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

Biljana Smiljanovic,Pascal Schendel,Gerd R Burmester,Sarah Ohrndorf,Sandra Hermann,Andreas Radbruch,Thomas Vogl,Marc Bonin,Till Sörensen,Karlfried Aupperle,Joachim R Grün,Anne Claussnitzer,Marina Backhaus,Thomas Häupl,Bruno Stuhlmüller,Andreas Grützkau

doi:10.1038/s41598-020-64431-4

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.

Highlights

Advances in microbiome research suggest involvement in chronic inflammatory diseases such as rheumatoid arthritis (RA)
Specificity of RA synovial tissue (RA-ST) genes when compared to OA-ST, which is frequently considered as control group because of limited accessibility to normal synovial tissue, was confirmed when RA-ST was compared to synovial tissues samples obtained i) after joint trauma or ii) post mortem from tissue donors
In this study we demonstrated that the dominant changes in long-standing RA-ST consist of infiltrating monocytes/macrophages with activation patterns that correspond best to activation induced by microbial stimuli

Summary

Introduction

Advances in microbiome research suggest involvement in chronic inflammatory diseases such as rheumatoid arthritis (RA). To relate transcriptional differences between RA and OA to immune cells and mechanisms of activation, 42 transcriptome data generated in our lab and relevant experiments collated from public GEO repositories were screened and a selected set of 182 reference transcriptomes was applied for pattern matching and quantification. This included resting, activated and differentiated cells of innate and adaptive immunity, synovial fibroblasts, endothelial cells and platelets. OA-ST specific transcripts overlapped with patterns of differentiating macrophages and fibroblasts These changes were confirmed by detecting the corresponding inflammation related proteins in synovial fluid of RA but not OA patients. These proteins were diluted and in part neutralised in the blood, these differences between RA and OA were even evident in serum

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