Background/Purpose: Psoriatic arthritis (PsA) develops in about 30% of individuals with psoriasis (PsO), highlighting a critical connection between skin and joint inflammation. However, the mechanisms driving the transition from skin-limited disease to joint involvement remain unclear. This study investigates the skin-joint axis in PsA pathogenesis using a preclinical model, with translational validation in human samples.

Methods: We employed the IL-23 overexpression (IL-23OE) mouse model in KAEDE mice, which facilitate the tracking of skin-derived immune cell migration via photo-conversion. Psoriatic skin lesions were converted to KAEDE-RED through UV irradiation, allowing for detailed analysis using light sheet fluorescence microscopy (LSFM) and flow cytometry. Immune cell populations were characterized through imaging flow cytometry, while single-cell RNA sequencing (scRNA-seq) offered insights into their phenotypic profiles. To corroborate these findings, we analyzed human samples from individuals with established PsO and early PsA, utilizing scRNA-seq and imaging mass cytometry. Cell trafficking in human was further examined by sequencing mitochondrial DNA (mtDNA-seq) from paired skin and synovial tissue samples of early PsA patients to identify shared lineages between skin- and joint-derived myeloid cells.

Results: The IL-23OE model successfully induced psoriatic skin lesions and enabled the migration of immune cells from inflamed skin to the synovial compartments. However, the presence of these skin-derived immune cells did not consistently correlate with the development of arthritis. Notably, although CD2⁺MHCII⁺ myeloid progenitors trafficked into the synovial membrane, some mice remained resistant to inflammation. Comparative analysis revealed no intrinsic differences in the myeloid progenitors between resistant and susceptible animals; rather, once within the synovium, these cells differentiated into pro-inflammatory macrophages in PsA-susceptible mice, whereas in resistant mice, they adopted an M2-like anti-inflammatory phenotype. CD200⁺ synovial fibroblasts emerged as key modulators of macrophage fate, promoting protective immune responses that mitigated arthritis development. In parallel, human scRNA-seq confirmed the presence of the corresponding myeloid precursors in psoriatic skin and in synovial tissue of both PsO and earla PsA patients, with flow cytometry detecting them in circulation. Imaging mass cytometry localized these precursors within synovial niches, showing an increase of CD200+ fibroblasts in the non-arthritic tissues. Finally, mtDNA sequencing further validated the skin origin of these myeloid precursors within the synovial tissue of early PsA patients.

Conclusion: This study identifies a key role for synovial fibroblasts in shaping macrophage differentiation and joint inflammation outcomes. Crucially, it provides the first direct evidence of a functional skin-joint axis in humans, showing that immune cells originating in the skin can contribute to joint pathology. These insights may inform early PsA diagnosis, risk stratification, and precision therapeutic strategies in PsO patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/skin-to-joint-immune-cell-migration-and-synovial-reprogramming-in-psoriatic-arthritis-onset/