Spatial mapping of rheumatoid arthritis synovial niches reveals specific macrophage networks associated with response to therapy

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting peripheral joints and for which approximately 40% of the patients respond insufficiently to the available synthetic or biologic disease modifying anti-rheumatic drugs (DMARDs). The infiltration of the synovial membrane by lymphocytes and monocytes profoundly alters its homeostatic functions, leading to chronic joint inflammation and bone destruction. A better understanding of how DMARDs impact the complex synovial cell social network in relationship to response / non-response remains an unmet need to design more targeted and active therapeutic strategies. Here, we used imaging mass cytometry (IMC) to comparatively profile more than 115,000 cells in the synovial tissue of healthy, low inflammatory osteoarthritis and matched active early treatment-naive RA patients at baseline and at 6 months after starting DMARDs treatment. We notably highlighted that tissue resident macrophages (LYVE1+CD206+) in perivascular synovial niches encompassing specific subsets of vascular cells, fibroblasts and immune cells vanished in active RA but were recovered in response to DMARDs treatment. Combined ligand-receptor analysis of single-cell RNA sequencing datasets identified that IL10, C-type lectin or TAM (TYRO3, AXL and MERTK) receptors were particularly involved in the restoration of these spatial cell interactions in the context of clinical remission. In addition to providing an unprecedented synovial spatial mapping, our work uncovered novel potential cellular and molecular targets for the development of therapies for RA.