Sodium chloride is an ionic checkpoint for human T H 2 cells and shapes the atopic skin microenvironment

Sci Transl Med. 2019 Feb 20;11(480):eaau0683. doi: 10.1126/scitranslmed.aau0683.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Polarity / drug effects
  • Cellular Microenvironment* / drug effects
  • Cytokines / metabolism
  • Dermatitis, Atopic / pathology
  • HEK293 Cells
  • Humans
  • Immunologic Memory / drug effects
  • Ions
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Skin / cytology*
  • Skin / drug effects
  • Sodium / metabolism
  • Sodium Chloride / pharmacology*
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Transcriptional Activation / drug effects

Substances

  • Cytokines
  • Ions
  • NFATC Transcription Factors
  • Sodium Chloride
  • Sodium