Spreading of psoriatic inflammation from skin to joints requires a two-step process: migration of disease-specific CD2+ MHC-II+ CCR2+ myeloid precursors from psoriatic skin to joints, followed by their pro-inflammatory activation in the joint microenvironment when CD200+ regulatory fibroblasts fail to engage the CD200R1 checkpoint receptor on these migrating precursors.

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis.