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

TL;DR

This study shows that during intestinal schistosomiasis, endothelial cells reduce P2Y6 receptor levels via proteasomal degradation, which may help limit inflammation and tissue damage.

Contribution

The paper identifies proteasomal-dependent downregulation of P2Y6 receptors in endothelial cells as a novel adaptive mechanism during schistosomiasis.

Findings

P2Y6R expression is significantly downregulated in endothelial cells of infected mice.

Proteasome inhibition restores P2Y6R expression and function in infected endothelial cells.

ROS-dependent proteasome activation is linked to P2Y6R degradation during infection.

Abstract

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.

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