PLZF调控ASC炎症小体参与类风湿性关节炎发病的分子机制及其靶点干预

最近研究表明炎症小体信号调控的关键因子凋亡相关斑点样蛋白(ASC)介导的白介素IL1β, IL-18的活化是类风湿性关节炎RA典型的病理变化特征,但其分子调控机制尚不清？我们前期工作发现RA患者外周血单核细胞中早幼粒细胞白血病锌指蛋白（PLZF）的基因表达比正常人高。在与人炎症性关节炎模型相似的K/BxN血清转移性关节炎中,PLZF缺失与ASC缺失的小鼠相似, 表现为临床和组织学评分明显降低,这表明PLZF在调节关节炎中起着重要作用。在多种NLRP3刺激剂作用下,PLZF缺乏的巨噬细胞Caspase-1和IL-1β的活化和分泌明显下降,并且ASC斑点及ASC多聚体的形成显著降低,这提示PLZF可能调控ASC炎症小体。通过探讨PLZF调节ASC活性的分子机制并对RA的临床影响,以PLZF与ASC相互作用作为潜在开发的药物靶点，来替代当前NLRP3,IL1β抑制剂临床效果不佳的新型靶向疗法。

Rheumatoid arthritis (RA) is a chronic autoinflammatory disease. Recently, apoptosis-associated speck-like protein (ASC) was considered an essential component in the inflammasome signals. ASC regulated inflammasome activity led to the characteristic pathological changes in RA that mediate the activation of caspase-1, interleukin IL-1b and IL-18, but the molecular regulation and target therapy are unclear? Our previous work found that: 1) Gene expression of the transcription factor promyelocytic leukemia zinc finger protein (PLZF) in peripheral blood mononuclear cells of clinically rheumatoid arthritis (RA) patients is higher than that of normal people, 2 ) At the same time, in the K / BxN serum transfer-induced arthritis model, PLZF-/- mice showed dramatic reduced clinical and histological scores in the arthritis model, which is similar to ASC-/- mice, indicating that PLZF is regulating arthritis plays an important role in the disease. 3) Molecular mechanism: The deficiency of PLZF show reduce the activation of Caspase-1 and IL-1β secretion in macrophages responses to various NLRP3 stimulation, and it also had significantly reduce the formation of ASC specks and ASC dimers and oligomers. Besides, we found that PLZF and ASC proteins have a direct interaction through immunoprecipitation and co-localization analysis, suggesting that PLZF may regulate ASC inflammasome activity. We have previously found that PLZF regulates inflammatory signals at the epigenetic level (PNAS & Nat Commun 2015), but it is the first time show that PLZF regulates inflammasome signals. To understand the molecular mechanism that regulates ASC inflammasome activity through PLZF and regulates clinical effects on RA, Exploring the site of PLZF interaction with ASC can be used as a potential drug target for the development of small molecules to replace NLRP3, IL-1β inhibitors with poor clinical efficacy of new targeted therapies.