Central serotonin attenuates LPS-induced systemic inflammation

Abstract

Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280-350g, 8-9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25±1°C), light (06:00-18:00) and humidity (60-65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) - the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100μg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40μg/μL) and measured Tb ("hallmark" of SI), AVPO prostaglandin E₂ [(PGE₂) - an essential mediator of fever] and prostaglandin D₂ [(PGD₂) - a cryogenic mediator], plasma corticosterone [(CORT) - a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) - an immune mediator] levels. Detection limits of PGE₂, PGD₂, CORT and IL-6 assays were 39.1-2500pg/mL, 19.5-2500pg/mL, 0.12-2000μg/dL, and 0.125-8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE₂ (whereas PGD₂ remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40μg/μL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10μg/μL) microinjection prevented the LPS-induced increases in AVPO PGE₂ (whereas not altering PGD₂), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE₂ synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases.

Keywords: Corticosterone; Endotoxin; Fever; Heat loss index; IL-6; LPS; Thermoregulation.