Proteasomal-dependent endothelial P2Y6 receptor downregulation as an adaptive mechanism limiting monocyte adhesion during intestinal schistosomiasis

Schistosomiasis, a complex chronic intravascular parasitic disease caused by Schistosoma mansoni, triggers a multifaceted host immune response and drives endothelial cells toward a sustained proinflammatory phenotype. The dysfunctional endothelial cells are a hallmark event that contributes to intestinal and liver damage mainly due to an increased monocyte adhesion, but the elevated morbidity unveils the lack of knowledge about disease pathogenesis. Purinergic P2Y₆ receptor (P2Y₆R) expression is induced in some inflammatory models; therefore, we hypothesized that endothelial P2Y₆R contributes to monocyte adhesion and mesenteric inflammation in S. mansoni-infected mice. Our results show that, unlike control mice, P2Y₆R stimulation failed to enhance monocyte adhesion to endothelial cells from infected animals. Molecular analyses using RT-qPCR and immunocytochemistry revealed significant downregulation of P2Y₆R expression in endothelial cells from the infected group at both transcript and protein levels. Importantly, pretreatment with a proteasome inhibitor restored both P2Y₆R expression and function, implicating proteasomal degradation as a key mechanism underlying receptor loss during infection. Elevated lipid peroxidation in endothelial cells from the infected group further supported a role for reactive oxygen species (ROS)-dependent proteasome activation and receptor degradation. Collectively, these findings suggest that infection selectively modulates P2Y₆R signaling by promoting proteasome-dependent downregulation of P2Y₆R in endothelial cells, which could be an adaptive mechanism to reduce mesenteric inflammation and limit host tissue damage and morbidity during chronic infection.