Inflammasomes are essential for inflammation and pathogen elimination in response to microbial infection and endogenous danger signals. However, the mechanism of inflammasome activation by endogenous danger signals mediated posttranslational modification and the connection between inflammasomes and inflammatory diseases remains elusive. In this study, we found that ADP was highly released from injured colonic tissue as a danger signal during inflammatory bowel disease. Consequently, extracellular ADP activated the NLRP3 inflammasome through P2Y₁ receptor-mediated calcium signaling, which led to the maturation and secretion of IL-1β and further aggravation of experimental colitis. Genetic ablation or pharmacological blockade of the P2Y₁ receptor significantly ameliorated DSS-induced colitis and endotoxic shock through reducing NLRP3 inflammasome activation. Moreover, ERK5-mediated tyrosine phosphorylation of ASC was essential for activation of the NLRP3 inflammasome. Thus, our study provides a novel theoretical basis for posttranslational modification of ASC in NLRP3 inflammasome activation and revealed that ADP/P2Y₁ is a potential drug target for inflammatory bowel disease.

炎症小体对于炎症和病原体消除至关重要，以应对微生物感染和内源性危险信号。然而，内源性危险信号介导的翻译后修饰激活炎性体的机制以及炎性体与炎症性疾病之间的联系仍然难以捉摸。在这项研究中，我们发现 ADP 从受损的结肠组织中大量释放，作为炎症性肠病期间的危险信号。_{因此，细胞外ADP通过P2Y 1}受体介导的钙信号激活NLRP3炎性体，导致IL-1β的成熟和分泌，进一步加重实验性结肠炎。_{P2Y 1}的基因消融或药理阻断受体通过减少 NLRP3 炎性体激活显着改善 DSS 诱导的结肠炎和内毒素休克。此外，ERK5 介导的 ASC 酪氨酸磷酸化对于 NLRP3 炎性体的激活至关重要。因此，我们的研究为 NLRP3 炎性体激活中 ASC 的翻译后修饰提供了新的理论基础，并揭示了 ADP/P2Y ₁是炎症性肠病的潜在药物靶点。