Spatial Transcriptomic and CITE-Seq Analyses Identify Clearance-Defective Signatures in Psoriatic Disease

Psoriatic lesions contain sustained inflammatory stress, but whether death-associated tissue activity is matched by adequate clearance capacity remains poorly defined. To address this, spatial transcriptomics was used to define clearance imbalance in psoriatic skin, with peripheral CITE-seq assessing circulating myeloid clearance states. Within leucocyte-rich tissue regions, stress-death and clearance-capacity modules identified clearance-competent niches, marked by matched stress and clearance activity and clearance-defective niches, marked by stress-death activity without comparable clearance capacity. This revealed that lesional psoriatic skin shows a selective epidermal clearance imbalance, with increased clearance defect, a higher defective-to-competent niche ratio and distinct clearance-defective transcriptional programming enriched for stress-processing and stress-response pathways. The clinical relevance of this epidermal axis was supported by a correlation between epidermal, but not dermal, clearance defect and psoriasis severity. Within this severity-linked compartment, a preserved monocyte/macrophage-rich burden masked reduced clearance-associated programming, indicating that defective epidermal niches retain myeloid-rich spatial contexts without matched clearance capacity. Peripheral profiling extended this axis to circulation, where psoriatic arthritis showed increased clearance defect scores in mononuclear myeloid cells and a clearance-defective surface phenotype linked to reduced efferocytosis-associated capacity. Together, these findings define clearance-defective psoriatic inflammation as an epidermal tissue programme with convergent circulating myeloid clearance defects in higher burden disease.