Synovial tissue transcriptomes of long-standing rheumatoid arthritis are dominated by activated macrophages that reflect microbial stimulation

Abstract

Advances in microbiome research suggest involvement in chronic inflammatory diseases such as rheumatoid arthritis (RA). Searching for initial trigger(s) in RA, we compared transcriptome profiles of highly inflamed RA synovial tissue (RA-ST) and osteoarthritis (OA)-ST with 182 selected reference transcriptomes of defined cell types and their activation by exogenous (microbial) and endogenous inflammatory stimuli. Screening for dominant changes in RA-ST demonstrated activation of monocytes/macrophages with gene-patterns induced by bacterial and fungal triggers. Gene-patterns of activated B- or T-cells in RA-ST reflected a response to activated monocytes/macrophages rather than inducing their activation. In contrast, OA-ST was dominated by gene-patterns of non-activated macrophages and fibroblasts. The difference between RA and OA was more prominent in transcripts of secreted proteins and was confirmed by protein quantification in synovial fluid (SF) and serum. In total, 24 proteins of activated cells were confirmed in RA-SF compared to OA-SF and some like CXCL13, CCL18, S100A8/A9, sCD14, LBP reflected this increase even in RA serum. Consequently, pathogen-like response patterns in RA suggest that direct microbial influences exist. This challenges the current concept of autoimmunity and immunosuppressive treatment and advocates new diagnostic and therapeutic strategies that consider microbial persistence as important trigger(s) in the etiopathogenesis of RA.

Macrophages: The Good, the Bad, and the Gluttony

“…RA sMacs have increased expression of TLR2 and TLR4 on their cell surface and when stimulated with DAMP ligands ex vivo, and secrete higher levels of pro-inflammatory factors (81,82). This correlates with a recent observation that synovial macrophages from established RA have a transcriptome profile similar to that observed in cells activated by pathogens (83). Sensitivity to these ligands can be further enhanced through exposure to oxidized oxysterols which are enriched in RA synovial fluid, resulting in increased secretion of proinflammatory factors (84).…”

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

“…Transcriptomic analysis of RA synovial tissue revealed activation patterns of infiltrating monocytes/macrophages. These patterns have corresponded to activation induced by microbial stimuli, whereas top proteins including MCP-1 and S100A8/A9 secreted by these cells in RA synovial tissue correlated with disease activity and reflected RA synovitis in blood [38]. Many research studies suggested that genetic contributions to RA disease susceptibility are not sufficient to completely explain the disease.…”

The macrophage reprogramming ability of antifolates reveals soluble CD14 as a potential biomarker for methotrexate response in rheumatoid arthritis

“…Moreover, synovium CD14 expression correlated positively with disease activity (padj 0.016) (53,54). Along the same line, sCD14 levels are increased in RA synovial fluid and serum compared to osteoarthritis patients (55,56). sCD14 plays an important role in mediating the immune responses to LPS of CD14-negative cells such as endothelial cells and epithelial cells, and induces proinflammatory cytokines in fibroblast-like synovial cells from RA patients (57).…”