Skewed inflammation is associated with aberrant interleukin-37 signaling pathway in atopic dermatitis.

BACKGROUND Atopic dermatitis (AD) is a severe global burden on physical, physiological, and mental health. The role of IL-37, a fundamental inhibitor of immunity, in AD was herein explored. METHOD Serum levels of IL-37 and T helper (Th) 2-related inflammatory mediators were quantified in subjects with or without AD. The expression of IL-37 receptors was determined by flow cytometry. Proteomics was employed to explore the serum protein profile and novel biomarkers. In vitro cell model, 3D-keratinocytes mimicking skin model, and the serum of subjects with or without AD were investigated to verify the proteomic results. RESULTS AD patients were found to present with higher levels of total and specific IgE as well as Th2 inflammatory mediators compared with healthy controls (HC). IL-37 level and its receptor IL18Rɑ expression in AD patients were significantly decreased, together with increased population of eosinophils, indicating that the signaling of IL37/IL18Rɑ was dampened. In addition, proteomic analysis revealed a significantly differential protein profile of AD patients compared with HC. IL-37 showed the strongest negative correlation with involucrin, a keratinizing epithelia protein. IL-37 was verified to suppress induced involucrin expression in in vitro skin cell models. AD patients show a significantly higher serum concentration of involucrin compared with HC. Together, our results demonstrated that IL-37 plays a regulatory role in AD. Its deficiency may lead to the aberrant involucrin expression in AD. CONCLUSIONS The dysregulation of serum protein and skin disruption in AD is related to the insufficiency of IL-37 and its attenuated anti-inflammatory signaling.