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Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes
Alexander A. Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Alexander A. Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Published July 28, 2022
Citation Information: JCI Insight. 2022;7(16):e159762. https://doi.org/10.1172/jci.insight.159762.
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Resource and Technical Advance Dermatology

Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes

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Abstract

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Authors

Alexander A. Merleev, Stephanie T. Le, Claire Alexanian, Atrin Toussi, Yixuan Xie, Alina I. Marusina, Steven M. Watkins, Forum Patel, Allison C. Billi, Julie Wiedemann, Yoshihiro Izumiya, Ashish Kumar, Ranjitha Uppala, J. Michelle Kahlenberg, Fu-Tong Liu, Iannis E. Adamopoulos, Elizabeth A. Wang, Chelsea Ma, Michelle Y. Cheng, Halani Xiong, Amanda Kirane, Guillaume Luxardi, Bogi Andersen, Lam C. Tsoi, Carlito B. Lebrilla, Johann E. Gudjonsson, Emanual Maverakis

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Figure 8

Lipid alterations in psoriasis skin.

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Lipid alterations in psoriasis skin.
(A) Abundance of epidermal lipids i...
(A) Abundance of epidermal lipids in different dermatologic diseases as determined by targeted mass spectrometry. Results are displayed as box-and-whisker plots (as described in Figure 1). Representative lipids were chosen to highlight the characteristic patterns of lipid expression in lesional psoriasis epidermis. Red, purple, and black arrows highlight the upregulation of NS ceramide Cer(d18:1/16:0) (upper left corner) in psoriasis, atopic dermatitis, and tinea corporis lesional epidermis, respectively. NS ceramide Cer(d18:1/16:0) is an example of how certain ceramides with 18-carbon sphingoid bases are upregulated in inflammatory skin. FA 24:1 illustrates the general upregulation of unsaturated fatty acids in psoriasis, and EOS ceramide ω-linoleoyloxy-Cer(d20:1/29:0) is an example of a differentially expressed EOS ceramide. (B) Additional examples illustrating the trends in ceramide expression in psoriasis lesional epidermis. Upper row presents lipid expression data from paired psoriasis lesional and nonlesional samples. Lower row presents data for psoriasis versus healthy controls. (Results for additional monitored ceramides demonstrating these same trends can be found in Supplemental Figure 7, and results for all monitored lipids can be found in Supplemental Table 5.) (C) Differential expression of EOS ceramides in psoriasis depends in part on the length of their sphingoid base. (D) Predicted alterations in ceramide synthesis in psoriasis skin based upon psoriasis-associated alterations in lipid-gene expression.

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