Authors
Derrac Soria, A., Hill, D., Hughes, S. T., Scott, R. N., Cardus Figueras, A., Dimonte, S., Costa, D., Vinh, N.-N., Monaco, F., Jenkins, R. H., Liu, X., Lewis, M. J., Twohig, J., Guy, C., Cossins, B. C., Morrin, A. S., Andrews, R., Szomolay, B., Fossati, L., Nowell, M. A., Williams, A. S., Choy, E. H., Jenkins, B. J., Williams, N. M., Yu, H., Kortylewski, M., Turner, S. J., Tiganis, T., Pitzalis, C., Jones, G. W., Jones, S. A.
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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Nov 2025.
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