IL-13 Mediates Skin Lipid Abnormalities in Atopic Dermatitis

RATIONALE: Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that these changes are driven by IL-13.

METHODS: Lipid profiles from skin tape strips of 25 healthy controls, 30 AD patients, skin-specific inducible K5-tTA-IL-13 transgenic mice and control mice were analyzed by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS). Ca²⁺-differentiated human keratinocytes were stimulated with IL-4/IL-13 with or without STAT6 silencing and lipids were analyzed by LC-MS/MS. Stable isotope pulse-labeling was employed to define changes in sphingolipid metabolism in treated keratinocytes.

RESULTS: Lesional skin (stratum corneum) from AD subjects and IL-13 transgenic mice is characterized by increased proportion of a short-chain (N-14:0-24:0) NS-ceramides, sphingomyelins, and 14:0-22:0-lysophosphatidylcholines (LPC) with simultaneous decline in the proportion of corresponding long-chain species (N-26:0-32:0 sphingolipids and 24:0-30:0-LPC) when compared to healthy controls. An increase in short-chain LPC species was also observed in non-lesional AD skin. IL-4/IL-13-driven responses in Ca²⁺-differentiated human keratinocytes in vitro revealed similar changes in aforementioned sphingolipids in response to IL-4/IL-13. Pulse-labeling studies with human keratinocytes in vitro suggest that IL-4/IL-13 inhibit sphingolipid biosynthesis and also inhibit sphingomyelin/ceramide degradation. These changes are blocked by STAT6 silencing with siRNA.

CONCLUSIONS: This study confirms the link between dysregulated type 2 immune response and skin lipid abnormalities in AD skin. The similarity in lipid changes between human (AD) and mouse (IL-13-driven) skin, as well as the STAT6-controlled changes in IL-13-treated human keratinocytes in vitro strongly support the pathogenic role of IL-13 in AD skin lipid metabolism.