Comparative transcriptomic analyses of atopic dermatitis and psoriasis reveal shared neutrophilic inflammation

Abstract

Background: Atopic dermatitis (AD) and psoriasis are common inflammatory diseases canonically described as involving distinct T(H) polarization and granulocytic infiltration. Acute AD lesions are associated with T(H)2 and eosinophilic inflammation, whereas psoriatic lesions are associated with T(H)1/T(H)17 and neutrophilic inflammation. Despite intensive investigation, these pathways remain incompletely understood in vivo in human subjects.

Objective: Using AD and psoriatic lesional skin as exemplar T(H)2 and T(H)1/T(H)17 diseased tissue, we sought to clarify common and unique molecular and pathophysiologic features in inflamed skin with different types of inflammatory polarization.

Methods: We conducted gene expression microarray analyses to identify distinct and commonly dysregulated expression in AD (based on Hanifin and Rajka criteria) and psoriatic lesions. We defined gene sets (GSs) as comprising genes encoding cytokines, chemokines, and growth factors that were uniquely or jointly dysregulated in patients with AD and those with psoriasis and calculated aggregate GS expression scores for lesional skin of patients with these dermatoses and healthy control skin.

Results: The atopic dermatitis gene set (AD-GS) score correlated with systemic and local measures of allergic inflammation, including serum IgE levels, blood eosinophil counts, and tissue eosinophil counts. Unexpectedly, genes encoding neutrophil chemoattractants among the common GS were highly expressed in AD lesional skin. Hematoxylin and eosin and immunohistochemical analyses showed the numbers of neutrophils in AD lesional skin were comparable with those in psoriatic lesional skin, and both were correlated with the extent of expression of neutrophil chemoattractant genes.

Conclusion: These data are evidence that neutrophilic inflammation is a feature of lesional AD pathology comorbid with allergic inflammation.

Fig 1. Comparative expression analysis of cytokines, chemokines, and growth factors (CCGf) defines gene sets

T-statistics of within disease lesional versus non-lesion comparisons are depicted by scatter plot. Atopic dermatitis gene set (AD-GS; red) and psoriasis (Ps)-GS (blue) comprise unique and opposingly differentially expressed genes (purple). Commonly and not differentially expressed (NOT DE) genes are represented by green and gray symbols, respectively.

Fig 2. Atopic Dermatitis-Gene Set

A, Genes comprising AD-GS are represented by expression heatmap, organized by PCA factors. Columns (samples) are arranged by PC1 score. Rows (genes) are organized by PC1 loadings. B, PC1 significantly correlates with serum IgE, C, blood eosinophils and D, biopsy eosinophils.

Fig 3. Psoriasis-gene set expression

Summary statistics (-log₁₀ false discovery rates and fold-change direction) of moderated paired t-tests of lesional psoriasis versus non-lesional psoriasis is plotted by annotated stripchart for all 217 CCGf’s. Ps-GS genes, which are all differentially expressed with false discovery rates < 0.05 are annotated.

Fig 4. Common-gene set expression signature correlates with blood neutrophil count

A Genes comprising C-GS are represented by expression heatmap, organized by PCA factors. Columns (samples) are arranged by PC1 score. Rows (genes) are organized by PC1 loadings. Missing expression values are represented in white. B PC1 significantly correlates with blood neutrophil count.

Fig 5. Common-gene set expression signature correlates with neutrophil enumeration by histology

A Detection of neutrophil elastase-2, lipocalin-2, and myeloperoxidase by immunohistochemistry (IHC), and H&E in representative atopic dermatitis lesional skin without excoriations from different individuals. B Cell counts for atopic dermatitis (AD) and psoriasis (Ps) lesions. C Scatterplot matrix of biopsy neutrophil indicators and C-GS PC1 score (all pairwise comparisons, p<0.05).