Transcription factor SPI1 drives immunosuppressive CD45erythroid progenitor cells to ameliorate rheumatoid arthritis.

Abstract

OBJECTIVE: Anaemia is common in rheumatoid arthritis (RA), but the role of erythroid-lineage cells is unclear. We investigated the function of CD45erythroid progenitor cells (CD45EPCs) in RA. METHODS: We analysed CD45EPC frequency in patients with RA and mice with collagen-induced arthritis (CIA). Transcriptomics, functional studies and mechanistic assays (Transwell and dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR) were used. Therapeutic potential was tested in RA synovial organoids and via splenectomy/adoptive transfer in mice with CIA. RESULTS: CD45EPCs were expanded in RA circulation and CIA mouse spleens, correlating positively with disease activity and negatively with haemoglobin. They displayed an immunosuppressive transcriptome, enriched for transforming growth factor (TGF)-β and chemokine signalling. RA-derived CD45EPCs showed enhanced proliferation and TGF-β/reactive oxygen species production. High C-C Motif Chemokine Receptor 2 (CCR2) expression made them susceptible to recruitment by macrophage-derived C-C Motif Chemokine Ligand 2 (CCL2). In RA synovial organoids, CD45EPCs suppressed growth and inflammation via TGF-β, while organoid-conditioned media promoted their migration via CCL2. Recruited CD45EPCs suppressed M1 and promoted M2-like macrophage polarisation. The transcription factor SPI1 was upregulated in RA CD45EPCs, bound thepromoter and drove TGF-β production. In vivo, splenectomy worsened CIA, whereas adoptive transfer of CD45EPCs ameliorated arthritis. CONCLUSION: We identify CD45EPCs as a novel, SPI1-driven immunosuppressive population in RA. Recruited via the CCR2-CCL2 axis, they attenuate inflammation by modulating macrophages through SPI1/TGF-β signalling, revealing a new immunoregulatory axis and potential therapeutic targets.