Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice.
Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice.
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DOI：
10.1371/journal.pbio.3000047
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发表时间：
2018-11
期刊：
影响因子：
9.8
通讯作者：
Mbalaviele G
中科院分区：
文献类型：
--
作者：
Xiao J;Wang C;Yao JC;Alippe Y;Xu C;Kress D;Civitelli R;Abu-Amer Y;Kanneganti TD;Link DC;Mbalaviele G
突变的NLRP3组装了一个过度活跃的炎症体，导致IL-1β和IL-18的过度分泌，最终导致一系列被称为低温肾炎的自体炎症性疾病，其中新生儿起病的多系统炎症性疾病是最严重的表型。NOMID小鼠表现出人类疾病的几个特征，因为它们出现了由IL-1β和IL-18过度产生引起的严重全身炎症，并与多个器官的损害有关，包括脾、皮肤、肝脏和骨骼。IL-1β和IL-18的分泌需要Gasdermin D(GSDMD)，当被炎症小体激活时，GSDMD被转移到质膜，在那里它形成毛孔，这些细胞因子通过毛孔释放。然而，由于GSDMD的持续激活而导致的过度毛孔形成损害了膜的完整性，并最终导致一种称为下垂的促炎形式的细胞死亡。在这项研究中，我们首先在体外建立了NLRP3炎性小体激活与GSDMD处理和上睑下垂之间的强烈相关性。接下来，我们使用NOMID小鼠来确定GSDMD驱动的上睑下垂影响这种疾病的发病机制的程度。值得注意的是，在GSDMD消融后，所有与NOMID相关的炎症症状都得到了预防。因此，GSDMD依赖的作用在NOMID小鼠的发病机制中是必需的。由致孔蛋白Gasdermin D介导的下睑下垂在新生儿多系统炎症性疾病的发病机制中起着关键作用。新生儿多系统炎症性疾病是一种严重的遗传性自身炎症性疾病，由NLRP3/低温比林基因的激活突变引起。NLRP3炎症体在IL-1、β和IL-18的成熟过程中起重要作用。因此，NLRP3功能获得突变导致一系列被称为低温比林相关周期性综合征(CAPS)的自体炎症性疾病，与IL-1β和IL-18的过度产生有关。虽然与CAPS相关的炎症症状是用IL-1阻滞剂治疗的，但新出现的证据表明，一些CAPS患者对这些药物只有部分反应。在缺乏IL-1β和IL-18信号的CAPS小鼠中也有持续炎症反应的报道，这可能是由炎性小体的另一种效应物Gasdermin D(GSDMD)诱导的促炎细胞死亡-下垂的后果。与这一观点一致，我们发现，在CAPS的小鼠模型中，GSDMD的消融可以防止对多个器官的损害。
Mutated NLRP3 assembles a hyperactive inflammasome, which causes excessive secretion of interleukin (IL)-1β and IL-18 and, ultimately, a spectrum of autoinflammatory disorders known as cryopyrinopathies of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID mice phenocopy several features of the human disease as they develop severe systemic inflammation driven by IL-1β and IL-18 overproduction associated with damage to multiple organs, including spleen, skin, liver, and skeleton. Secretion of IL-1β and IL-18 requires gasdermin D (GSDMD), which—upon activation by the inflammasomes—translocates to the plasma membrane where it forms pores through which these cytokines are released. However, excessive pore formation resulting from sustained activation of GSDMD compromises membrane integrity and ultimately causes a pro-inflammatory form of cell death, termed pyroptosis. In this study, we first established a strong correlation between NLRP3 inflammasome activation and GSDMD processing and pyroptosis in vitro. Next, we used NOMID mice to determine the extent to which GSDMD-driven pyroptosis influences the pathogenesis of this disorder. Remarkably, all NOMID-associated inflammatory symptoms are prevented upon ablation of GSDMD. Thus, GSDMD-dependent actions are required for the pathogenesis of NOMID in mice. Pyroptosis mediated by the pore-forming protein gasdermin D plays a crucial role in the pathogenesis of neonatal-onset multisystem inflammatory disease, a severe genetic autoinflammatory disorder resulting from activating mutations in the NLRP3/cryopyrin gene. The NLRP3 inflammasome plays an important role in the maturation of interleukin (IL)-1β and IL-18. Accordingly, NLRP3 gain-of-function mutations, which cause a spectrum of autoinflammatory disorders known as cryopyrin-associated periodic syndromes (CAPS), are associated with excessive IL-1β and IL-18 production. Although CAPS-associated inflammatory symptoms are treated with IL-1-blocking agents, emerging evidence indicates that some CAPS patients only partially respond to these drugs. Persistent inflammatory responses have also been reported in CAPS mice deficient in IL-1β and IL-18 signaling and may be the consequences of the pro-inflammatory cell death, pyroptosis, which is induced by gasdermin D (GSDMD), the other effector of the inflammasomes. Consistent with this view, we found that damage to multiple organs that manifested in a mouse model of CAPS was prevented by ablation of GSDMD.
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影响因子：
8.7
作者：
Man SM;Karki R;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
4.6
作者：
Man SM;Karki R;Briard B;Burton A;Gingras S;Pelletier S;Kanneganti TD
通讯作者：
Kanneganti TD
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
影响因子：
15.9
作者：
McGeough, Matthew D.;Wree, Alexander;Hoffman, Hal M.
通讯作者：
Hoffman, Hal M.
DOI：
10.1073/pnas.1722041115
发表时间：
2018-06-26
影响因子：
11.1
作者：
McKenzie, Brienne A.;Mamik, Manmeet K.;Power, Christopher
通讯作者：
Power, Christopher