Ciliated keratinocytes define a spatially restricted pro-inflammatory state in psoriasis and atopic dermatitis

Abstract Background: Psoriasis vulgaris (Pso) and atopic dermatitis (AD) are characterized by recurrent flares and incomplete disease resolution. Primary cilia are antenna-like sensory organelles that project from the cell surface and coordinate extracellular signaling. Although epidermal ciliated cells are rarely detected in healthy skin and are selectively increased in AD and Pso, their molecular identity, functional properties, and clinical relevance remain unclear. Objective: To characterize epidermal ciliated cells in Pso and AD and determine their molecular identity, functional properties, and clinical relevance. Methods: We integrated single-cell-resolved spatial transcriptomics with primary cilia immunostaining in healthy skin (n=6), AD lesions (n=10), and paired psoriatic skin before and after phototherapy (n=7 each). Functional analyses using HaCaT cells with increased primary cilia formation included MAPK/NFkB signaling assays, ATAC-seq, and pathway inhibition assays. Results: Ciliated cells were largely restricted to AD and both pre and post treatment psoriatic skin, with KCs accounting for more than 70% of all ciliated cells. Ciliated KCs were predominantly localized to the basal and spinous layers. These cells exhibited disease and stage specific inflammatory programs and formed spatially organized communication networks with surrounding cells, including non ciliated KCs, fibroblasts, endothelial cells, and myeloid cells, suggesting a ciliated KC centered inflammation niche. Mechanistically, increased primary cilia formation enhanced MAPK and NFkB signaling and increased chromatin accessibility at inflammatory gene loci enriched for AP1 motifs, even in the absence of stimulation, consistent with a chromatin primed state. Higher residual ciliated KC abundance after phototherapy was associated with subsequent treatment escalation. ERK1/2 inhibition reduced cytokine induced primary cilia formation. Conclusions: Ciliated KCs represent an inflammatory epithelial cell state associated with residual disease activity in AD and Pso. The suppression of cytokine-induced primary cilia formation by ERK1/2 inhibition suggests that inflammation associated primary cilia formation may be modifiable process in persistent skin inflammation.