Role of the P2Y2 nucleotide receptor in inflammation and inflammatory diseases

Abstract

Nucleotides are released from cells in response to tissue damage and activate P2X and P2Y receptors on the cell surface to regulate inflammation, a critical process for wound repair. During inflammation, leukocytes are recruited from the bone marrow (BM) to the bloodstream and cross the vasculature at sites of injury or infection. Accumulating evidence indicates that the P2Y2 nucleotide receptor (P2Y2R) is an important regulator of many inflammatory events, especially leukocyte infiltration. Here, we show that the endothelial P2Y2R contributes to the transmigration of leukocytes and macromolecules through blood vessels by interacting with vascular endothelial cadherin (VE-cadherin) and vascular endothelial growth factor receptor-2 to control phosphorylation of VE-cadherin and associated signaling molecules that regulate RhoA and Rac1 activities, which modulate the junctional integrity of endothelium through remodeling of the cytoskeleton. In vivo studies using the TgCRND8 (Tg+) mouse model of Alzheimer's disease, a chronic inflammatory and neurodegenerative disease, demonstrate that the P2Y2R regulates the release of neutrophils and monocytes from the BM to the peripheral blood, which may contribute to clearance of toxic β-amyloid plaques in the brain. The impaired emigration of leukocytes out of the BM in Tg+P2Y2R+/− mice is likely due to the essential role of the leukocytic P2Y2R in sensing and amplifying chemoattractant signals while the retention signals for blood cells in the BM is strikingly reduced compared to Tg+ mice. In summary, this work has revealed novel functions of the P2Y2R in regulation of leukocyte trafficking from the BM to the blood and to sites of inflammation.