Abstract
Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metabolism [Cer synthases (CerS) and ceramidases (Asah1/Asah2)], which revealed augmented CerS 4, 5 and 6 and Asah1. Given the overall pro-apoptotic nature of Cer, local apoptosis was assessed, then quantified using novel morphometric measurements of cleaved caspase (Casp)-3-restricted immunofluorescence signal in skin samples. Apoptosis was induced in response to OVA. Because apoptosis may occur downstream of endoplasmic reticulum (ER) stress, we measured markers of ER stress-induced apoptosis and found elevated skin-associated CHOP protein upon OVA treatment. We previously substantiated the importance of mast cells (MC) in initiating early skin inflammation. OVA-induced Cer increase and local apoptosis were prevented in MC-deficient mice; however, they were restored following MC reconstitution. We propose that the MC/Cer axis is an essential pathogenic feature of pre-lesional AD, whose targeting may prevent disease development.
Highlights
Eczema, known as atopic dermatitis (AD), is one of the most common chronic diseases, featuring severe itch and skin lesions
We have recently shown that localized changes occur very early in response to allergic stimuli [15,23]; we sought to investigate the status of Cer at AD onset
To determine if the accumulated Cer were produced de novo, we explored the gene expression of Cer synthases (CerS)
Summary
Known as atopic dermatitis (AD), is one of the most common chronic diseases, featuring severe itch and skin lesions. The stratum corneum (SC) is the outermost layer of the epidermis that prevents water loss and protects underlying tissues from external factors including allergens and pathogens. It comprises a lipid matrix of cholesterol, free fatty acids and ceramides (Cer) [2,3,4,5]. Recent studies have highlighted the importance of Cer chain length in skin barrier dysfunction, highlighting a decrease in very long chain C24 at the expense of long-chain C16 during the chronic phase of AD [4,12,13]. The role of Cer during the early phase of AD has not yet been explored
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