Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Pediatric Internal Medicine, Anhui Province Children's Hospital, Hefei, China.
Oxid Med Cell Longev. 2023 Jan 12;2023:3317307. doi: 10.1155/2023/3317307. eCollection 2023.
Activation of the nod-like receptor protein 3 (NLRP3) inflammasome by monosodium urate (MSU) crystals has been identified as the molecular basis for the acute inflammatory response in gouty arthritis. However, MSU crystals alone are not sufficient to induce acute gouty arthritis (AGA). Adenosine triphosphate (ATP) is an endogenous signaling molecule involved in the NLRP3 inflammasome activation. We aimed to explore the role of ATP in MSU crystal-induced AGA development. In peripheral blood mononuclear cell-derived macrophages obtained from gout patients, we observed a synergistic effect of ATP on MSU crystal-induced IL-1 release. Furthermore, in a rat model of spontaneous gout, we demonstrated that a synergistic effect of ATP and MSU crystals, but not MSU crystals alone, is essential for triggering AGA. Mechanistically, this synergistic effect is achieved through the purinergic receptor P2X7 (P2X7R). Blockade of P2X7R prevented AGA induction in rats after local injection of MSU crystals, and carrying the mutant gene contributed to the inhibition of NLRP3 inflammasome activation induced by costimulation of MSU crystals and ATP . Taken together, these results support the synergistic effect of ATP on MSU crystal-induced NLRP3 inflammasome activation facilitating inflammatory episodes in AGA. In this process, P2X7R plays a key regulatory role, suggesting targeting P2X7R to be an attractive therapeutic strategy for the treatment of AGA.
尿酸单钠（MSU）晶体激活核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体被认为是痛风性关节炎急性炎症反应的分子基础。然而，单纯的 MSU 晶体不足以诱导急性痛风性关节炎（AGA）。三磷酸腺苷（ATP）是一种参与 NLRP3 炎性小体激活的内源性信号分子。我们旨在探讨 ATP 在 MSU 晶体诱导 AGA 发展中的作用。在从痛风患者中获得的外周血单核细胞衍生的巨噬细胞中，我们观察到 ATP 对 MSU 晶体诱导的 IL-1 释放具有协同作用。此外，在自发性痛风大鼠模型中，我们证明了 ATP 和 MSU 晶体的协同作用，而不仅仅是 MSU 晶体本身，对于引发 AGA 至关重要。从机制上讲，这种协同作用是通过嘌呤能受体 P2X7（P2X7R）实现的。P2X7R 阻断可防止 MSU 晶体局部注射后大鼠 AGA 的诱导，而携带突变 基因有助于抑制 MSU 晶体和 ATP 共刺激诱导的 NLRP3 炎性小体激活。总之，这些结果支持 ATP 对 MSU 晶体诱导的 NLRP3 炎性小体激活的协同作用，促进 AGA 中的炎症发作。在这个过程中，P2X7R 发挥了关键的调节作用，提示靶向 P2X7R 可能是治疗 AGA 的一种有吸引力的治疗策略。
