Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients.
Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients.
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针对MyD88的MyD8下调了炎症介质和DMARDS未经类风湿关节炎患者的PBMC的致病过程。
DOI：
10.3389/fphar.2021.800220
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发表时间：
2021
影响因子：
5.6
通讯作者：
Bhattaram P
中科院分区：
文献类型：
--
作者：
Ramirez-Perez S;Oregon-Romero E;Reyes-Perez IV;Bhattaram P
MyD88 依赖性细胞内信号级联和随后的 NF-kappaB 介导的转录导致类风湿性关节炎 (RA) 和相关自身免疫性疾病发病机制中的动态炎症过程。本研究旨在确定 MyD88 二聚化抑制剂 ST2825 作为致病基因表达特征和系统性炎症调节剂在未接受过疾病缓解抗风湿药物 (DMARD) 的 RA 患者中的作用。我们分析了未接受过 DMARD 治疗的 RA 患者经 LPS 和 IL-1β 刺激后的外周血单核细胞 (PBMC) 的批量 RNA 测序。分析 ST2825 处理的 PBMC 的转录谱以确定其治疗潜力。实施独创性途径分析来识别下调的致病过程。我们的分析揭示了 ST2825 治疗前后未接受 DMARD 的 RA 患者之间有 631 个差异表达基因。 ST2825 处理的 RA PBMC 通过下调促炎细胞因子、趋化因子和基质金属蛋白酶的表达，表现出与健康对照 PBMC 相似的基因表达特征。此外，B 细胞受体、IL-17 和 IL-15 信号通路被 ST2825 严重下调。此外，我们还确定了参与致病过程的八个基因（MMP9、CXCL9、MZB1、FUT7、TGM2、IGLV1-51、LINC01010 和 CDK1），ST2825 可以潜在地抑制 RA 滑膜内不同细胞类型的致病过程。总体而言，我们的研究结果表明，靶向 MyD88 可有效下调全身炎症介质，并调节未接受过 DMARD 的 RA 患者 PBMC 的致病过程。 ST2825 还可能抑制 RA 滑膜中上调的基因，预防滑膜炎和关节退化。
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)-naïve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β. 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-naïve 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-naïve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.
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影响因子：
7.3
作者：
Boutet MA;Nerviani A;Lliso-Ribera G;Leone R;Sironi M;Hands R;Rivellese F;Del Prete A;Goldmann K;Lewis MJ;Mantovani A;Bottazzi B;Pitzalis C
通讯作者：
Pitzalis C
影响因子：
--
作者：
Abdollahi-Roodsaz, Shahla;van de Loo, Fons A. J.;van den Berg, Wim B.
通讯作者：
van den Berg, Wim B.
影响因子：
3.8
作者：
Lee, Eun Jung;Lilja, Sandra;Benson, Mikael
通讯作者：
Benson, Mikael
影响因子：
3
作者：
Fattah, Shaimaa A.;Fattah, Maha A. Abdel;Mehanna, Eman T.
通讯作者：
Mehanna, Eman T.
影响因子：
4
作者：
Meng, Qing;Qiu, Bing
通讯作者：
Qiu, Bing