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.

Jackeline Franco,John P Sundberg,Christina R Ferreira,Bartek Rajwa,Harm Hogenesch

doi:10.3390/metabo10070299

Jackeline Franco, John P Sundberg + Show 3 more

Open Access

https://doi.org/10.3390/metabo10070299

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Journal: Metabolites	Publication Date: Jul 21, 2020
Citations: 10	License type: CC BY 4.0

Affiliation: Purdue University West Lafayette, Jackson Laboratory

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.

Highlights

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease that affects people and domestic animals worldwide [1]
We identified specific changes in ceramides and fatty acids in the epidermis of female SHARPIN-deficient mice with chronic proliferative dermatitis using a novel accelerated mass spectrometry strategy, multiple reaction monitoring (MRM)-profiling [31]
Our results show that sexual dimorphism is related strongly to the relative amounts of epidermal lipids in mice, and suggest that sex-related differences species are altered at the same stage of the disease and/or by the same mechanisms in males and females [23,48]

Summary

Introduction

Atopic dermatitis (AD) is a multifactorial inflammatory skin disease that affects people and domestic animals worldwide [1]. Multiple variants (endotypes) of AD occur based on differences in the genetic background of patients, environment, immune activation pathways, and epidermal barrier status [1,2,3]. The classical AD presentation includes increased IgE serum levels, increased concentration of type 2 cytokines [4,5], and filaggrin (FLG) mutations that underlie skin barrier dysfunction [6,7,8]. Variants of AD with normal levels of serum IgE and an increase of Th22 and Th17 cytokines. Clinical assessment of disease severity and diagnosis of AD relies on subjective observation of clinical signs, which change with the chronicity of the disease phase [6,7]. Several assessment indices are used to diagnose and score the disease, but these have poor inter-observer agreement highlighting the need for molecular disease biomarkers [12,13,14,15]

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Discussion

Conclusion