Quantitative uncoupling of immune density and inflammatory output reveals tissue-liability niches in psoriatic skin

Psoriatic disease is characterised by chronic inflammation, yet spatially defined immune-poor tissue regions that sustain high inflammatory output remain difficult to formalise as measurable spatial disease features. Here, peripheral CITE-seq profiling and spatial transcriptomic datasets were analysed to examine inflammatory organisation in psoriatic disease through relationships between paired biological axes. In circulation, tissue-homing-associated surface states were assessed in relation to activation-associated markers to determine whether trafficking potential is accompanied by inflammatory readiness. In skin, inflammatory output was assessed in relation to local immune density to determine whether spatial inflammatory activity is aligned with immune abundance. Across circulating immune compartments, tissue-homing-associated, low activation-associated surface-defined populations were more frequent in psoriasis (PsO) and psoriatic arthritis (PsA), with strongest enrichment in PsA, suggesting enhanced trafficking potential in the absence of parallel activation-associated marker elevation. Using atopic dermatitis (AD) as a non-psoriatic inflammatory reference, spatial analysis revealed that tissue-liability niches, defined by low immune density and high inflammatory output, are enriched in PsO lesions. Layer-resolved mapping demonstrated that this enrichment was concentrated primarily in the dermis, where greater tissue-liability niche burden tracked with increasing psoriasis severity. Together, these findings define tissue-liability niches as a quantifiable spatial feature of psoriatic inflammation, revealing inflammatory activity that is not explained by local immune density. By converting this imbalance into a measurable tissue state, this framework exposes immune-poor inflammatory regions that may be overlooked by immune-density-based analyses and provides a spatial basis for stratifying inflammatory burden within psoriatic lesions.