Children with atopic dermatitis show increased activity of β‐glucocerebrosidase and stratum corneum levels of glucosylcholesterol that are strongly related to the local cytokine milieu

Abstract

Summary Background Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), β‐glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD. Objectives To investigate GBA activity in the SC of children with AD before and after topical corticosteroid therapy and to compare it with healthy controls; to determine SC levels of GlcCER‐ and CER‐containing hydroxysphingosine base (GlcCER[H] and CER[H], respectively) and GlcChol; and to relate them to disease severity, skin barrier function and the local cytokine milieu. Methods Lipid markers and cytokines of innate, T helper 1 and T helper 2 immunity were determined in SC collected from healthy children and from clinically unaffected skin of children with AD, before and after 6 weeks of therapy with topical corticosteroids. AD severity was assessed by Scoring Atopic Dermatitis and skin barrier function by transepidermal water loss (TEWL). Results Baseline GBA activity and GlcChol levels were increased in children with AD but declined after therapy. CER[H] levels and the CER[H] to GlcCER[H] ratio were increased in AD. GBA activity and GlcChol correlated with TEWL and levels of multiple cytokines, especially interleukin‐1α and interleukin‐18. GlcChol was strongly associated with disease severity. Conclusions We show increased GBA activity and levels of GlcChol in AD. Our data suggest an important role of inflammation in disturbed lipid processing. GBA activity or GlcChol might be useful biomarkers in the monitoring of therapeutic responses in AD. What is already known about this topic? Patients with atopic dermatitis (AD) have a reduced skin barrier, mainly caused by altered lipid organization. The mechanisms underlying these lipid anomalies are not fully understood but likely reflect both genetic abnormalities in AD skin and the local cutaneous inflammatory environment. What does this study add? We show increased activity of the ceramide‐generating enzyme β‐glucocerebrosidase in AD. Activity of this enzyme was correlated with the local cytokine milieu and declined after local corticosteroid therapy. We show that glucosylcholesterol levels in the stratum corneum are increased in AD. The function of glucosylcholesterol and the physiological consequences of increased levels are not clear yet; however, its levels were strongly correlated with skin barrier function: high transepidermal water loss strongly correlated with high levels of glucosylcholesterol. What is the translational message? Correction of cutaneous inflammation largely restores alterations in lipid metabolism in the stratum corneum of infants with AD.

Epidermal biomarkers of the skin barrier in atopic and contact dermatitis

“…This is not unexpected, considering that AD is characterized by a compromised skin barrier and dry skin, both of which are influenced by the composition and organization of intercellular lipid matrix as well as the presence on hygroscopic NMF in the SC. [1][2][3] A broad range of lipid biomarkers, such as the (relative) composition of sphingoid bases (SB's), 7 specific lipid classes or their relative composition 8,11,71 and enzymes involved in lipid biosynthesis [18][19][20] showed a strong correlation with the skin barrier function. The application of comprehensive lipidomic analysis has enabled progress in lipid research, revealing that not only lipid (sub)classes but also the carbon chain length in FFA and CER may influence skin barrier function.…”

“…18 Kezic et al found increased activity of β-glucocerebrosidase (GBA) and elevated levels of its enzymatic product glucosylcholesterol (GlcChol) in the scTS of patients with AD. 19 Both GBA activity and GlcChol levels were correlated with TEWL and the levels of proinflammatory IL-1 cytokines. Importantly, GBA activity and GlcChol levels normalized following corticosteroid therapy, suggesting their potential as biomarkers for monitoring therapeutic responses in AD.…”

“…Importantly, GBA activity and GlcChol levels normalized following corticosteroid therapy, suggesting their potential as biomarkers for monitoring therapeutic responses in AD. 19 Another lipid enzyme that showed significant association with TEWL was ceramide synthase 4 (CERS 4). The gene expression level of CERS 4 in this study was determined from skin biopsy.…”

Skin biomarkers predict development of atopic dermatitis in infancy

“…Free SBs and their CERs were determined in a 2‐step procedure which is described in detail elsewhere 21 . Briefly, free SBs were separated from CERs by extraction with methanol:chloroform:ammonium formate buffer, yielding CERs in the lower phase and free SBs in the upper phase 22 .…”

“…Free SBs and their CERs were determined in a 2-step procedure which is described in detail elsewhere. 21 Briefly, free SBs were separated from CERs by extraction with methanol:chloroform:ammonium formate buffer, yielding CERs in the lower phase and free SBs in the upper phase. 22 The CERs in the lower phase were subsequently deacylated to corresponding SBs by use of microwave-assisted hydrolysis in methanolic NaOH.…”