From the outset, the project pursued an integrative examination of PsO and PsA through the lens of a skin–joint axis. Work encompassed both preclinical models and human tissue analyses to move beyond a trafficking hypothesis toward a mechanism-based framework. In murine IL-23-driven models, skin inflammation was shown to mobilize myeloid progenitors that can migrate to the joints, with arthritis development depending on the joint’s stromal milieu. Through innovative lineage-tracing approaches, including photoconvertible reporter systems, researchers demonstrated that skin-derived myeloid cells access articular and entheseal compartments, and single-cell analyses identified a CD2⁺MHCII⁺CCR2⁺ migratory subset as a key trafficking population. Importantly, the presence of skin-derived cells in the joint did not uniformly predict arthritis, reinforcing the view that the joint environment governs fate decisions. In human studies, single-cell RNA sequencing, imaging mass cytometry, and mitochondrial DNA lineage tracing provided direct evidence of shared clonotypes and lineage relationships between cells in psoriatic skin and early PsA joints, supporting a functional skin–joint axis. The mtDNA lineage tracing demonstrated that skin-derived myeloid precursors and T cells share somatic variants across tissues, underscoring a cross-compartment lineage relationship.
A central discovery concerns synovial fibroblasts, which emerge as stromal gatekeepers that shape the fate of arriving immune cells. Distinct fibroblast subsets were identified, including pro-resolving CD200⁺ populations and pathogenic FAP⁺ subsets, with the former promoting anti-inflammatory macrophage differentiation and the latter fostering inflammatory trajectories. This stromal heterogeneity helps explain why, despite similar levels of upstream inflammation and cellular trafficking, some individuals progress to persistent synovitis while others do not. The concept of permissive versus protective joint niches crystallized, illustrating that the same skin-derived emigrants can fuel arthritis in a permissive joint milieu but be restrained or redirected in a protective stromal context.
The translational thrust integrates these mechanistic insights into a practical framework for clinical translation. The project outlined multi-compartment biomarker strategies, including cutaneous signatures of TRM/Tc17 activity, circulating skin-educated T cells and myeloid precursors, and advanced joint imaging to interrogate stromal networks and fibroblast states. It proposed integrated care pathways and “at-risk PsA” clinics to facilitate early rheumatology assessment, cross-compartment biomarker readouts, and mechanistically informed endpoints in prevention trials. In terms of exploitation, the work delineates how to pair conventional cytokine-targeted therapies with strategies aimed at reprogramming stromal niches, thereby broadening the therapeutic horizon beyond anti-cytokine approaches to intercept the PsO-to-PsA trajectory. Overall, the results strengthen the evidence base for a skin–joint axis in human disease and establish concrete avenues for biomarker development, risk stratification, and early intervention.
