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.

几十年前就观察到了肠道对关节炎发展的影响；但其中的联系机制仍有待充分阐明，我们也在胶原诱导关节炎（CIA）小鼠模型中发现了出现临床关节炎症状之前的早期亚临床肠道炎症。到目前为止，血清素主要由肠嗜铬细胞在肠道中产生，在 RA 进展过程中的不同阶段都有影响。然而，关于血清素对 RA 疾病改善方向的影响尚未达成共识，尽管血清素对一般免疫反应的影响已被广泛研究，但细胞外血清素与细胞内血清素化在 RA 进展中的潜在双相作用尚未得到证实。血清酰化是一种选择性翻译后修饰，最早于 2000 年代初被描述，迄今为止尚未被考虑，它调节多种细胞过程，最近因被重新关注而重新受到关注。在这里，我们追求较高的血清素水平可以预防早期临床 RA 发病，而随后树突状细胞 (DC)、单核细胞和巨噬细胞中持续的细胞内血清素化通过维持促炎表型来促进疾病进展和慢性化。根据我们的假设，我们在 CIA 模型的早期和晚期发现了两个清晰的血清血清素峰值。此外，早期口服血清素前体 5-羟色氨酸 5-HTP 有效，而晚期治疗则加剧了临床关节炎评分。该提案旨在通过关注来揭示血清素的作用。 RA 进展过程中骨髓先天免疫细胞内血清素化的后果。