{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T12:56:08Z","timestamp":1773060968427,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR070736"],"award-info":[{"award-number":["R01 AR070736"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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)-na\u00efve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-na\u00efve RA patients after stimulation with LPS and IL-1\u03b2. 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-na\u00efve 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 (<jats:italic>MMP9<\/jats:italic>, <jats:italic>CXCL9<\/jats:italic>, <jats:italic>MZB1<\/jats:italic>, <jats:italic>FUT7<\/jats:italic>, <jats:italic>TGM2<\/jats:italic>, <jats:italic>IGLV1-51<\/jats:italic>, <jats:italic>LINC01010<\/jats:italic>, and <jats:italic>CDK1<\/jats:italic>) 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-na\u00efve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.<\/jats:p>","DOI":"10.3389\/fphar.2021.800220","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T18:31:05Z","timestamp":1640284265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Na\u00efve Rheumatoid Arthritis Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Sergio","family":"Ramirez-Perez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith","family":"Oregon-Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itzel Viridiana","family":"Reyes-Perez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pallavi","family":"Bhattaram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1002\/art.34328","article-title":"Destructive Role of Myeloid Differentiation Factor 88 and Protective Role of TRIF in Interleukin-17-dependent Arthritis in Mice","volume":"64","author":"Abdollahi-Roodsaz","year":"2012","journal-title":"Arthritis Rheum."},{"key":"B2","doi-asserted-by":"publisher","first-page":"102405","DOI":"10.1016\/j.jaut.2020.102405","article-title":"Precision Medicine and Management of Rheumatoid Arthritis","volume":"110","author":"Aletaha","year":"2020","journal-title":"J. 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