The biphasic spatiotemporal role of serotonin in RA progression

血清素在 RA 进展中的双相时空作用

• 批准号: 528341753
• 负责人: Professor Dr. Michael Bader
• 金额: --
• 依托单位: Forschungsgruppe Molekularbiologie von Hormonen im Herz-Kreislaufssystem
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/528341753?language=en
• 关键词: biphasic; spatiotemporal; role; serotonin; RA

The influence of the gut on the development of arthritis was observed decades ago; but the linking mechanism involved remains to be fully elucidated. We have identified early subclinical gut inflammation preceding clinical arthritic symptoms in the collagen-induced arthritis (CIA) mouse model as well as in new-onset, treatment-naive rheumatoid arthritis (RA) patients. Until now, serotonin, which is primarily produced in the gut by enterochromaffin cells, was shown to impact different stages during RA progression. However, no consensus of serotonin´s influence on the disease-modifying direction in RA could be revealed. Although serotonin´s effects on general immune responses have been extensively studied, a potential biphasic role of extracellular serotonin vs. intracellular serotonylation in RA progression has not been considered so far. Serotonylation is a selective posttranslational modification first described in the early 2000s, which regulates several cellular processes and recently gained renewed attention by being described as a novel epigenetic regulatory mechanism. Here, we hypothesize that higher serotonin levels prevent early clinical RA onset, whereas later sustained intracellular serotonylation in dendritic cells (DCs), monocytes, and macrophages promotes disease progression and chronicity by maintaining a pro-inflammatory phenotype. In line with our hypothesis, we identified two clear peaks of serum serotonin, early and late during the CIA model. Treatment with selective serotonin reuptake inhibitor (SSRI) was only effective during the late clinical stages of CIA. Furthermore, early oral treatment with the serotonin precursor 5-Hydroxytryptophan 5-HTP) prevented inflammatory arthritis whereas late treatment exacerbated clinical arthritis scores. This proposal aims to unravel the role of serotonin by focusing on the consequences of intracellular serotonylation in myeloid innate immune cells during RA progression.

观察到肠道对关节炎发展的影响。但是涉及的链接机制尚待充分阐明。我们已经确定了早期的亚临床肠道注射早期临床关节炎（CIA）小鼠模型以及新的，治疗的，不接受治疗的类风湿关节炎（RA）患者。到目前为止，主要由肠球毒细胞在肠道中产生的5-羟色胺被证明会影响RA进展过程中的不同阶段。但是，无法揭示血清素对RA中疾病改良方向的影响的共识。尽管血清素对一般免疫反应的影响已广泛研究，但迄今为止尚未考虑到细胞外血清素与细胞内串行的潜在双相作用。血清素化是一种选择性的翻译后修饰，首先描述了2000年代初期，它调节了几种细胞过程，并通过被描述为一种新型的表观遗传调节机制，从而引起了人们的重新注意。在这里，我们假设较高的5-羟色胺水平可以预防早期临床RA发作，而后来在树突状细胞（DCS），单核细胞和巨噬细胞中持续持续的细胞内血清素化来促进疾病的进展，并通过维持促炎性表型来促进疾病的进展和慢性。根据我们的假设，我们确定了CIA模型的早期和晚期血清素5-羟色胺的两个透明峰。选择性5-羟色胺再摄取抑制剂（SSRI）的治疗仅在CIA晚期临床阶段有效。此外，用5-羟色胺前体的早期口服治疗5-羟基trypophan 5-HTP可以防止炎症性关节炎，而晚期治疗加剧了临床关节炎评分。该建议旨在通过关注RA进展过程中髓样固有免疫细胞中细胞内血清素化的后果来阐明5-羟色胺的作用。