Роль 5-HT2B-серотонинового рецептора в модулярном воздействии флюоксина на взаимодействие макрофагов с CD4+T-клетками при множественном склерозе.

The role of 5-HT2B-serotonin receptor in the modulatory effect of fluoxetine on interaction of macrophages with CD4+ T-cells in multiple sclerosis.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that also has an effect on the immune system and may affect neuroinflammation. We investigated the influence of fluoxetine on CD4+ T-cell activation induced by primary monocyte-derived macrophages (MPHs) in 26 patients with relapsing-remitting multiple sclerosis (MS) and 25 healthy subjects. We found that fluoxetine suppressed the expression of mRNA and secretion of the Th17-promoting cytokines IL-6 and IL-1β by interferon-γ/lipopolysaccharide (IFN-γ/LPS)-activated MPHs in both groups. Fluoxetine also suppressed the ability of MPHs to induce IL-17 and IFN-γ production by autologous CD4+ T-cells in both MS patients and healthy subjects. This effect was reversed by a selective antagonist of the 5-HT2B-receptor (5-HT2BR, RS 127445) or by monoclonal antibody to 5-HT2BR. Furthermore, stimulation of 5-HT2BR with a specific agonist (BW 723C86) suppressed the cytokine production and CD4+ T-cells activation by IFN-γ/LPS-stimulated MPHs in both groups. Finally, we found that IFN-γ/LPS-stimulated MPHs do not produce serotonin and that fluoxetine causes no increase of serotonin levels in MPHs supernatants. Furthermore, exogenous serotonin does not affect the functions of MPHs in either patients or donors, assuming a serotonin-independent mechanism of MPHs modulation by fluoxetine. Taken together, the results of the study suggest an anti-inflammatory effect of fluoxetine on the MPHs - CD4+ T-cells interaction in MS through 5-HT2BR activation, which allows us to consider 5-HT2BR targeting by fluoxetine as a potential additional therapeutic approach in MS.