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.

Addictions and gambling are more prevalent in patients with psoriasis compared with the general population. Respective screening measures are recommended in daily practice for doctors treating psoriasis patients, and PeakPASI is suggested as a score to document patients' lifetime highest PASI. Parallel to new drug approvals and even more detailed insights into the pathomechanism of psoriasis, public health strategies and interdisciplinary approaches are essential for a general sustained psoriasis treatment.

Interface dermatitis is a characteristic histological pattern that occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different interface dermatitis positive skin diseases, lichen planus and lupus erythematosus. The shared transcriptome signature pointed toward a strong type I immune response, and biopsy-derived T cells were dominated by IFN-γ and tumor necrosis factor alpha (TNF-α) positive cells. The transcriptome of keratinocytes stimulated with IFN-γ and TNF-α correlated significantly with the shared gene regulations of lichen planus and lupus erythematosus. IFN-γ, TNF-α, or mixed supernatant of lesional T cells induced signs of keratinocyte cell death in three-dimensional skin equivalents. We detected a significantly enhanced epidermal expression of receptor-interacting-protein-kinase 3, a key regulator of necroptosis, in interface dermatitis. Phosphorylation of receptor-interacting-protein-kinase 3 and mixed lineage kinase domain like pseudokinase was induced in keratinocytes on stimulation with T-cell supernatant-an effect that was dependent on the presence of either IFN-γ or TNF-α in the T-cell supernatant. Small hairpin RNA knockdown of receptor-interacting-protein-kinase 3 prevented cell death of keratinocytes on stimulation with IFN-γ or TNF-α. In conclusion, type I immunity is associated with lichen planus and lupus erythematosus and induces keratinocyte necroptosis. These two mechanisms are potentially involved in interface dermatitis.