Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis.
Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis.
复制标题
衣康酸通过抑制 NF-κB/NLRP3/caspase-1 炎性体轴促进炎症减轻并减轻肝脏缺血再灌注损伤
DOI：
10.21037/atm-22-3388
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发表时间：
2022-08
影响因子：
--
通讯作者：
Wang, Zhengxin
中科院分区：
文献类型：
--
作者：
Ma, Ensi;Xing, Hao;Pei, Jiahao;Zhang, Quanbao;Li, Ruidong;Shen, Conghuan;Tao, Yifeng;Li, Jianhua;Ma, Zhenyu;Zhao, Jing;Wang, Zhengxin
研究背景缺血再灌注损伤（IRI）严重限制了肝移植的疗效和供体来源，控制炎症反应是减轻IRI的关键。衣康酸是内在免疫细胞（特别是巨噬细胞）在炎症状态下产生的代谢产物，可促进炎症消退。然而，其在肝脏缺血-再灌注中的作用尚不清楚。方法建立小鼠肝脏缺血再灌注模型，在预先设定的时间点采用序贯安乐死法收集血液和肝组织标本。检测肝功能、炎性因子浓度，并进行HE染色。在缺氧复氧模型中，于预先设定的时间点收集蛋白质，采用Western blot、免疫组化和免疫荧光法检测NF-κB通路相关蛋白及其下游炎症相关蛋白NLRP 3和caspase-1的表达。免疫荧光法检测细胞核内P-P65的表达。结果在小鼠肝脏缺血再灌注模型中，肝功能和炎症因子随再灌注时间呈动态变化，在此过程中，衣康酸可明显改善肝功能和炎症状态。NF-κB通路活性在缺氧-复氧过程中呈动态变化，衣康酸显著抑制该通路活性，并显著抑制其下游炎症相关蛋白的表达。结论衣康酸可抑制NF-κB通路的激活，减少P-P65在细胞核内的积聚。反过来，这降低了下游炎症相关蛋白的NLRP 3和半胱天冬酶-1表达，促进炎症消退，并减弱肝脏IRI。
Background Ischemia-reperfusion injury (IRI) severely limits the efficacy and donor source of liver transplantation, and the crucial step in alleviating it is to control inflammation. Itaconic acid is a metabolite produced by intrinsic immune cells (especially macrophages) in the inflammatory state and can promote inflammation subsidence. However, its role in liver ischemia-reperfusion is insufficiently clarified. Methods A mouse liver ischemia-reperfusion model was constructed, and blood and liver tissue samples were collected by sequential euthanasia of mice at pre-set time points. Liver function and inflammatory factor concentrations were measured, and HE staining was conducted. In the hypoxia-reoxygenation model, proteins were collected at pre-set time points, and the expression of NF-κB pathway-associated protein and its downstream inflammation-associated protein NLRP3 and caspase-1 were detected by Western blot, immunohistochemistry, and immunofluorescence. The level of P-P65 in the nucleus was detected by immunofluorescence. Results In the liver ischemia-reperfusion model, liver function and inflammatory factors were dynamically varied with reperfusion time in mice, and itaconic acid significantly modified liver function and inflammatory status during this process. NF-κB pathway activity was dynamically varied during hypoxia-reoxygenation, and itaconic acid significantly inhibited the activity of the pathway and significantly suppressed the expression of its downstream inflammation-related proteins. Conclusions Itaconic acid inhibits NF-κB pathway activation and reduces the accumulation of P-P65 in the nucleus. In turn, this reduces NLRP3 and caspase-1 expression of downstream inflammation-related proteins, promotes inflammation regression, and attenuates liver IRI.
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Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
6.7
作者：
Naujoks J;Tabeling C;Dill BD;Hoffmann C;Brown AS;Kunze M;Kempa S;Peter A;Mollenkopf HJ;Dorhoi A;Kershaw O;Gruber AD;Sander LE;Witzenrath M;Herold S;Nerlich A;Hocke AC;van Driel I;Suttorp N;Bedoui S;Hilbi H;Trost M;Opitz B
通讯作者：
Opitz B
影响因子：
5.6
作者：
Nemeth N;Peto K;Magyar Z;Klarik Z;Varga G;Oltean M;Mantas A;Czigany Z;Tolba RH
通讯作者：
Tolba RH
DOI：
10.1172/jci148548
发表时间：
2022-01-18
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Peace CG;O'Neill LA
通讯作者：
O'Neill LA
影响因子：
3.8
作者：
de Seymour, Jamie V.;Conlon, Cathryn A.;Baker, Philip N.
通讯作者：
Baker, Philip N.