The P2Y1 receptor-mediated leukocyte adhesion to endothelial cells is inhibited by melatonin

Abstract

Extracellular ATP (released by endothelial and immune cells) and its metabolite ADP are important pro-inflammatory mediators via the activation of purinergic P2 receptors (P2Y and P2X), which represent potential new targets for anti-inflammatory therapy. Endothelial P2Y receptor (P2YR) induces endothelial cell activation triggering leukocyte adhesion. A number of data have implicated melatonin as a modulator of immunity, inflammation, and endothelial cell function, but to date no studies have investigated whether melatonin modulates endothelial P2YR signaling. Here, we evaluated the putative effect of melatonin on P2YR-mediated leukocyte adhesion to endothelial cells and TNF-α production, using mesenteric endothelial cells and fresh peripheral blood mononuclear cells isolated from rats. Endothelial cells were treated with the P2YR agonist 2MeSATP, alone or in combination with melatonin, and then exposed to mononuclear cells. 2MeSATP increased leukocyte adhesion to endothelial cells and TNF-α production in vitro, and melatonin inhibited both effects without altering P2YR protein expression. In addition, assays with the Ca chelator BAPTA-AM indicate that the effect of melatonin on 2MeSATP-stimulated leukocyte adhesion depends on intracellular Ca modulation. P2YR is considered a potential target to control chronic inflammation. Therefore, our data unveiled a new endothelial cell modulator of purinergic P2Y receptor signaling.

Inflammation and thrombosis in COVID-19 pathophysiology: proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets

“…P2Y 12 -mediated ADP signaling can promote inflammation via actions on innate immune cells, especially dendritic cells and macrophages ( 99 , 100 ). P2Y 1 and P2X 2 may also have proinflammatory effects on immune cells ( 92 , 101 ). In addition, P2Y 12 may contribute to endothelial cell pathology ( 102 , 103 ).…”

Role of endothelial cell receptors in the context of SARS-CoV-2 infection (COVID-19)

“…33 The purinergic P2Y 1 receptor (P2Y 1 R) on ECs induces EC activation and mediates leukocyte adhesion and TNF-a production. 34 The other purinergic receptors, P2X7 and P2X4, are also involved in high glucose and palmitate-mediated EC activation and EC dysfunction. 35 Exposure of human umbilical vein ECs to high glucose and palmitate causes activation of P2X7 and P2X4, which results in increased intracellular reactive oxygen species and reduced endothelial nitric oxide synthase, which contribute to EC dysfunction.…”

Immune‐pineal axis – acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes

“…The regulation of leukocyte migration by melatonin relies on melatonin inhibition of the expression of adhesion molecules in the endothelial layer (Tamura et al, 2010). The suppression of nocturnal melatonin synthesis by the pineal gland makes the endothelial cells more reactive to PAMPs and DAMPs, including ATP, from inflammatory sites (Cardoso et al, 2017). Activated macrophages/microglia synthesize melatonin in an NFκB-dependent manner at the site of the inflammatory response.…”