The NLRP3 Inflammasome Has a Critical Role in Peritoneal Dialysis-Related Peritonitis
The NLRP3 Inflammasome Has a Critical Role in Peritoneal Dialysis-Related Peritonitis
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DOI：
10.1681/asn.2016070729
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发表时间：
2017-07-01
影响因子：
13.6
通讯作者：
Devuyst, Olivier
中科院分区：
文献类型：
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作者：
Hautem, Nicolas;Morelle, Johann;Devuyst, Olivier
细菌性腹膜炎是腹膜透析技术失败的主要原因。在腹膜炎期间，腹膜经历由IL-1 β介导的结构和功能改变。NLRP 3炎性体是一种半胱天冬酶-1激活多蛋白复合物，其将微生物和应激产物的传感与促炎细胞因子（包括IL-1 β）的激活联系起来。尚未研究急性腹膜炎期间腹膜中NLRP 3炎性体和IL-1 β的潜在作用。在这里，我们发现NLRP 3炎性小体在PD患者的急性细菌性腹膜炎期间被激活，并且这种激活与透析液中IL-1 β的释放有关。在小鼠中，脂多糖或大肠杆菌诱导的腹膜炎导致腹膜释放IL-1 β。编码NLRP 3的Nalp 3的基因缺失消除了急性腹膜炎期间溶质转运的缺陷并恢复了超滤。在人脐静脉内皮细胞中，IL-1 β处理直接增强内皮细胞增殖并增加微血管通透性。这些体外效应需要内皮IL-1受体，免疫荧光显示其在小鼠腹膜毛细血管中表达。此外，给予IL-1 β受体拮抗剂阿那白滞素可有效降低腹膜炎小鼠模型中一氧化氮的产生和血管增殖，并恢复腹膜功能，即使在接受标准护理抗生素治疗的小鼠中也是如此。这些数据表明，NLRP 3激活和IL-1 β释放在PD相关腹膜炎期间溶质转运缺陷和组织重塑中具有关键作用。阻断NLRP 3/IL-1 β轴为急性腹膜炎期间挽救形态学改变和转运缺陷提供了一种新方法。
Bacterial peritonitis remains the main cause of technique failure in peritoneal dialysis (PD). During peritonitis, the peritoneal membrane undergoes structural and functional alterations that are mediated by IL-1 beta. The NLRP3 inflammasome is a caspase-1-activating multiprotein complex that links sensing of microbial and stress products to activation of proinflammatory cytokines, including IL-1 beta. The potential roles of the NLRP3 inflammasome and IL-1 beta in the peritoneal membrane during acute peritonitis have not been investigated. Here, we show that the NLRP3 inflammasome is activated during acute bacterial peritonitis in patients on PD, and this activation associates with the release of IL-1 beta in the dialysate. In mice, lipo-polysaccharide-or Escherichia coli-induced peritonitis led to IL-1 beta release in the peritoneal membrane. The genetic deletion of Nalp3, which encodes NLRP3, abrogated defects in solute transport during acute peritonitis and restored ultrafiltration. In human umbilical vein endothelial cells, IL-1 beta treatment directly enhanced endothelial cell proliferation and increased microvascular permeability. These in vitro effects require endothelial IL-1 receptors, shown by immunofluorescence to be expressed in peritoneal capillaries in mice. Furthermore, administration of the IL-1 beta receptor antagonist, anakinra, efficiently decreased nitric oxide production and vascular proliferation and restored peritoneal function in mouse models of peritonitis, even in mice treated with standard-of-care antibiotherapy. These data demonstrate that NLRP3 activation and IL-1 beta release have a critical role in solute transport defects and tissue remodeling during PD-related peritonitis. Blockade of the NLRP3/IL-1 beta axis offers a novel method for rescuing morphologic alterations and transport defects during acute peritonitis.