Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.
Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.
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肝细胞焦亡和炎性体颗粒的释放可诱导星状细胞活化和肝纤维化。
DOI：
10.1016/j.jhep.2020.07.041
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发表时间：
2021-01
影响因子：
25.7
通讯作者：
Feldstein AE
中科院分区：
文献类型：
--
作者：
Gaul S;Leszczynska A;Alegre F;Kaufmann B;Johnson CD;Adams LA;Wree A;Damm G;Seehofer D;Calvente CJ;Povero D;Kisseleva T;Eguchi A;McGeough MD;Hoffman HM;Pelegrin P;Laufs U;Feldstein AE
肝细胞死亡增加导致急、慢性肝病的病理改变。肝细胞下垂和细胞外炎性小体释放在肝病中的作用尚不清楚。我们使用原代小鼠和人肝细胞、肝细胞特异性L351P Nlrp3KICreA小鼠和GsdmdKO小鼠来研究肝细胞中嗜热细胞的死亡及其对肝脏炎症和损伤的影响。从突变的NLRP3-YFP HEK细胞中分离细胞外NLRP3炎性小体，并研究其在Lx2和原代人肝星状细胞中的内化。我们进一步利用了154名经活检证实为NAFLD的成人受试者(西澳大利亚州内德兰兹的查尔斯·盖尔德纳爵士医院)。我们证明了原代小鼠和人肝细胞可以在NLRP3炎性小体激活后发生下垂，随后释放NLRP3炎性小体蛋白，从而放大和维持炎症小体驱动的纤维化形成。抑制caspase-1和Gasdermin D的激活，从而抑制下垂。在NASH患者的肝脏和血清中检测到caspase-1的激活形式，并与疾病严重程度相关。Nlrp3KICreA小鼠在正常饮食条件下出现自发性肝纤维化，并在低剂量脂多糖治疗后对肝损伤和炎症反应增加敏感性。从机制上讲，肝星状细胞吞噬细胞外NLRP3炎性小体颗粒，导致IL-1？分泌增加和α-SMA表达增加。当细胞内吞作用抑制剂细胞松弛素B处理细胞时，这种作用被取消。这些结果表明，肝细胞松弛和炎性小体成分的释放是传播肝损伤和肝纤维化发展的新机制。我们的发现确定了肝脏炎症的一种新机制。在细胞培养、小鼠和人类样本中的实验表明，一种特殊的细胞死亡形式，称为下垂，会导致复杂的炎症颗粒NLRP3炎症小体从肝细胞内释放到细胞外空间。从那里，它们被其他细胞摄取，从而介导炎症和促纤维化的应激信号。这一机制的发现可能会在未来为慢性肝病带来新的治疗方法。
Increased hepatocyte death contributes to the pathology of acute and chronic liver diseases. The role of hepatocyte pyroptosis and extracellular inflammasome release in liver disease is unknown. We used primary mouse and human hepatocytes, hepatocyte-specific L351P Nlrp3KICreA mice and GsdmdKO mice to investigate pyroptotic cell death in hepatocytes and its impact on liver inflammation and damage. Extracellular NLRP3 inflammasomes were isolated from mutant NLRP3-YFP HEK cells and internalization was studied in LX2 and primary human hepatic stellate cells. We further utilized a cohort of 154 adult subjects with biopsy-proven NAFLD (Sir Charles Gairdner Hospital, Nedlands, Western Australia). We demonstrated that primary mouse and human hepatocytes can undergo pyroptosis upon NLRP3 inflammasome activation with subsequent release of NLRP3 inflammasome proteins that amplify and perpetuate inflammasome-driven fibrogenesis. Pyroptosis was inhibited by blocking caspase-1 and Gasdermin D activation. The activated form of caspase-1 was detected in the livers and in serum from patients with NASH and correlated with disease severity. Nlrp3KICreA mice showed spontaneous liver fibrosis under normal chow diet, and increased sensitivity to liver damage and inflammation after treatment with low dose LPS. Mechanistically, hepatic stellate cells engulfed extracellular NLRP3 inflammasome particles leading to increased IL-1ß secretion and α-SMA expression. This effect was abrogated when cells were pre-treated with the endocytosis inhibitor Cytochalasin B. These results identify hepatocyte pyroptosis and release of inflammasome components as a novel mechanism to propagate liver injury and liver fibrosis development. Our findings identify a novel mechanism of inflammation in the liver. Experiments in cell cultures, mice and human samples show that a specific form of cell death, called pyroptosis, leads to the release of complex inflammatory particles, the NLRP3 inflammasome, from inside hepatocytes into the extracellular space. From there they are taken up by other cells and thereby mediate inflammatory and pro-fibrogenic stress signals. The discovery of this mechanism may lead to novel treatments for chronic liver diseases in the future.
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DOI：
10.1016/j.jcmgh.2015.07.007
发表时间：
2015-11-01
影响因子：
7.2
作者：
Povero D;Panera N;Eguchi A;Johnson CD;Papouchado BG;de Araujo Horcel L;Pinatel EM;Alisi A;Nobili V;Feldstein AE
通讯作者：
Feldstein AE
影响因子：
29.4
作者：
Luedde T;Kaplowitz N;Schwabe RF
通讯作者：
Schwabe RF
影响因子：
13.5
作者：
Wree, Alexander;Eguchi, Akiko;McGeough, Matthew D.;Pena, Carla A.;Johnson, Casey D.;Canbay, Ali;Hoffman, Hal M.;Feldstein, Ariel E.
通讯作者：
Feldstein, Ariel E.
影响因子：
13.5
作者：
Csak, Timea;Ganz, Michal;Pespisa, Justin;Kodys, Karen;Dolganiuc, Angela;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
DOI：
10.1002/jbm.a.36013
发表时间：
2017-05
期刊：
Journal of biomedical materials research. Part A
影响因子：
--
作者：
Hachim D;Wang N;Lopresti ST;Stahl EC;Umeda YU;Rege RD;Carey ST;Mani D;Brown BN
通讯作者：
Brown BN