MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients.
MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients.
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DOI：
10.1186/s13075-023-03145-0
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发表时间：
2023-09-25
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
骨髓分化初级反应 88 蛋白 (MyD88) 的二聚化在类风湿关节炎 (RA) 对先天免疫依赖性信号传导的加剧反应中发挥着关键作用。 ST2825 是一种高度特异性的 MyD88 二聚化抑制剂，之前已被证明可以抑制 RA 患者外周血单核细胞 (RA PBMC) 中的促炎基因表达。在这项研究中，我们阐明了 ST2825 破坏 MyD88 二聚化对 RA 患者滑膜成纤维细胞 (RA SF) 病理特性的影响。在存在或不存在细菌脂多糖 (LPS) 的情况下，用不同浓度的 ST2825 处理 RA SF，以激活先天免疫依赖性 TLR 信号传导。通过成像细胞术定量 RA SF 的 DNA 含量，以研究 ST2825 对细胞周期不同阶段和凋亡的影响。 RNA-seq 用于评估 RA SF 对 ST2825 的整体反应。在类器官培养物中测量基质胶基质中 RA SF 的侵袭性。来自骨关节炎 (OA SF) 患者的 SF 和健康真皮成纤维细胞用作对照。 ST2825 通过将细胞阻滞在细胞周期的 G0/G1 期来减少 SF 的增殖。为了支持这一发现，RNA-seq 转录组分析表明 ST2825 可能通过主要抑制关键细胞周期调节因子 Cyclin E2 和 E2F 家族转录因子成员的表达来诱导细胞周期停滞。同时，ST2825 还下调编码疼痛、炎症和关节分解代谢介质的基因，同时上调核蛋白易位至线粒体和线粒体呼吸复合体 1 成员所需的基因。最后，我们通过在球状培养物中显示经 LPS 处理的 RA SF 迁移减少，证明 ST2825 抑制 RA SF 的侵袭性。 ST2825 治疗减弱了 RA SF 的病理特性，包括异常增殖、侵袭性增加、疼痛和炎症介质上调以及线粒体稳态破坏。结合之前报道的 ST2825 在 RA PBMC 中的抗炎作用，这项研究强烈表明，针对 MyD88 二聚化可以减轻多种炎症性关节炎疾病的全身和滑膜病理。在线版本包含可在 10.1186/s13075-023-03145-0 获取的补充材料。
Dimerization 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). RA 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. ST2825 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. The 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. The online version contains supplementary material available at 10.1186/s13075-023-03145-0.
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影响因子：
3.4
作者：
Jones K;Angelozzi M;Gangishetti U;Haseeb A;de Charleroy C;Lefebvre V;Bhattaram P
通讯作者：
Bhattaram P
影响因子：
5.4
作者：
Manivel, Vivek Anand;Sohrabian, Azita;Ronnelid, Johan
通讯作者：
Ronnelid, Johan
影响因子：
7.7
作者：
Chen, Li;Song, Zhenzhen;Cao, Xiaowan;Fan, Mingsong;Zhou, Yan;Zhang, Guoying
通讯作者：
Zhang, Guoying
影响因子：
5.8
作者：
He Z;Song Y;Yi Y;Qiu F;Wang J;Li J;Jin Q;Sacitharan PK
通讯作者：
Sacitharan PK
DOI：
10.1002/art.40386
发表时间：
2018-03
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Bhattaram P;Muschler G;Wixler V;Lefebvre V
通讯作者：
Lefebvre V