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

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 11

Analysis of epidermal lipid expression uncovers highly significant lipid-lipid expression patterns.

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Analysis of epidermal lipid expression uncovers highly significant lipid...
(A) Correlation matrix depicting every possible pairwise lipid-lipid correlation among the 351 monitored lipids, with 123,201 combinations in total. The 351 columns and rows represent the monitored lipid analytes. The intensity of the color at the intersect between a column and row represents the strength of the correlation for that particular lipid-lipid combination (positive correlation, red; negative correlation, blue; no correlation, yellow). The checkerboard pattern indicates a consistent pattern of intraclass and interclass lipid correlations. (B) Scatter plots of representative lipid-lipid correlations. Intrasubclass ceramides with the same sphingoid base and similar fatty acid moieties positively correlated with one another. For example, the AH ceramide Cer(t18:1[6OH]/20:0[2OH]) positive correlated with AH ceramide Cer(t18:1[6OH]/22:0[2OH]) (r = 0.99, FDR = 2.5 × 10–86). Likewise, interclass ceramides with the same length sphingoid base and the same or similar fatty acid moieties positively correlated with one another. Shown here, the AS ceramide Cer(d18:1/20:0[2OH]) positively correlated with AH ceramide Cer(t18:1[6OH]/22:0[2OH]) (r = 0.93, FDR = 2.9 × 10–44). Also, 18-carbon sphingoid base ceramides negatively correlated with 20- and 22-carbon sphingoid base ceramides, usually with dissimilar length fatty acids. Also shown, the NP ceramide Cer(t22:0/26:0) negatively correlated with the AH ceramide Cer(t18:1[6OH]/22:0[2OH]) (r = –0.93, FDR = 1.5 × 10–46). (C) Unsaturated fatty acids of similar length tended to positively correlate with one another. Shown here, FA 22:1 positively correlated with FA 24:1 (r = 0.95, FDR = 2.9 × 10–55). FA 24:1 (and to a lesser extent FA 22:1 and sometimes FA 20:1) positively correlated with NS(C18) and NDS(C18) ceramides. Also shown, FA 24:1 positively correlated with the NS ceramide Cer(d18:1/20:0) (r = 0.88, FDR = 2.2 × 10–33) and the NDS ceramide Cer(d18:0/20:0) (r = 0.87, FDR = 3.0 × 10–32). (D) Bar graphs illustrate the percent of ceramides that follow the patterns described in B.