A sinalização adenosinérgica na regulação da gravidade da sepse e da liberação de armadilhas extracelulares de neutrófilos (NETs)

Abstract

Neutrophils express different purinergic receptors, including four adenosine-ligand P1 receptors, which regulate their primary functions, such as migration and production of inflammatory mediators, including neutrophil extracellular traps (NETs). In sepsis, NETs exhibit a dual role: microbicidal properties but also contribute to organ damage, leading to multiple organ failure and worsening the clinical condition. In this study, we investigated the role of adenosine in NETs release and the progression of experimental sepsis induced by the Cecum Ligation and Puncture (CLP) or endotoxemia models. We observed that treatment of mice subjected to both models with adenosine deaminase (ADA), which metabolizes adenosine to inosine, aggravates organ damage and reduces the survival rate of septic animals. Supporting these findings, we demonstrated that NET production in vitro by neutrophils stimulated with PMA was enhanced by ADA treatment and reduced by NECA, a molecule that mimics adenosine's actions. The modulation of NET production by adenosine was attributed to the activation of A2AAR receptors. In conclusion, our results suggest that during sepsis, adenosine is released and decrease NET production via A2AAR activation.