Atopic dermatitis displays stable and dynamic skin transcriptome signatures

Background: Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as improvementunder therapy. These observations were mainly made in trials and based on microarray data. Objectives: Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry. Methods: Biopsy specimens from 59 patients with moderate-tosevere AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted. Results: Both lesional and nonlesional skin showed a stable coresignature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, T(H)17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized T(H)17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab. Conclusion: The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of T(H)17 and natural killer cell signaling.

Automated summary

Skin transcriptome studies in atopic dermatitis have shown core features of disturbed epidermal differentiation and IL-31/IL-1 signaling activation, along with type 2 inflammation, T(H)17 signaling, and natural killer cell function. IL4RA is a key dysregulated gene, and cyclosporine and dupilumab have distinct effects on the transcriptome in AD patients.