Study of miRNA interactome in active rheumatoid arthritis patients reveals key pathogenic roles of dysbiosis in the infection-immune network

Abstract

Objectives: To characterize serum microRNA (miR) and the miR interactome of active RA patients in RA aetiology and pathogenesis.

Methods: The differentially expressed miRs (DEmiRs) in serum of naïve active RA patients (NARAPs, n = 9, into three pools) vs healthy controls (HCs, n = 15, into five pools) were identified with Agilent human miR microarray analysis. Candidate driver genes in epigenetic and pathogenic signalling pathway modules for RA were analysed using miRTarBase and a molecular complex detection algorithm. The interactome of these DEmiRs in RA pathogenesis were further characterized with gene ontology and Kyoto Encyclopaedia of Genes and Genomes.

Results: Three upregulated DEmiRs (hsa-miR-187-5p, -4532, -4516) and eight downregulated DEmiRs (hsa-miR-125a-3p, -575, -191-3p, -6865-3p, -197-3p, -6886-3p, -1237-3p, -4436b-5p) were identified in NARAPs. Interactomic analysis from heterogeneous experimentally validated sources yielded 1719 miR-target interactions containing 5.67% strong and 94.33% less strong experimental evidence. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses allocated the upregulated DEmiRs in the infection modules and the downregulated DEmiRs in the immune signalling pathways. Specifically, these DEmiRs revealed the significant contributions of the intestinal microbiome dysbiosis in the infection-inflammation-immune network for activation of T cells, immune pathways of IL-17, Toll-like receptor, TNF, Janus kinase-signal transducer and activator of transcription, osteoclast cell differentiation pathway and IgA production to the active RA pathogenesis.

Conclusions: Our experiment-based interactomic study of DEmiRs in serum of NARAPs revealed novel clinically relevant miRs interactomes in the infection-inflammation-immune network of RA. These results provide valuable resources for understanding the integrated function of the miR network in RA pathogenesis and the application of circulating miRs as biomarkers for early aetiologic RA diagnosis.

Keywords: bioinformatics; biomarkers; circulating microRNA; infection-immune network; interactome; intestinal microbiome; rheumatoid arthritis.