Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin 1 in acute kidney disease
Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin 1 in acute kidney disease
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Caspase-11 在急性肾病中通过裂解 pannexin 1 促进 NLRP3 炎症小体激活
DOI：
10.1038/s41401-021-00619-2
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Lu LM （陆利民）
中科院分区：
文献类型：
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作者：
Yin F;Zheng PQ;Zhao LQ;Wang YZ;Miao NJ;Zhou ZL;Cheng Q;Chen PP;Xie HY;Li JY;Ni JY;Zhou L;Zhang W;Wang XX;Liu J;Lu LM （陆利民）
缺血再灌注(I/R)损伤是临床上引起急性肾损伤(AKI)的主要原因。NLRP3炎性小体的激活与I/R所致AKI的炎症和肾损伤密切相关。在本研究中，我们探讨了NLRP3在肾I/R后炎症小体激活的分子和细胞机制。结果表明，大鼠肾脏缺血再灌注损伤后，caspase-11的表达和pAnnexin 1(Panx1)的裂解明显增加，同时伴有NLRP3炎症体的激活，表现为caspase-1的激活和IL-1β(IL-1β)的成熟。在Casp-11−/−小鼠中，I/R诱导的Panx1裂解、NLRP3炎症小体激活以及肾功能恶化和肾小管形态改变明显减轻。在原代培养的肾小管上皮细胞(PTCs)和NRK-52E细胞中，缺氧/复氧(H/R)显著增加Caspase-11的表达、NLRP3炎性小体的激活、IL-1β的成熟和Panx1的裂解。Caspase-11的基因敲除可以减弱所有这些变化；从Casp-11−/−小鼠分离的PTCs中也观察到了类似的效果。在NRK-52E细胞中，caspase-11的过表达促进了Panx1的裂解，用Panx1抑制剂Carbenoxolone或Panx1被敲除后，NLRP3炎性小体的激活和细胞内ATP的降低均显著减弱，而对H/R诱导的caspase-11的升高无明显影响；用P2X7受体抑制剂AZD9056预处理后，NLRP3的炎性小体激活也明显减弱。以上结果表明，上调的caspase-11对Panx1的裂解参与了脑缺血再灌流后促进ATP释放和NLRP3炎性小体激活的过程。本研究为研究AKI中NLRP3炎性小体激活的分子机制提供了新的思路。
Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1β (IL-1β) maturation. InCasp-11−/−mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK-52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1β maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated fromCasp-11−/−mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R-induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.