The biphasic spatiotemporal role of serotonin in RA progression

几十年前就观察到肠道对关节炎发展的影响；但其中的连接机制仍有待充分阐明。我们已经在胶原诱导关节炎（CIA）小鼠模型以及新发、未接受治疗的类风湿性关节炎（RA）患者中发现了早期亚临床肠道炎症先于临床关节炎症状。到目前为止，主要由肠色素细胞在肠道中产生的血清素被证明影响类风湿关节炎进展的不同阶段。然而，血清素对RA疾病改善方向的影响尚未达成共识。尽管5 -羟色胺对一般免疫反应的影响已被广泛研究，但迄今为止尚未考虑到细胞外5 -羟色胺与细胞内5 -羟色胺在RA进展中的潜在双相作用。5 -羟色胺化是一种选择性的翻译后修饰，在21世纪初首次被描述，它调节了几个细胞过程，最近被描述为一种新的表观遗传调控机制而重新受到关注。在这里，我们假设较高的血清素水平可以预防早期临床RA发病，而随后在树突状细胞（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。与我们的假设一致，我们在CIA模型的早期和晚期发现了血清血清素的两个明显峰值。选择性血清素再摄取抑制剂（SSRI）治疗仅在CIA临床晚期有效。此外，早期口服5-羟色胺前体5-羟色氨酸（5-HTP）治疗可以预防炎症性关节炎，而晚期治疗会加重临床关节炎评分。本研究旨在通过关注类风湿性关节炎进展过程中髓系先天免疫细胞内5 -羟色胺化的后果来揭示5 -羟色胺的作用。

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.