-γ) production in memory T cells. It diverted alternative T cell fates into the TH2 cell phenotype and also induced de novo TH2 cell polarization from naïve T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated TH2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce TH2 cell responses, the orchestrators of atopic diseases.

Presented by Julia Matthias

Immunology & Microbiology, MedicineNicholas Liao2019-02 (Feb)