Lipidomic Profiling of the Epidermis in a Mouse Model of Dermatitis Reveals Sexual Dimorphism and Changes in Lipid Composition before the Onset of Clinical Disease

Abstract

Atopic dermatitis (AD) is a multifactorial disease associated with alterations in lipid composition and organization in the epidermis. Multiple variants of AD exist with different outcomes in response to therapies. The evaluation of disease progression and response to treatment are observational assessments with poor inter-observer agreement highlighting the need for molecular markers. SHARPIN-deficient mice (Sharpincpdm) spontaneously develop chronic proliferative dermatitis with features similar to AD in humans. To study the changes in the epidermal lipid-content during disease progression, we tested 72 epidermis samples from three groups (5-, 7-, and 10-weeks old) of cpdm mice and their WT littermates. An agnostic mass-spectrometry strategy for biomarker discovery termed multiple-reaction monitoring (MRM)-profiling was used to detect and monitor 1,030 lipid ions present in the epidermis samples. In order to select the most relevant ions, we utilized a two-tiered filter/wrapper feature-selection strategy. Lipid categories were compressed, and an elastic-net classifier was used to rank and identify the most predictive lipid categories for sex, phenotype, and disease stages of cpdm mice. The model accurately classified the samples based on phospholipids, cholesteryl esters, acylcarnitines, and sphingolipids, demonstrating that disease progression cannot be defined by one single lipid or lipid category.

Local and Systemic Changes in Lipid Profile as Potential Biomarkers for Canine Atopic Dermatitis

“…This procedure yielded sufficient material for lipid extractions and mass-spectrometry analysis. The specimens were analyzed by a direct sample infusion high-throughput lipidomics approach, as previously described for mice [ 25 , 26 ].…”

“…The lipid changes in the skin of atopic dogs were notably dependent on sex. We previously reported sexual dimorphism of skin lipids in a mouse model of dermatitis with significant effects on sphingolipids and phospholipids [ 26 ]. Here, we found that the relative amounts of lipids were also linked to the sex of the dogs; some lipids, specifically sphingolipids, CEs, and PLs, were affected differently by AD in males and in females.…”

“…In skin swabs from lesional CAD skin, relative amounts of long-chain acylcarnitines were increased compared to controls. Dysregulation of acylcarnitines has also been reported in human AD and in a mouse model [ 25 , 26 , 45 ]. Elevated long-chain acylcarnitines can play a proinflammatory role in disease by activating the JNK/ERK/p38 MAPK stress pathways [ 46 ] and triggering cellular stress [ 46 , 47 ].…”

“…Cholesterol is one of the major lipid components of skin and is fundamental to the epidermal lipid barrier function [ 50 ], but a previous analysis did not show differences in atopic dogs versus controls [ 20 ]. In our mouse model, CEs were identified as one of the most important lipid categories for the classification of disease progression [ 26 ].…”

“…Therefore, the development of a rapid method that allows repeated testing before and during treatment to evaluate the changes in skin lipid composition and correlations with severity score is needed. While previous reports of lipid changes in CAD used targeted approaches based on previous knowledge, we recently described the development and utility of a nontargeted lipidomics approach, called multiple reaction monitoring (MRM) profiling, to investigate changes in the epidermal lipid composition in a mouse model of atopic dermatitis [ 25 , 26 ]. This method allows for rapid identification of a sample’s lipid fingerprint in a high-throughput manner with minimal sample preparation and a straightforward data-processing workflow.…”