Understanding psoriatic disease at single-cell resolution: an update.

Abstract

Purpose of review: This review examines recent advancements in psoriasis research through single-cell technologies, including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. These methods have uncovered the cellular diversity underlying psoriasis, identifying immune cell, keratinocyte, and fibroblast subtypes that play pivotal roles in disease progression. Such insights are vital for addressing the complexity and heterogeneity of psoriasis, paving the way for targeted therapies.

Recent findings: Recent studies emphasize the roles of IL-17-producing T cells (T17), keratinocytes, and fibroblasts in driving inflammation. T-cell cytokines, including IL-17A and IL-17F, induce keratinocyte hyperproliferation and amplify inflammation through an IL-36 feed-forward loop. Fibroblast subsets, such as SFRP2+ and WNT5A+/IL24+ fibroblasts, contribute to extracellular matrix remodeling and cytokine release, worsening the inflammatory environment. These studies also reveal the intricate fibroblast-keratinocyte crosstalk via the IL-17/IL-36 and PRSS3-F2R pathways. More recently, advancement with spatial transcriptomics has uncovered metabolic dysregulation in psoriatic keratinocytes, highlighting HIF1α-driven glycolysis and lactate production as critical in sustaining chronic inflammation. Furthermore, nonlesional skin from severe psoriasis patients exhibits transcriptomic changes resembling lesional skin, suggesting systemic "prelesional" state with the upregulation of lipid metabolism genes.

Summary: These discoveries have significant clinical implications. Integrating single-cell and spatial technologies into psoriasis research offers promising avenues for developing tailored treatments and improving patient outcomes. Specifically, with spatial transcriptomics revealing immune signatures and cell-cell colocalization that may serve as early indicators of disease severity and systemic involvement. Targeting metabolic pathways in keratinocytes and localized immune microenvironments may enhance precision therapies for psoriasis.