CONICET | Buscador de Institutos y Recursos Humanos

Reactive arthritis (ReA) prone mice have higher basal serotonin (5-HT) serumlevels, as we have previously observed. Serotonin can regulate innate andadaptive immune functions; accordingly, selective serotonin receptor inhibitors(SSRIs) such as fluoxetine that modify 5-HT availability also have an antiinflammatory effect. On this line, fluoxetinereduces the severity of ReA in ourmurine model. This outcome could be related to reduced 5-HT availability andtransglutaminase-2 (TG2)-dependent pos-traduction modifications known asserotonylation. Nevertheless, the mechanism involved is still unknown. Thus, inthis work, we aim to evaluate the impact of serotonylation blockade in thedevelopment of reactive arthritis (ReA). In our study model, mice deficient in TNFreceptor 1 (TNFR1 KO) develop ReA as a sequela after infection with Yersiniaenterocolitica (Ye). Thus, TNFR1 KO mice were orally infected with Ye O:3 (1-5x108 bacteria/mouse) and divided into four groups. Group 1 received water(control) in the drinking bottle, Group 2 received fluoxetine, Group 3 cysteamine(TG2 inhibitor) and Group 4 received the combined treatment (fluoxetine andcysteamine) administrated in the drinking water. The mice that survived theinfection developed ReA. The incidence and clinical score were periodicallyrecorded, considering the inflammation of the four legs. On day 21, the mice wereeuthanized, and flow cytometry was performed from bloodand draining lymphnode samples. DCs, macrophages, neutrophils and T cell infiltrates wereevaluated in the samples. Finally, one-way ANOVA and linear regression wasusedto determine statistically significant differences. Our results indicate thatchronic inhibitionof TG2 with cysteamine and the serotonin reduction by fluoxetineattenuates ReA severitysimilarly in TNFR1 KO mice. In addition, the combinedtreatment not only reduces the clinical score but also delays the onset of ReA andreduces the incidence (p=0.0004). Importantly, at day 21 post-infection, areduction in neutrophils and DCs infiltrate was observed in the joint draininglymph nodes of treated mice compared with control mice (p=0.027). Besides, asignificant positive correlation was detected between neutrophil infiltration andclinical score (p=0.026, r=0,29). On the other hand, a negative correlationbetween T cell infiltration and ReA clinical score was also observed (p=0.032,r=0.33). Toconclude, the inhibition of serotonylation by reduction of serotoninlevels and TG2 activity attenuates the ReA severity in the murine model,decreases the neutrophils and DCs migration and enhances the T cells infiltrationof lymph nodes. Our results suggest that the increment in serotonylation eventsunder inflammatory contexts could be involved in the establishment andmaintenance of a chronic condition. On the same line, SSRIs andTG2 inhibitorscould be proposed as a therapy to reduce ReA severity

enviar mensaje