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Spatial transcriptomics combined with single-cell RNA-sequencing unravels the complex inflammatory cell network in atopic dermatitis [ST]

ABSTRACT: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease with complex pathogenesis. Using spatial and single-cell transcriptomics of whole skin biopsy and suction blister material, we investigated the cellular and molecular features of the leukocyte-infiltrated area in AD. We identified unique clusters of fibroblasts, dendritic cells, macrophages, and T cells in the lesional AD skin and molecular interactions between these cells. The leukocyte-infiltrated areas in lesional AD skin showed upregulation of COL6A5, COL4A1, TNC, IL32, CCL19 in COL18A1-expressing fibroblasts. Additionally, M2 macrophages expressed CCL13 and CCL18 in the same localization. Ligand–receptor interaction analysis of the spatial transcriptome identified a neighboring infiltration and interaction between activated COL18A1-expressing fibroblasts, activated CCL13- and CCL18-expressing M2 macrophages, CCR7- and LAMP3-expressing DCs, and T cells. As observed in skin lesions, serum levels of TNC and CCL18 were significantly elevated in AD and correlated with clinical disease severity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197023 | GEO | 2023/06/14

REPOSITORIES: GEO

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Project description:Background: Dupilumab is an IL-4 receptor a mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and 210.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and Th17/Th22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P 5 .001; week 16, P 5 .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen- specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor a blockade significantly and progressively improved disease activity, suppressed cellular/ molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities. (J Allergy Clin Immunol 2019;143:155-72.)