The epidermal immune microenvironment plays a dominant role in psoriasis development, as revealed by mass cytometry.

Psoriasis is a common chronic inflammatory skin disease. The diversity and heterogeneity of immune cells in human skin have been studied in recent years, but the spatial distribution of immune cells at the single-cell level in the human psoriatic epidermis and dermis remains unclear. In this study, we mapped psoriatic skin immune cells from paired lesional, perilesional, and nonlesional skin samples using mass cytometry. Phenotypic dendritic cells (DCs) were found in the psoriatic epidermis and dermis. Psoriatic dermal CD1cCD11b cDC2s migrated to the epidermis in the perilesional skin during the preinitiation stage. CD1cCD11b cDC2s rapidly replaced EpCAMCD11c LC cells and initiated inflammation. Simultaneously, CD207CD11c LC and CD5 T cells accumulated in the psoriatic epidermis and orchestrated epidermal inflammation in psoriasis. The immune cell pool in the psoriatic dermis primarily included APCs and T cells. However, unlike that in the dermis, the epidermal immune environment was more significant and coincided with the inflammation occurring during psoriasis.The epidermal immune microenvironment plays a dominant role in psoriasis. Langerhans cells, epidermis-resident memory T cells and macrophages together contribute to healthy epidermal immune homeostasis. However, psoriatic CD1cCD11b epidermal cDC2s are positioned in the perilesional area, replacing EpCAMCD11c LCs rapidly and initiating inflammation. Epidermal CD141 cDC1s, CD1c cDC2s, CD14 moDCs, and BDCA2 pDCs orchestrate psoriatic inflammation. Meanwhile, CD11c LCs and CD5 T cells accumulate in the psoriatic epidermis.