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

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.

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

“…NaCl can also skew Th1 and Th17 cells to acquire Th2 cell properties on the memory T cell level, thus exploiting the plasticity of non‐Th2 cells in favor of type 2 cell responses. These effects on T cells are contingent on the acute presence of elevated concentrations of NaCl and cannot be maintained upon NaCl withdrawal . This is in accordance with a lack of epigenetic imprinting of a NaCl induced Th2 signature in contrast to its effect on epigenetic marks in macrophages .…”

“…In the skin, NaCl has previously been shown to exert immunoregulatory functions on rat macrophages with an impact on blood pressure control . Interestingly, NaCl concentrations were further elevated in skin lesions of atopic dermatitis patients in accordance with the Th2‐associated pathogenesis of this disease . It is currently unclear, whether this lesional enrichment of cutaneous sodium is associated with dietary salt intake.…”

“…Availability of tissue‐specific factors might further shape the heterogeneity and distribution of distinct T cell subsets. Recently, a role for sodium chloride (NaCl) for cytokine independent polarization of human naïve T cells into Th2 cells was identified (Fig. ).…”

“…It is currently unclear, whether this lesional enrichment of cutaneous sodium is associated with dietary salt intake. Normal sodium concentrations in unaffected skin of atopic dermatitis patients rather suggest localized events as a mechanism of lesional sodium deposition . NaCl exerts Th2 cell polarization and Th2 cell expansion through upregulation of serum‐ and glucocorticoid‐regulated kinase 1 (SGK1), which represents a downstream target of mTOR Complex 2 (mTORc2), as T cell specific deletion of the mTORC2 specific adaptor Rictor abrogates the activation of SGK1 .…”

“…This links environmental NaCl sensing with metabolic Th2 programming. SGK1 and NFAT5 were shown to upregulate GATA‐3 as well as phosphorylation of STAT6 in hypersaline conditions . NaCl can also skew Th1 and Th17 cells to acquire Th2 cell properties on the memory T cell level, thus exploiting the plasticity of non‐Th2 cells in favor of type 2 cell responses.…”