Discrete cytokine signaling networks instruct distinct synovial pathotypes in inflammatory arthritis

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Abstract Patients with rheumatoid arthritis (RA) display distinct patterns of synovitis. To define the inflammatory mechanisms driving this heterogeneity, we analyzed the inflamed synovium of wild-type (WT), Il6ra -/- , and Il27ra -/- mice with antigen-induced arthritis (AIA). Remarkably, each strain developed a joint pathology mirroring a major RA synovial pathotype: myeloid-rich (WT), fibroblast-rich/pauci-immune ( Il6ra -/- ), and lymphoid-rich ( Il27ra -/- ) synovitis. Histology confirmed minimal immune infiltration in Il6ra -/- joints, while WT and Il27ra -/- mice exhibited prominent immune involvement, including organized synovial lymphoid-like aggregates in Il27ra -/- mice. Transcriptomic and epigenomic profiling revealed both shared and distinct regulatory programs among genotypes. Il6ra -/- mice showed increased WNT, DKK, and AMPK signaling associated with fibroblast, chondrocyte, and osteoclast activation (e.g., Adamts19 , Dkk1 , Ecm1 ). Consistent with synovial ectopic lymphoid-like structures, Il27ra -/- mice showed enrichment of lymphocyte activation (e.g., Il17a , Il22 , Bhlhe40 ). WT mice exhibited hallmarks of MAP kinase activation. These molecular signatures parallel those of fibroblast-, lymphoid-, and myeloid-rich synovitis in RA. Defining a STAT1–STAT3 regulatory interplay influencing transcriptional decisions in WT and Il27ra -/- mice, our findings offer insights into cytokine-driven disease heterogeneity. Together, these results establish a framework for mechanism-based classification of synovitis and introduce new mouse models to study the molecular drivers of synovial pathotypes and treatment response.

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