Constitutive Activation of the Nlrc4 Inflammasome Prevents Hepatic Fibrosis and Promotes Hepatic Regeneration after Partial Hepatectomy.
Constitutive Activation of the Nlrc4 Inflammasome Prevents Hepatic Fibrosis and Promotes Hepatic Regeneration after Partial Hepatectomy.
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DOI：
10.1155/2015/909827
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发表时间：
2015
影响因子：
4.6
通讯作者：
Croniger CM
中科院分区：
文献类型：
--
作者：
DeSantis DA;Ko CW;Wang L;Lee P;Croniger CM
导致肝纤维化发展的分子机制尚不完全清楚。NLRC4炎症体检测胞浆中细菌成分的存在，激活炎症细胞因子，促进病原体和受感染细胞的清除。我们推测，NLRC4炎性小体的低级别结构性激活可能导致肝细胞的增殖，从而阻止肝纤维化的发展。NLRC4基因包含两个单核苷酸多态(SNP)，一个位于NLRC4启动子内，另一个位于外显子5内。通过基因报告实验和IL-1β的分泌，这些SNP调节NLRC4基因的转录和激活。与B6小鼠相比，慢性给予四氯化碳后17C-6小鼠血浆中IL-1β水平升高。在2/3肝部分切除(2/3PH)后，在多个时间点，17C-6小鼠的肝质量恢复得比B6小鼠更早，Cyclin D1蛋白和BrdU的掺入更多。这些数据揭示了NLRC4炎症体的轻度结构性激活，这是两个SNPs的结果，导致刺激肝细胞的增殖。肝再生的增加导致肝切除后肝质量的快速恢复，并可能阻止肝毒素诱导的肝纤维化的发展。
TThe molecular mechanisms responsible for the development of hepatic fibrosis are not fully understood. The Nlrc4 inflammasome detects cytosolic presence of bacterial components, activating inflammatory cytokines to facilitate clearance of pathogens and infected cells. We hypothesized that low-grade constitutive activation of the Nlrc4 inflammasome may lead to induced hepatocyte proliferation and prevent the development of hepatic fibrosis. The gene of Nlrc4 contains two single nucleotide polymorphisms (SNPs), one located within the Nlrc4 promoter and one contained within exon 5. These SNPs regulate Nlrc4 gene transcription and activation as measured through gene reporter assays and IL-1β secretion. The 17C-6 mice have increased IL-1β in plasma after chronic carbon tetrachloride (CCl4) administration compared to B6 mice. After two-thirds partial hepatectomy (2/3PH) 17C-6 mice have earlier restoration of liver mass with greater cyclin D1 protein and BrdU incorporation compared to B6 mice at several time points. These data reveal mild constitutive activation of the Nlrc4 inflammasome as the results of two SNPs, which leads to the stimulation of hepatocyte proliferation. The increased liver regeneration induces rapid liver mass recovery after hepatectomy and may prevent the development of hepatotoxin-induced liver fibrosis.