Hepatocytes Are Resistant to Cell Death From Canonical and Non-Canonical Inflammasome-Activated Pyroptosis.
Hepatocytes Are Resistant to Cell Death From Canonical and Non-Canonical Inflammasome-Activated Pyroptosis.
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DOI：
10.1016/j.jcmgh.2021.11.009
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发表时间：
2022
影响因子：
7.2
通讯作者：
Scott MJ
中科院分区：
文献类型：
--
作者：
Sun P;Zhong J;Liao H;Loughran P;Mulla J;Fu G;Tang D;Fan J;Billiar TR;Gao W;Scott MJ
焦亡，gasdermin介导的程序性细胞死亡，很容易在巨噬细胞中通过激活典型炎性小体（半胱天冬酶-1）或通过细胞内脂多糖（LPS）介导的非典型炎性小体（半胱天冬酶-11）激活诱导。然而，在肝细胞中是否类似地诱导焦亡仍然存在很大争议，但与肝脏病理学高度相关，如酒精性/非酒精性肝病，药物诱导的肝损伤，缺血再灌注和肝移植损伤，或继发于脓毒症的器官损伤。在这项研究中，我们发现，肝细胞激活和切割gasdermin-D（GSDMD）在低水平处理后，LPS。过表达caspase-1或caspase-11 p10/p20激活结构域能够在体外和体内诱导典型的GSDMD依赖性肝细胞焦亡。然而，巨噬细胞中的焦亡形态学特征（例如，焦亡小体、细胞扁平化、细胞结构丧失）未发生在焦亡肝细胞中，尽管细胞膜被破坏，但细胞结构保持相对完整。我们的研究结果表明，肝细胞激活pyroptosis途径和裂解GSDMD，但这不会导致细胞破裂，并赋予相同的pyroptotic形态学变化，如以前报道的巨噬细胞。这是真实的，甚至与半胱天冬酶-1或半胱天冬酶-11人工过表达的方式，甚至在引发后或在病理条件下观察到的内源性水平以上。我们的新发现表征了焦亡中的肝细胞形态，并建议替代使用典型/非典型炎性小体激活/信号传导和随后的GSDMD裂解，因为没有像巨噬细胞中那样的快速细胞死亡。对这些途径在肝细胞中的作用的进一步理解和认识可能会导致一系列肝脏疾病的新疗法。
Pyroptosis, gasdermin-mediated programmed cell death, is readily induced in macrophages by activation of the canonical inflammasome (caspase-1) or by intracellular lipopolysaccharide (LPS)-mediated non-canonical inflammasome (caspase-11) activation. However, whether pyroptosis is induced similarly in hepatocytes is still largely controversial but highly relevant to liver pathologies such as alcoholic/nonalcoholic liver disease, drug-induced liver injury, ischemia-reperfusion and liver transplant injury, or organ damage secondary to sepsis. In this study we found that hepatocytes activate and cleave gasdermin-D (GSDMD) at low levels after treatment with LPS. Overexpression of caspase-1 or caspase-11 p10/p20 activated domains was able to induce typical GSDMD-dependent pyroptosis in hepatocytes both in vitro and in vivo. However, morphologic features of pyroptosis in macrophages (eg, pyroptotic bodies, cell flattening, loss of cell structure) did not occur in pyroptotic hepatocytes, with cell structure remaining relatively intact despite the cell membrane being breached. Our results suggest that hepatocytes activate pyroptosis pathways and cleave GSDMD, but this does not result in cell rupture and confer the same pyroptotic morphologic changes as previously reported in macrophages. This is true even with caspase-1 or caspase-11 artificial overexpression way above levels seen endogenously even after priming or in pathologic conditions. Our novel findings characterize hepatocyte morphology in pyroptosis and suggest alternative use for canonical/non-canonical inflammasome activation/signaling and subsequent GSDMD cleavage because there is no rapid cell death as in macrophages. Improved understanding and recognition of the role of these pathways in hepatocytes may result in novel therapeutics for a range of liver diseases.
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影响因子：
25.7
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
通讯作者：
Feldstein AE
CCR2/5信号的药理抑制可防止和逆转小鼠酒精诱导的肝损伤，脂肪变性和炎症。
DOI：
10.1002/hep.30249
发表时间：
2019-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ambade A;Lowe P;Kodys K;Catalano D;Gyongyosi B;Cho Y;Iracheta-Vellve A;Adejumo A;Saha B;Calenda C;Mehta J;Lefebvre E;Vig P;Szabo G
通讯作者：
Szabo G
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：
10.1126/science.1240988
发表时间：
2013-09-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hagar JA;Powell DA;Aachoui Y;Ernst RK;Miao EA
通讯作者：
Miao EA
DOI：
10.4049/jimmunol.1402658
发表时间：
2015-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Katsnelson MA;Rucker LG;Russo HM;Dubyak GR
通讯作者：
Dubyak GR