Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury.
Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury.
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DOI：
10.4049/jimmunol.1202733
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Tsung A
中科院分区：
文献类型：
--
作者：
Huang H;Chen HW;Evankovich J;Yan W;Rosborough BR;Nace GW;Ding Q;Loughran P;Beer-Stolz D;Billiar TR;Esmon CT;Tsung A
肝缺血/再灌注（I/R）损伤后驱动无菌炎症损伤的细胞过程尚未完全了解。炎性小体的激活在响应侵入细胞内病原体中起关键作用，但越来越多的证据表明，它也在缺血性损伤后释放的内源性DAMP分子驱动的炎症中起作用。核苷酸结合结构域，富含亮氨酸重复序列的蛋白3（NLRP 3）炎性体就是这样一个过程，其激活导致肝脏I/R后损伤和炎症反应的机制尚不清楚。在这里，我们报告了NLRP 3及其下游靶点Caspase-1都是活化的I/R，并且对于肝脏I/R损伤是必需的，因为NLRP 3和Caspase-1 KO小鼠都受到保护免受损伤。此外，炎性小体介导的损伤依赖于肝非实质细胞中Caspase-1的表达。虽然在缺血性损伤过程中激活炎性小体的上游信号没有得到很好的表征，但我们表明内源性细胞外组蛋白在肝脏I/R过程中通过Toll样受体9（TLR 9）激活NLRP 3炎性小体。这通过TLR 9依赖性的活性氧物质的产生而发生。这种机制在驻留的肝枯否细胞中起作用，枯否细胞通过招募额外的细胞类型（包括中性粒细胞和炎性单核细胞）在I/R损伤后驱动先天免疫应答。这些新的发现阐明了一种新的机制，通过这种机制，细胞外组蛋白和NLRP 3炎性体的激活有助于无菌炎症期间的肝损伤和先天免疫的激活。
Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests it also plays a role in inflammation driven by endogenous danger-associate molecular pattern (DAMP) molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. Here we report that both NLRP3 and its downstream target Caspase-1 are activated I/R and are essential for hepatic I/R injury as both NLRP3 and Caspase-1 KO mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on Caspase-1 expression in liver non-parenchymal cells. While upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through Toll-like Receptor-9 (TLR9). This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and activation of innate immunity during sterile inflammation.
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DOI：
10.1016/j.niox.2013.02.084
发表时间：
2013-05-31
期刊：
Nitric oxide : biology and chemistry
影响因子：
--
作者：
Loughran PA;Stolz DB;Barrick SR;Wheeler DS;Friedman PA;Rachubinski RA;Watkins SC;Billiar TR
通讯作者：
Billiar TR
影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
4.8
作者：
Evankovich, John;Cho, Sung W.;Tsung, Allan
通讯作者：
Tsung, Allan
影响因子：
5.8
作者：
Martín, C;Martínez, R;Ruiz-Larrea, MB
通讯作者：
Ruiz-Larrea, MB
影响因子：
3.7
作者：
Gowda NM;Wu X;Gowda DC
通讯作者：
Gowda DC