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Loss of synovial tissue macrophage homeostasis precedes Rheumatoid Arthritis clinical onset.

ABSTRACT: This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of Rheumatoid Arthritis (RA) patients, ‘individuals-at-risk’ of RA and healthy controls (HC). Flow-cytometric analysis demonstrated for the first time, the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease-activity and treatment response. RNAseq/metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory, and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. scRNAseq profiling of 67908 RA and HC synovial-tissue cells identified nine transcriptionally distinct macrophage-clusters. IL- 1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and importantly are enriched pre-disease onset. Combined these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246416 | GEO | 2024/09/25

REPOSITORIES: GEO

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Project description:Purposes Recurrent synovial bleeding is the major cause of Hemophilic Arthritis (HA). Up to now, the transcriptomic profiles of bleeding syvonium in HA patient have largely remained unknown. Exploring the transcriptomic characteristics of synovium obtained from HA patients undergoing total knee arthroplasty (TKA), and uncovering potential pathological mechanisms of HA synovium through bioinformatics analysis and differential analysis. Methods Single-cell RNA sequencing (scRNA-seq) technology was utilized to identify distinct cellular subsets within HA synovium. Comparative analysis was conducted with scRNA-seq data from osteoarthritis (OA) and rheumatoid arthritis (RA) synovium to assess transcriptional differences. Histological evaluation, immunofluorescence (IF), immunohistochemistry (IHC) and in vitro cell testing were performed for validation. Results We observed that the single-cell transcriptomic characteristics of HA synovium differ significantly from those of OA and RA patients. Mast cells, identified as unique immune cells in HA synovium, are actively involved and may be the initiating factor for changes in vascular permeability or bleeding in HA synovium. The transcriptomic features of endothelial cells and fibroblasts, which are non-immune stromal cells, reveal the synovial microenvironment: repeated bleeding leads to iron deposition, which causes substantial ferroptosis within the synovium. Based on the pseudotime analysis of endothelial cells, along with IHC staining and in vitro cell assays, it was demonstrated that ferroptosis in endothelial cells induces vascular damage and triggers a significant migration of endothelial cells. The stress of ferroptosis leads to the differentiation of HMOX1+ endothelial cells. Cell interaction analysis shows that HMOX1+ endothelial cells can induce the SCARA5+ fibroblast subtypes via FTL/SCARA5. This may be a critical target for alleviating cellular ferroptosis in HA synovium. Conclusions Through scRNA-seq, we elucidated the heterogeneity of synovial tissues in three diseases. Activated mast cells around blood vessels may be potential target cells for bleeding and rebleeding, with TPSB2 emerging as a potential target. We also identified endothelial cell subpopulations under ferroptosis stress and their interactions with fibroblasts. Notably, we discovered a SCARA5+ fibroblast subpopulation that regulates ferroptosis, which could serve as a potential target gene for preventing and treating recurrent bleeding in HA.

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Loss of synovial tissue macrophage homeostasis precedes Rheumatoid Arthritis clinical onset.

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