Skin-Derived Myeloid Precursors and Joint-Resident Fibroblasts Spread Psoriatic Disease from Skin to Joints

Psoriatic disease is a systemic, immune-mediated condition that affects the skin and/or joints.³  Skin inflammation (psoriasis) typically precedes joint inflammation (psoriatic arthritis (PsA)) in about 80% of individuals,⁴ with approximately 30% of individuals with psoriasis developing arthritis.⁵  Indeed, this sequential progression of psoriatic disease, from skin to joints, suggests a mechanistic axis and spatio-temporal link between both organs.

It is well established that psoriatic disease is associated with increased expression of interleukin-23/interleukin-17 (IL-23/IL-17) and tumor necrosis factor (TNF)-a.^6,7  In addition, genome-wide association studies have identified genetic variants associated with psoriatic disease, including HLA-C and HLA-B.⁸  However, the underlying mechanism of progression from psoriasis to PsA remains largely unknown, and currently, there is no reliable molecular mechanism or biomarker that can predict which individuals with psoriasis will develop PsA.⁹

In this paper, the authors induced psoriasis-like skin disease in photoconvertible mice.  Following this, sequencing and computational characterization of skin-derived cells in the joints identified a population of CD2+MHC-II+CCR2+ myeloid precursors that build a skin-derived myeloid cell compartment in the joints.   Single-cell cross-species reference mapping and mitochondrial variant tracing demonstrated the migration of an orthologous human population of CD2+MHC-II+CCR2+ myeloid precursors between the skin and synovium, evidencing that leukocyte trafficking is conserved between mice and humans.  However, migration of CD2+ MHC-II+ CCR2+ myeloid precursors alone was insufficient to induce arthritis.

Further studies, including interactome analysis of the joints, demonstrated that, in a second step, resident regulatory CD200+ fibroblasts prime CD2+MHC-II+CCR2+ myeloid precursors, which subsequently control IL-17 expression in T cells.  These data establish that the local microenvironment, particularly CD200+ fibroblasts, acts as gatekeepers of arthritis, engaging the checkpoint receptor CD200R1 on migrating CD2+ MHC-II+ CCR2+ myeloid precursors.  Consequently, intervention with an antibody to CD200 polarized CD2+MHC-II+CCR2+ myeloid precursors toward a proinflammatory phenotype in vitro and enabled the in vivo spread of psoriatic disease from the skin to the joints, even in initially arthritis-resistant mice.

Taken together, these data confirm that the spread of inflammation (from skin to joints) requires a distinct migratory myeloid precursor population and a permissive local tissue environment, analogous to tumor metastasis.

In summary, this paper sheds light on a previously unexplored aspect of psoriatic disease pathogenesis.  Taking a translational perspective and by extrapolating their observations to humans, the authors confirmed conservation of leukocytes from the skin and synovia across species.  By utilizing the MAESTER method¹⁰ to track mitochondrial variants based on mRNA, the authors successfully corroborated the presence of a skin–joint axis in humans.  In elegant studies, the authors demonstrated increased abundance of precursors in individuals with psoriasis/PsA compared with healthy controls, suggesting that their migration occurs independently of joint involvement but also constitutes a prerequisite for the spread of inflammation from the skin to the joints. The consistency of their results across species highlights the conserved nature of this pathomechanism and offers new perspectives for developing novel diagnostic and therapeutic strategies.  Indeed, this work specifically highlights the CD200–CD200R1 axis as a promising target for preventive medicine, and, notably, the research team recently identified a CD200+ fibroblast subtype that contributes to the resolution of inflammation in arthritis.¹¹

Nevertheless, although many cases of PsA are preceded by cutaneous psoriasis, a notable proportion of individuals develop PsA without a history of skin symptoms.  Furthermore, genetic studies reveal both shared and distinct genetic factors between skin-limited psoriasis and PsA, suggesting partially divergent pathogenic pathways.¹²  Although this study focused on the predominant skin-to-joint axis, there remains a need for future research to explore alternative mechanisms.