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<p>Schistosomiasis, a complex chronic intravascular parasitic disease caused by <i>Schistosoma mansoni</i>, 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 P2Y<sub>6</sub> receptor (P2Y<sub>6</sub>R) expression is induced in some inflammatory models; therefore, we hypothesized that endothelial P2Y<sub>6</sub>R contributes to monocyte adhesion and mesenteric inflammation in <i>S. mansoni</i>-infected mice. Our results show that, unlike control mice, P2Y<sub>6</sub>R stimulation failed to enhance monocyte adhesion to endothelial cells from infected animals. Molecular analyses using RT-qPCR and immunocytochemistry revealed significant downregulation of P2Y<sub>6</sub>R expression in endothelial cells from the infected group at both transcript and protein levels. Importantly, pretreatment with a proteasome inhibitor restored both P2Y<sub>6</sub>R 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 P2Y<sub>6</sub>R signaling by promoting proteasome-dependent downregulation of P2Y<sub>6</sub>R in endothelial cells, which could be an adaptive mechanism to reduce mesenteric inflammation and limit host tissue damage and morbidity during chronic infection.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Nathalia F. Oliveira,
  • Matheus M. L. V. Monteiro,
  • Leticia D. Crepaldi,
  • Robson Coutinho-Silva,
  • Luiz Eduardo B. Savio,
  • Claudia L. Martins Silva

摘要

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.

Graphical Abstract