MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients

Arthritis Research & Therapy

Research

Itzel Viridiana Reyes-Perez¹  Rushi Vekariya²  Pallavi Bhattaram²  Sergio Ramirez-Perez²  Surabhi Gautam²  Hicham Drissi³ 

[1] Department of Molecular Biology and Genomics, University Center for Health Science, University of Guadalajara, 44340, Guadalajara, Jalisco, Mexico;Department of Orthopaedics, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Cell Biology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Emory Musculoskeletal Institute, Emory University School of Medicine, 30329, Atlanta, GA, USA;Department of Orthopaedics, Emory University School of Medicine, 30322, Atlanta, GA, USA;Department of Cell Biology, Emory University School of Medicine, 30322, Atlanta, GA, USA;Emory Musculoskeletal Institute, Emory University School of Medicine, 30329, Atlanta, GA, USA;Atlanta VA Medical Center, 30033, Decatur, GA, USA;

关键词: Rheumatoid arthritis;    MyD88;    ST2825;    Cell cycle;    Invasion;    Inflammation;    Synovial fibroblasts;   

DOI  :  10.1186/s13075-023-03145-0

 received in 2022-11-18, accepted in 2023-08-23,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundDimerization of the myeloid differentiation primary response 88 protein (MyD88) plays a pivotal role in the exacerbated response to innate immunity-dependent signaling in rheumatoid arthritis (RA). ST2825 is a highly specific inhibitor of MyD88 dimerization, previously shown to inhibit the pro-inflammatory gene expression in peripheral blood mononuclear cells from RA patients (RA PBMC). In this study, we elucidated the effect of disrupting MyD88 dimerization by ST2825 on the pathological properties of synovial fibroblasts from RA patients (RA SFs).MethodsRA SFs were treated with varying concentrations of ST2825 in the presence or absence of bacterial lipopolysaccharides (LPS) to activate innate immunity-dependent TLR signaling. The DNA content of the RA SFs was quantified by imaging cytometry to investigate the effect of ST2825 on different phases of the cell cycle and apoptosis. RNA-seq was used to assess the global response of the RA SF toward ST2825. The invasiveness of RA SFs in Matrigel matrices was measured in organoid cultures. SFs from osteoarthritis (OA SFs) patients and healthy dermal fibroblasts were used as controls.ResultsST2825 reduced the proliferation of SFs by arresting the cells in the G0/G1 phase of the cell cycle. In support of this finding, transcriptomic analysis by RNA-seq showed that ST2825 may have induced cell cycle arrest by primarily inhibiting the expression of critical cell cycle regulators Cyclin E2 and members of the E2F family transcription factors. Concurrently, ST2825 also downregulated the genes encoding for pain, inflammation, and joint catabolism mediators while upregulating the genes required for the translocation of nuclear proteins into the mitochondria and members of the mitochondrial respiratory complex 1. Finally, we demonstrated that ST2825 inhibited the invasiveness of RA SFs, by showing decreased migration of LPS-treated RA SFs in spheroid cultures.ConclusionsThe pathological properties of the RA SFs, in terms of their aberrant proliferation, increased invasiveness, upregulation of pain and inflammation mediators, and disruption of mitochondrial homeostasis, were attenuated by ST2825 treatment. Taken together with the previously reported anti-inflammatory effects of ST2825 in RA PBMC, this study strongly suggests that targeting MyD88 dimerization could mitigate both systemic and synovial pathologies in a variety of inflammatory arthritic diseases.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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