P2Y₁₃ receptor involved in HIV-1 gp120 induced neuropathy in superior cervical ganglia through NLRP3 inflammasome activation

Cardiac autonomic neuropathy resulting from human immunodeficiency virus (HIV) infection is common; however, its mechanism remains unknown. The current work attempted to explore the function and mechanism of the P2Y₁₃ receptor in HIV-glycoprotein 120 (gp120)-induced neuropathy in cervical sympathetic ganglion. The superior cervical ganglion (SCG) of the male SD rat was coated with HIV-gp120 to establish a model of autonomic neuropathy. In each group, we measured heart rate, blood pressure, heart rate variability, sympathetic nerve discharge and cardiac function. The expression of P2Y₁₃ mRNA and protein in the SCG was tested by real-time polymerase chain reaction and western blotting. Additionally, this study focused on identifying the protein levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3), Caspase-1, Gasdermin D (GSDMD), interleukin (IL)-1β and IL-18 in the SCG using western blotting and immunofluorescence. In gp120 rats, increased blood pressure, heart rate, cardiac sympathetic nerve activity, P2Y₁₃ receptor levels and decreased cardiac function could be found. P2Y₁₃ shRNA or MRS2211 inhibited the above mentioned changes induced by gp120, suggesting that the P2Y₁₃ receptor may be engaged in gp120-induced sympathetic nerve injury. Moreover, the levels of NLRP3, Caspase-1, GSDMD, IL-1β and IL-18 in the gp120 group were increased, while significantly decreased by P2Y₁₃ shRNA or MRS2211. Therefore, the P2Y₁₃ receptor is involved in gp120-induced sympathetic neuropathy, and its molecular mechanism shows an association with the activation of the NLRP3 inflammasome, followed by GSDMD formation along with the release of inflammatory factors including IL-1β and IL-18. This article is part of the Special Issue on “Purinergic Signaling: 50 years”.