Two of the most common forms of inflammatory arthritis are rheumatoid arthritis (RA) and psoriatic Arthritis (PsA). Common pathogenic features exist between RA and PsA, however significant differences are observed at the clinical, immunological, cellular and molecular levels. While some therapies are effective in both patient groups, different responses have been demonstrated to new targeted therapies. At a molecular single-cell level little is known about the distinct underlying mechanisms involved in driving this differential pathogenesis in the target tissue of disease ‘the-synovium’. Two of the most prominent cell-types in the RA and PsA synovium are macrophages and fibroblasts (FLS), which play a key role in joint inflammation through immune-cell regulation, potent secretion of pro-inflammatory mediators and synovial invasion of adjacent cartilage and bone. Recently, using advanced flow-cytometry and scRNAseq, we identified significant enrichment of a dominant macrophage-subtype CD206+CD163+ co-expressing CD40+ in RA inflamed synovial-tissue compared to healthy-control, and have shown in co-culture that RA sorted macrophages induce a proinflammatory phenotype in FLS. Preliminary data also demonstrated significantly higher frequency of Thy1+FAPα+FLS in RA compared to PsA, thus demonstrating functional diversity of macrophage/FLS cellular phenotypes in the joint. In parallel, we have identified that circulating monocytes in RA and PsA differ, an effect that is memorised in monocyte-derived macrophages. Finally, preliminary data from scRNAseq analysis has shown distinct receptor-ligand interactions between macrophages-FLS that potentially drives the Thy1+FAPα+FLS subtype in RA compared to PsA. Therefore, in this project, using advanced flow-cytometry, scRNAseq, metabolic-analysis along with extensive mechanistic studies using physiologically relevant patient models of RA/PsA disease we will (i) examine circulatory monocyte function and activation, (ii) determine distinct synovial tissue macrophage-FLS crosstalk in RA and PsA, (iii) correlate with disease-activity, progression and response and (iv) identify new targets for novel therapeutic strategies in ‘pre-clinical proof-of-concept studies’ using ex-vivo models of RA/PsA disease.
