Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis

Abstract

ObjectivesImmune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation.MethodsSingle cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters.ResultsGlobal transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor–ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.

Molecular reframing of fibroblasts during resolution of arthritis

“…To avoid analytical bias due to unrelated exclusion of certain fibroblast subtypes 7 , we integrated 33 scRNA-seq datasets (unpublished and public, Supplemental Fig 1 a-e) from different arthritis models and their controls, resulting in to a total of 52,131 mesenchymal cells from joints, and performed unbiased graph-based clustering. Consistent with previous reports [8][9][10][11][12][13][14] , the integrated dataset confirmed a high heterogeneity of mesenchymal cells in joints. Unsupervised clustering revealed seven distinct mesenchymal cell types (Fig.…”

“…4 a). Therefore, we created a comprehensive map of human RA and PsA synovial single cells by integrating four publicly available datasets 11,21 and identified the major cellular heterogeneity (Fig. 4 b, Extended Data Fig.…”

Molecular Imaging with Fibroblast Activation Protein Tracers depicts Inflammatory Joint Damage and its Transition to Resolution of Inflammation

“…Finally, we examined the potential translation of the functional relationship between joint damage and FAPI-04 uptake, and the reduction of FAPI-04 accumulation during cellular shift in the mesenchymal compartment to pro-resolving CD200 + fibroblasts in humans. Therefore, we first created a comprehensive map of human PsA synovial single cells by integrating four publicly available datasets 16,24 and identified the major cellular heterogeneity (Fig. 6a) .…”

“…Two publicly available datasets of human PsA single cell RNA sequencing from whole synovial tissue 38 and CD45+ sorted cells 39 , were analysed. Quality control included exclusion of low quality cells with the criteria UMI count < 1000-500, number of features < 500-250, mitochondrial ratio > 0.25-0.12 and complexity < 0.95 - >0.8, and by removing genes expressed in less than five percent of the cells as well as mitochondrial, ribosomal and stress associated genes.…”

Ablation of PDIA3 attenuates rheumatoid arthritis by restraining Th1 and Th17 polarization program

“…The etiology and pathogenesis of RA remain largely unknown but are suggested to rely heavily on the interplay between SFs and immune cells. Immune derived cytokines activate the SFs, which in turn produce metalloproteinases (MMPs) and inflammatory mediators that damage bone and cartilage (41,42). At the same time, SFs could activate the immune cells, especially macrophages and T cells, to actively participate in autoimmune response.…”