Lipid abnormalities in atopic skin are driven by type 2 cytokines

Abstract

Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that hyperactivated type 2 immune response alters AD skin lipid metabolism. We have analyzed stratum corneum lipids from nonlesional and lesional skin of AD subjects and IL-13 skin-specific Tg mice. We also directly examined the effects of IL-4/IL-13 on human keratinocytes in vitro. Mass spectrometric analysis of lesional stratum corneum from AD subjects and IL-13 Tg mice revealed an increased proportion of short-chain (N-14:0 to N-24:0) NS ceramides, sphingomyelins, and 14:0-22:0 lysophosphatidylcholines (14:0-22:0 LPC) with a simultaneous decline in the proportion of corresponding long-chain species (N-26:0 to N-32:0 sphingolipids and 24:0-30:0 LPC) when compared with healthy controls. An increase in short-chain LPC species was also observed in nonlesional AD skin. Similar changes were observed in IL-4/IL-13-driven responses in Ca2+-differentiated human keratinocytes in vitro, all being blocked by STAT6 silencing with siRNA. RNA sequencing analysis performed on stratum corneum of AD as compared with healthy subjects identified decreased expression of fatty acid elongases ELOVL3 and ELOVL6 that contributed to observed changes in atopic skin lipids. IL-4/IL-13 also inhibited ELOVL3 and ELOVL6 expression in keratinocyte cultures in a STAT6-dependent manner. Downregulation of ELOVL3/ELOVL6 expression in keratinocytes by siRNA decreased the proportion of long-chain fatty acids globally and in sphingolipids. Thus, our data strongly support the pathogenic role of type 2 immune activation in AD skin lipid metabolism.

Identification of genes mediating branched chain fatty acid elongation

“…ELOVL3‐ablated mice showed skin dysfunction and no obvious fatty acid with more than 20 carbons . Both ELOVL3 and ELOVL6 are downregulated in the stratum corneum of atopic dermatitis patients, which had significant effects on the proportion of skin lipids, especially long‐chain fatty acids . Human skin sebum is unique in its fatty acid profile, with the highest monounsaturated being sapienic acid (16:1n‐10) produced by action of FADS2 on 16:0 .…”

First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis

“…PC and PE are lipids known to enhance barrier function, provide direct and indirect protection against S. aureus, and modulate skin immunity (17,(31)(32)(33)(34). Furthermore, while the bioactivities of PC and PE with these specific acyl chains have not been assessed, recent studies have demonstrated that abnormalities in skin lipid content and metabolism are strongly associated with AD (35,36). Taken together with our clinical findings, these data suggest that repairing the strain-level dysbiosis in R. mucosa in patients with AD could R. mucosa growth is impacted by environmental exposures.…”

Moisturizers versus Current and Next-Generation Barrier Repair Therapy for the Management of Atopic Dermatitis

“…2). Th2 cytokines further compromise the barrier by downregulating the synthesis of: (i) epidermal structural proteins [19], (ii) tight-junction proteins [20], (iii) ceramides [21], (iv) fatty acid elongases [22], and (v) a key antimicrobial peptide, LL-37 [23]. Hence, the initial outside-to-inside cytokine cascade in AD quickly morphs into an “outside-to-inside back to outside” vicious circle [24].…”