Discrete cytokine signaling networks instruct distinct synovial pathotypes in inflammatory arthritis
Year: 2025
Type: preprint
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.
Authors: Alicia Derrac Soria, David G. Hill, Stuart TO. Hughes, Reuben N. Scott, Ana Cardus Figueras, Sandra Dimonte, Daniela Costa, Ngoc-Nga Vinh, Federica Monaco, Robert H. Jenkins, Xiao Liu, Myles Lewis, Jason P. Twohig, Carol Guy, Aisling Morrin, Benjamin C. Cossins, Robert Andrews, Barbara Szomolay, Liliane Fossati-Jimack, Mari A. Nowell, Anwen S. Williams, Ernest H. Choy, Brendan J. Jenkins, Nigel M. Williams, Hua Yu, Marcin Kortylewski, Stephen Turner, Tony Tiganis, Costantino Pitzalis, Gareth W. Jones, Simon A. Jones
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, Versus Arthritis
OpenAlex ID: W4415832909