The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2⁺ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2⁺ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2⁺ myeloid cells, CCR7⁺LAMP3⁺ dendritic cells, and CXCR4 expressed on both CD8⁺ Tc17 cells and keratinocytes, respectively. The SFRP2⁺ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.