Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naive Rheumatoid Arthritis Patients

MyD88-dependent intracellular signalling cascades and subsequently NF-kappaB-mediated transcription lead to the dynamic inflammatory processes underlying the pathogenesis of rheumatoid arthritis (RA) and related autoimmune diseases. This study aimed to identify the effect of the MyD88 dimerization inhibitor, ST2825, as a modulator of pathogenic gene expression signatures and systemic inflammation in disease-modifying antirheumatic drugs (DMARDs)-naive RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naive RA patients after stimulation with LPS and IL-1 beta. The transcriptional profiles of ST2825-treated PBMC were analyzed to identify its therapeutic potential. Ingenuity Pathway Analysis was implemented to identify downregulated pathogenic processes. Our analysis revealed 631 differentially expressed genes between DMARDs-naive RA patients before and after ST2825 treatment. ST2825-treated RA PBMC exhibited a gene expression signature similar to that of healthy controls PBMC by downregulating the expression of proinflammatory cytokines, chemokines and matrix metalloproteases. In addition, B cell receptor, IL-17 and IL-15 signalling were critically downregulated pathways by ST2825. Furthermore, we identified eight genes (MMP9, CXCL9, MZB1, FUT7, TGM2, IGLV1-51, LINC01010, and CDK1) involved in pathogenic processes that ST2825 can potentially inhibit in distinct cell types within the RA synovium. Overall, our findings indicate that targeting MyD88 effectively downregulates systemic inflammatory mediators and modulates the pathogenic processes in PBMC from DMARDs-naive RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.

Automated summary

The study demonstrated that the MyD88 dimerization inhibitor ST2825 effectively downregulates inflammatory mediators in PBMC from DMARDs-naive RA patients and may potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.