Internal medicine

Receptor

Pyroptosis

Biology

Necroptosis

Caspase 1

Apoptosis

P2Y receptor

Chemistry

Immunology

Inflammation

Forskolin

Inflammasome

Programmed cell death

Purinergic receptor

Cell biology

Biochemistry

Medicine

Cell Death and Disease

Nod-like receptor protein 3 (NLRP3)-mediated pyroptosis has a causal role in the pathogenesis of gout. P2Y 14 receptor (P2Y 14 R) distributed in immune cells including macrophages is a Gi-coupled receptor that inhibits the synthesis of cAMP, which has been regarded as a potential regulator of inflammatory response. Nevertheless, the role of P2Y 14 R in MSU-induced pyroptosis of macrophages involved in acute gouty arthritis is still unclear. In our present study, P2Y 14 R knockout (P2Y 14 R-KO) disrupted MSU-induced histopathologic changes in rat synoviums, accompanied with a significant inhibition of pyroptotic cell death characterized by Caspase-1/PI double-positive and blockade of NLRP3 inflammasome activation in synovial tissues, which was consistent with that observed in in vitro studies. Owing to the interaction of NLRP3 inflammasome and cAMP, we then investigated the effect of adenylate cyclase activator (Forskolin) on macrophage pyroptosis and gout flare caused by MSU stimulation. The reversal effect of Forskolin verified the negative regulatory role of cAMP in MSU-induced pyroptosis. More importantly, adenylate cyclase inhibitor (SQ22536) intervention led to a reversal of protection attributed to P2Y 14 R deficiency. Findings in air pouch animal models also verified aforementioned experimental results. Our study first identified the role of P2Y 14 R/cAMP/NLRP3 signaling pathway in acute gouty arthritis, which provides a novel insight into the pathological mechanisms of pyroptosis-related diseases.

P2Y14 receptor has a critical role in acute gouty arthritis by regulating pyroptosis of macrophages