Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis

Background: Elderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified. Objective: We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. Methods: Skin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. Results: Compared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. Conclusion: We identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.