SPHK2/S1P通路调控巨噬细胞NLRP3炎症小体激活导致ARDS失控性炎症的分子机制及其临床意义

SPHK2/S1P信号通路和NLRP3炎症小体的激活是急性呼吸窘迫综合征（ARDS）失控性炎症发生的关键环节，我们的前期研究显示SPHK2/S1P信号通路参与调控巨噬细胞NLRP3炎症小体的激活，促进ARDS发展，但具体分子机制不清；预实验结果表明LPS呈时间依赖性上调SPHK2和NLRP3水平；敲减SPHK2可升高核内P53乙酰化水平，抑制NLRP3炎症小体的激活；生物信息学软件预测P53含有与NLRP3启动子的结合序列，因此本课题假设，发生ARDS时SPHK2高表达，产生大量核S1P，抑制去乙酰化酶（HDACs）活性，维持核P53高水平乙酰化，促进其与NLRP3启动子结合并激活NLRP3介导的炎症通路，产生大量的炎症因子，引起失控性炎症。本研究从分子相互作用和表观遗传修饰的层面进一步完善ARDS的发病机制，为抗炎治疗提供新的依据。

SPHK2/S1P signaling pathway and the activation of NLRP3 inflammasome were two key components of inflammatory cascade. Our previous studies have shown that the SPHK2/S1P signaling pathway was involved in the regulation of NLRP3 inflammasome in macrophage and exacerbating acute respiratory distress syndrome (ARDS). Meanwhile, the expression level of SPHK2 and NLRP3 was increased in a time-dependent manner treating with LPS; knockdown of SPHK2 increased the level of acetylated P53 in the nucleus and inhibited NLRP3 inflammasome activation. In addition, bioinformatics software predicted that P53 contains a binding sequence to the NLRP3 promoter. Therefore, we hypothesized that SPHK2, a lipid kinase, which was upregulated during ARDS, produced a large amount of nuclear S1P that specifically bound to HDACs, inhibited their enzymatic activities and increased P53 acetylation. Then, promoting the binding of the transcription factor P53 to the NLRP3 promoter and further activating the NLRP3-mediated inflammatory. The results will enrich the pathogenesis of lung injury from the level of gene epigenetic modification, and provide the scientific basis for ARDS anti-inflammatory treatment.