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Comparative Study
. 2016 Feb 5;11(2):e0148450.
doi: 10.1371/journal.pone.0148450. eCollection 2016.

Molecular and Cellular Profiling of Scalp Psoriasis Reveals Differences and Similarities Compared to Skin Psoriasis

Juan Ruano  1   2 , Mayte Suárez-Fariñas  3   4   5   6 , Avner Shemer  7 , Margeaux Oliva  8 , Emma Guttman-Yassky  3   6 , James G Krueger  6
Affiliations
Comparative Study

Molecular and Cellular Profiling of Scalp Psoriasis Reveals Differences and Similarities Compared to Skin Psoriasis

Juan Ruano et al. PLoS One. .

Abstract

Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis in other skin areas. We sought to determine the cellular and molecular phenotype of scalp psoriasis by performing a comparative analysis of scalp and skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement and 10 control subjects without psoriasis. Our results suggest that even in the scalp, psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprint were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with that of skin psoriasis, which was mainly associated with activation of TNFα/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Distribution and number of CD3+, CD11c+, DC-Lamp+ and CD83+ cells in the various compartments of the study groups.
Panels a, c, e and g show the histological pictures. Graphs b, d, f and h show the number of cells and statistical analysis. IFL, interfolicular; inFD, infundibular; LF, low follicule; Epid, epidermis; Epith, epithelium; Ors, outer root sheath; Periinf, periinfundibular area; Perifoll, perifollicular area. Cells were counted per mm2 epidermis and dermis in the IFL area. Median and ranges of log transformed values are given. Statistics: <0.05 = *; p<0.01 = **; p<0.001 = ***.
Fig 2
Fig 2. Descriptive analysis of scalp vs skin transcriptomes.
(a) Principal component analysis (PCA) was performed to reveal the internal structure of the individual transcriptomes and to best explain the variance among samples when comparing the studied areas. In our data, PCA showed a better discrimination for skin samples than for scalp biopsies. (b) Scatter plot of log2FCH of LS vs NL DEGs on skin vs scalp transcriptomes. (c) Venn diagram of LS vs NL DEGs on scalp vs skin or MAD5 transcriptomes. (d) Heat map of genomic expression differences in scalp or skin psoriasis comparing LS, NL and N samples and (e) heat map showing three clusters of genes involved in differentiation of LS/NL samples in scalp vs skin areas. (f) Clustering heatmap of GSVA estimate values for a group of immune-related gene-sets comparing LS vs NL on scalp vs skin psoriasis. Terms of the X-axis refer to several set of genes up-regulated in cell culture by addition of cytokines. Unique: when a gene set is unique for that cell-cytokines combination, and no gene appears in other gene set. Synergistic: effect due to adding two cytokines to the cell culture at the same time. Additive: effect due to adding two cytokines to the cell culture sequentially. KC: Keratinocytes; RHE: Reconstituted Epidermis; DC: Dendritic Cells; iDC: inflammatory Dendritic Cells.
Fig 3
Fig 3. Triangle plot of GSEA results.
Each panel represents NES values and p-values of GSEA analysis for LS and NL comparisons considering scalp vs skin areas for ‘psoriasis genetic print’ (a), ‘immune response’ (b, e), ‘cells biology’ (c), ‘epidermis biology’ (d), and ‘genetic regulation’ (f) gene-sets. NGS, next generation sequencing; MAD5, meta-analysis derived transcriptome of psoriasis 5; MAD3, meta-analysis derived transcriptome of psoriasis 3; SF7, Suarez-Farinas transcriptome 7; PsO, psoriasis; EDC, epidermal differentiation complex; CE, cornified envelope; KC, keratinocyte; TNFα, tumor necrosis factor alpha; IFNα, interferon α; IFNγ, interferon γ; PMBCs: peripheral blood mononucleated cells; DCs, dendritic cells; iDCs, immature dendritic cells; BDCA, blood dendritic cell antigen; Treg, regulatory T-cells; MIFT, microphthalmia-associated transcription factor; Met, methylated; RDGP, residual disease genomic profile.
Fig 4
Fig 4. Enrichment of cytokine-related inflammatory pathways (gene sets) in human psoriasis transcriptomes as compared with murine models of psoriasis.
Each panel represents NES values and p-values of GSEA analysis for LS and NL comparisons of STAT3, Tie2, and TGFβ transgene models and the imiquimod-induced model; KC, keratinocyte; TNFα, tumor necrosis factor α; IFNα, interferon α; IFNγ, interferon γ; PMBCs: peripheral blood mononucleated cells; DCs, dendritic cells; iDCs, immature dendritic cells; BDCA, blood dendritic cell antigen; Treg, regulatory T cells; KC, keratinocytes; DCs, Myeloid dendritic cells; RHE, reconstituted human epidermis. (a-d) Expression of these cytokine pathways in human psoriasis vulgaris is shown for lesional (LS) versus non lesional (NL) and for NL versus normal (N) skin and scalp. (e–k) Cytokine enrichment in the six mouse models is illustrated as follows: K14-amphiregulin (AREG) ear skin (e) and tail skin (f), IL-23 (g), K5-Stat3C (Stat-3) (h), K5-Tie2 (Tie-2) (i), K5-TGF-β1 (TGF-β) (j), and Imiquimod (k).
Fig 5
Fig 5. RT-PCR analysis of cytokine mRNA expression in scalp psoriasis.
The cytokine microenvironment in the scalp biopsies of our study groups: Lesional (LS), non lesional (NL) and normal (N) scalp biopsies. Statistics: p<0.05 = *; p<0.01 = **; p<0.001 = ***.
Fig 6
Fig 6. Keratin and immune-set gene expression profile of scalp psoriasis vs skin psoriasis, atopic dermatitis, and alopecia areata.
Average log2FCH for alopecia areata (AA), atopic dermatitis (AA), scalp psoriasis and skin psoriasis for a representative group of (a) keratin and keratin associated proteins (KRTAPs) and (b) immune-related pathways genes adjusted by region (normalized to normal scalp [AA and scalp psoriasis] or normal skin [AD and skin psoriasis].
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