P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis
P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis
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DOI：
10.1189/jlb.0612284
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发表时间：
2013-01-01
影响因子：
5.5
通讯作者：
Behmoaras, Jacques
中科院分区：
文献类型：
--
作者：
Deplano, Simona;Cook, H. Terence;Behmoaras, Jacques
P2 RX 7是IL-1 β和IL-18加工和释放的介质，是由巨噬细胞表达的配体门控阳离子通道。在实验性Crgn中，P2 RX 7缺乏可减轻肾损伤，但其潜在机制尚不清楚。在这里，我们表明，P2 RX 7的水平和属于Nlrp 3-炎性体途径的几个基因的表达上调的WKY大鼠，一个株独特的巨噬细胞依赖性NTN敏感的巨噬细胞。重要的是，在P2 RX 7活化后，与NTN抗性LEW大鼠BMDM相比，WKY BMDM产生显著增加水平的活性半胱天冬酶-1、IL-1 β和IL-18。在NTN诱导后4天，WKY肾炎肾小球中P2 RX 7和活性IL-1 β、IL-18和半胱天冬酶-1蛋白水平显著增加，并且使用P2 RX 7拮抗剂降低分泌的活性IL-1 β水平。有趣的是，P2 RX 7介导的炎性小体激活的翻译后控制是在WKY大鼠的BMDM和肾炎肾小球中的两个先前鉴定的Crgn数量性状基因座的遗传调控下。总之，我们提出了一种新的机制，即基因决定的P2 RX 7水平在巨噬细胞调节Nlrp 3-炎性小体激活和易感性Crgn。J. Leukoc.生物学93：127-134; 2013年。
P2RX7, a mediator of IL-1 beta and IL-18 processing and release, is a ligand-gated cation channel that is expressed by macrophages. In experimental Crgn, P2RX7 deficiency attenuates renal injury, but the underlying mechanism is unknown. Here, we show that P2RX7 levels and the expression of several genes belonging to the Nlrp3-inflammasome pathway are up-regulated in the macrophages of the WKY rat, a strain uniquely susceptible to macrophage-dependent NTN. Importantly, following P2RX7 activation, WKY BMDMs produce markedly increased levels of active caspase-1, IL-1 beta, and IL-18 when compared with the NTN-resistant LEW rat BMDMs. P2RX7 and active IL-1 beta, IL-18, and caspase-1 protein levels were markedly increased in the WKY nephritic glomeruli 4 days following induction of NTN, and the use of a P2RX7 antagonist reduced the levels of secreted active IL-1 beta. Interestingly, the post-translational control of P2RX7-mediated inflammasome activation is under the genetic regulation of two previously identified Crgn quantitative trait loci in the BMDMs and nephritic glomeruli of the WKY rat. In conclusion, we propose a novel mechanism, whereby genetically determined P2RX7 levels in macrophages regulate Nlrp3-inflammasome activation and susceptibility to Crgn. J. Leukoc. Biol. 93: 127-134; 2013.