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

Abstract

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.

IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis

“…The poor anti-inflammatory effects observed in IL-37b+/− mice may be due to insufficient expression of IL-37b in the IL-37 heterozygous transgenic mice. In our previous study, AD patients showed a significant decrease in serum levels of IL-37 compared to healthy controls [ 29 ], in compliance with the significant reduction in IL-37 expression in skin lesions of AD patients, as revealed by other groups [ 30 , 31 ]. In parallel, IL-37 has been reported to be reduced in allergic or inflammatory diseases [ 32 , 33 , 34 ].…”

Current Understanding of IL-37 in Human Health and Disease

“…IL-37 levels in AD patients were significantly decreased, together with increased population of eosinophils (53). The serum concentration of involucrin, a keratinizing epithelia protein, in AD patients is significantly higher than that of HCs, which is related to the insufficiency of IL-37 (53). IL-37b suppresses the production of pro-inflammatory cytokines and chemokines in AD, increases autophagosome LC3B protein biogenesis and reduces the ubiquitinated protein p62 associated with autophagy through the activation of AMPK and the inhibition of mTOR (54).…”

“…The interaction between human eosinophils and dermal fibroblasts triggers allergic inflammation in atopic dermatitis (AD). IL-37 levels in AD patients were significantly decreased, together with increased population of eosinophils (53). The serum concentration of involucrin, a keratinizing epithelia protein, in AD patients is significantly higher than that of HCs, which is related to the insufficiency of IL-37 (53).…”

Integrated bioinformatic analysis of gene expression profiling data to identify combinatorial biomarkers in inflammatory skin disease

“…Gudjonsson et al reported evidence of altered Wnt signalling in the psoriatic skin 41 ; therefore, DKK1, a Wnt antagonist, can be a possible biomarker in inflammatory skin disease. The bioinformatics analysis of the proteome from the serum of AD patients demonstrated the altered landscape of immunological aberrations, and MANF was significantly increased in AD patients compared to HC 42 . These findings support the assumption that DKK1 and MANF are potential biomarkers despite the protein–gene gap.…”