Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Recombinant ASC specks accelerated SAA fibril formation and mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain (PYD). In a murine model of inflammatory AA amyloidosis, splenic amyloid load was conspicuously decreased in Pycard-/- mice which lack ASC. Treatment with anti-ASCPYD antibodies decreased amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50 ≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. These findings expand the role played by ASC and IL-1 independent inflammasome employments to extraneural proteinopathies and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.

中文翻译：

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ASC 炎症小体接头在炎症性淀粉样变性中控制 SAA 衍生蛋白的聚集。


细胞外释放的分子炎性体组装体 -ASC 斑点 - 在阿尔茨海默病中交叉传播 Aβ 淀粉样蛋白。在这里，我们表明，ASC 控制炎症诱导的淀粉样蛋白 A (AA) 淀粉样变性的程度，淀粉样变性是一种由急性期反应物血清淀粉样蛋白 A (SAA) 在慢性炎症条件下聚集和外周沉积引起的全身性疾病。使用超分辨率显微镜，我们发现 ASC 与人类 AA 淀粉样变性中的 SAA 紧密共定位。重组 ASC 斑点加速了 SAA 原纤维的形成，有限蛋白水解后的质谱分析表明，ASC 通过其热蛋白结构域 (PYD) 与 SAA 相互作用。在炎症性 AA 淀粉样变性小鼠模型中，缺乏 ASC 的 Pycard-/- 小鼠脾脏淀粉样蛋白负荷显着减少。使用抗 ASCPYD 抗体治疗可减少患有 AA 淀粉样变性的野生型小鼠的淀粉样蛋白负荷。 19,334 名医院患者中天然抗 ASC IgG (-logEC50 ≥ 2) 的患病率为 <0.01%，表明抗 ASC 抗体治疗方式不会与自然自身免疫相混淆。这些发现扩大了 ASC 和 IL-1 独立炎症小体在神经外蛋白病中发挥的作用，并表明抗 ASC 免疫疗法可能有助于解决此类疾病。