Project Details
Projekt
The biphasic spatiotemporal role of serotonin in RA progression
Subject Area
Rheumatology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 528341753
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.
DFG Programme
Research Grants
Co-Investigator
Dr. Natalia Alenina, Ph.D.
