Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β.
Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β.
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DOI：
10.1084/jem.20142384
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Masters SL
中科院分区：
文献类型：
--
作者：
Kim ML;Chae JJ;Park YH;De Nardo D;Stirzaker RA;Ko HJ;Tye H;Cengia L;DiRago L;Metcalf D;Roberts AW;Kastner DL;Lew AM;Lyras D;Kile BT;Croker BA;Masters SL
Kim等人在小鼠中发现了一种由IL-18驱动的自身炎症性疾病，该疾病是由肌动蛋白解聚辅因子Wdr 1的失活突变引起的。肌动蛋白动力学的这种改变被pyrin炎性体识别，并导致单核细胞IL-18产生增加，而成熟巨噬细胞中的炎性体活化没有改变。激活先天免疫系统的功能获得性突变可导致与IL-1β产生增加相关的全身性自身炎性疾病。这种细胞因子被称为炎性体的细胞内蛋白质复合物与IL-18相同地激活;然而，IL-18尚未特别涉及遗传性自身炎性疾病的发病机制。我们现在已经确定了一种由IL-18而不是IL-1β驱动的小鼠自身炎症性疾病，其由肌动蛋白解聚辅因子Wdr 1的失活突变引起。这种肌动蛋白聚合的扰动导致全身性自身炎症，当IL-18缺失时，但当IL-1信号传导被去除时，这种自身炎症减少。值得注意的是，成熟巨噬细胞中的炎性小体活化没有改变，但单核细胞的IL-18产生被大大夸大，并且体内单核细胞的消耗防止了疾病。肌动蛋白聚合的小分子抑制可以从系统中去除潜在的危险信号，并阻止单核细胞IL-18的产生。最后，我们表明，在这个系统中的肌动蛋白动力学的炎症传感器需要caspase-1，凋亡相关的斑点样蛋白含有caspase的招聘结构域，和先天免疫受体pyrin。以前，由病原体引起的肌动蛋白聚合的扰动被证明可以激活pyrin炎性体，因此我们的数据现在将这一守卫假说扩展到宿主调节的肌动蛋白依赖性过程和自身炎症性疾病。
Kim et al. identify an autoinflammatory disease in mice that is driven by IL-18, resulting from an inactivating mutation in the actin-depolymerizing cofactor Wdr1. This alteration in actin dynamics is recognized by the pyrin inflammasome and results in exaggerated monocyte IL-18 production, whereas inflammasome activation in mature macrophages is unaltered. Gain-of-function mutations that activate the innate immune system can cause systemic autoinflammatory diseases associated with increased IL-1β production. This cytokine is activated identically to IL-18 by an intracellular protein complex known as the inflammasome; however, IL-18 has not yet been specifically implicated in the pathogenesis of hereditary autoinflammatory disorders. We have now identified an autoinflammatory disease in mice driven by IL-18, but not IL-1β, resulting from an inactivating mutation of the actin-depolymerizing cofactor Wdr1. This perturbation of actin polymerization leads to systemic autoinflammation that is reduced when IL-18 is deleted but not when IL-1 signaling is removed. Remarkably, inflammasome activation in mature macrophages is unaltered, but IL-18 production from monocytes is greatly exaggerated, and depletion of monocytes in vivo prevents the disease. Small-molecule inhibition of actin polymerization can remove potential danger signals from the system and prevents monocyte IL-18 production. Finally, we show that the inflammasome sensor of actin dynamics in this system requires caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain, and the innate immune receptor pyrin. Previously, perturbation of actin polymerization by pathogens was shown to activate the pyrin inflammasome, so our data now extend this guard hypothesis to host-regulated actin-dependent processes and autoinflammatory disease.
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