Serotonin Synthesis Enzyme Lack Linked With Rheumatoid Arthritis

Experimentally-induced rheumatoid arthritis in serotonin-deficient mice is worse than the same disease reported in no-deficient mice, a recent study shows. Additionally, it was found that some effects of rheumatoid arthritis (RA) can be reduced by serotonin or its agonists (compounds that activate serotonin receptors).

This is the first time, serotonin (5-hydroxytryptamine, 5-HT) has been directly implicated in the pathophysiology of rheumatoid arthritis. Although serotonin is predominantly known as a neurotransmitter within the central nervous system, new evidence points to additional important functions for serotonin in the periphery.

The findings could lay the groundwork for new treatment approaches for rheumatoid arthritis. Co-lead investigator Marie-Christine de Vernejoul of the Hôpital Lariboisière, Université Paris Diderot, explains:

“Our study highlights that 5-HT has a direct immunoregulatory role in arthritis. The development of treatments targeting 5-HT or 5-HT receptors could represent an exciting prospect to regulate the immune response in RA and open new perspectives to improve the therapeutic options for patients.”

Collagen-induced Arthritis

The investigators used a mouse model of RA known as collagen-induced arthritis (CIA) that produces features similar to that of human RA. Disease manifestations include cartilage and bone destruction, as well as the activation of cells responsible for bone resorption, known as osteoclasts.

They compared the effects of CIA in normal mice to those in mice genetically bred with a deficiency in tryptophan hydroxylase-1, a key enzyme needed for serotonin production in peripheral tissues.

Investigators found that both the number and activity of osteoclasts were higher in 5-HT-deficient mice with arthritis. In addition, more bone resorption was detected both at the affected joints and at remote sites.

The serotonin-deficient mice with arthritis also showed changes in certain cell-signaling molecules known as cytokines (higher IL-17, higher TNF-α, and lower IL-4) in their paws. Specifically, they displayed a shift in the balance between T cell subtypes, especially regulatory T cells and Th17 lymphocytes.

New Therapeutic Target?

Co-lead investigator Francine Côté of the Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Hôpital Necker in Paris, noted:

“Altogether, our data show that 5-HT deficient mice are characterized by a relative, dampened expansion of Treg associated with an enhanced shift toward a Th17 phenotype, a situation previously described in patients with arthritis.”

Subsequent experiments using cell cultures showed that the balance between Th17/Treg cells could be normalized by the addition of 5-HT or 5-HT receptor agonists, revealing a direct regulatory role of serotonin in RA. These novel data suggest a new therapeutic target that could be important for this disabling disease.

Yasmine Chabbi-Achengli, Tereza Coman, Corinne Collet, Jacques Callebert, Michelangelo Corcelli, Hilène Lin, Rachel Rignault, Michel Dy, Marie-Christine de Vernejoul, Francine Côté
Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption
The American Journal of Pathology, 2016; DOI: 10.1016/j.ajpath.2015.11.018

Image: Alan Handyside, Wellcome Images

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