The complex roles of neutrophils in APAP-induced liver injury.
The complex roles of neutrophils in APAP-induced liver injury.
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中性粒细胞在 APAP 诱导的肝损伤中的复杂作用
DOI：
10.1111/cpr.13040
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发表时间：
2021-06
影响因子：
8.5
通讯作者：
Zheng M
中科院分区：
文献类型：
--
作者：
Guo H;Chen S;Xie M;Zhou C;Zheng M
对乙酰氨基酚（APAP）是一种广泛应用的缓解疼痛和发热的药物，也是一种剂量依赖性毒素。APAP引起的急性肝损伤已成为肝衰竭的主要原因之一，对人类健康的威胁日益严重。中性粒细胞是人体内主要的免疫细胞，是抵御病原体侵袭的第一道屏障。有研究表明，中性粒细胞参与APAP诱导的肝损伤的发生和发展。然而，不断发展的证据表明，中性粒细胞也有助于组织修复，并积极协调炎症的解决。本文在简要介绍中性粒细胞活化、募集和迁移的基础上，阐述了APAP在肝损伤中的复杂作用。在APAP诱导的肝损伤中，多种因素对中性粒细胞的活化、募集和迁移有着深刻的影响。DAMP如HMGB1和ATP从受损的肝细胞释放，分别被β 2受体、P2Y2受体识别，诱导中性粒细胞的活化和募集。但是，中性粒细胞上表达的TLR9识别mtDNA，然后中性粒细胞可以释放miR-223，从而抑制中性粒细胞的激活和募集。至于其他免疫细胞，它们分为促进和抑制中性粒细胞激活和募集的细胞。首先，巨噬细胞在APAP处理后表达OPN，然后吸引中性粒细胞。此外，HMGB1还能识别巨噬细胞上表达的TLR4受体，释放IL-23，诱导γ δ T细胞释放IL-17A，最终激活和募集中性粒细胞。然而，Ly6Chi单核细胞通过CCR2和M-CSF途径抑制中性粒细胞的活化和募集。巨噬细胞还能产生MerTK抑制中性粒细胞。TNF-α/LPS MDSCs可表达iNOS，减少肝内中性粒细胞浸润，诱导活化中性粒细胞凋亡。激活和募集的中性粒细胞然后迁移到损伤部位以减轻炎症并诱导组织修复。GRPR拮抗剂可通过激活MAPKs途径下调CD11b/CD66b的表达，从而显著影响中性粒细胞向损伤部位的迁移。
Acetaminophen (APAP) is a widely applied drug for the alleviation of pain and fever, which is also a dose‐depedent toxin. APAP‐induced acute liver injury has become one of the primary causes of liver failure which is an increasingly serious threat to human health. Neutrophils are the major immune cells in human serving as the first barrier against the invasion of pathogen. It has been reported that neutrophils patriciate in the occurrence and development of APAP‐induced liver injury. However, evolving evidences suggest that neutrophils also contribute to tissue repair and actively orchestrate resolution of inflammation. Here, we addressed the complex roles in APAP‐induced liver injury on the basis of brief introduction of neutrophil's activation, recruitment and migration. A lot of factors deeply influence the neutrophil's activation, recruitment and migration in APAP‐induced liver injury. DAMPs like HMGB1 and ATP are released from damaged hepatocytes, recognized by RAGE, P2Y2 receptors, respectively, inducing the activation and recruitment of neutrophils. But the TLR9 expressed on neutrophils recognize mtDNA and then neutrophils could release miR‐223, which inhibits the neutrophil's activation and recruitment. As for other immune cells, they are divided into cells that promote and inhibit the activation and recruitment of neutrophils. Firstly, macrophages express OPN after APAP treatment and then attract neutrophils. Moreover, HMGB1 could recognize TLR4 receptor expressed on macrophages, release IL‐23 to induce the release of IL‐17A in γδ T cells and finally activate and recruit neutrophils. However, Ly6Chi monocytes inhibit the activation and recruitment of neutrophils via CCR2 and M‐CSF pathways. Macrophages could also generate MerTK to inhibit neutrophils. Furthermore, TNF‐α/LPS MDSCs could express iNOS to decrease the intrahepatic neutrophils infiltration and induce the apoptosis of activated neutrophil. Activated and recruited neutrophils then migrate to the site of injury to alleviate the inflammation and induce tissue repair. GRPR antagonist could downregulate the expression of CD11b/CD66b via activating MAPKs pathways, which significantly influence the migration of neutrophils to the injury site.
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DOI：
10.26355/eurrev_201811_16296
发表时间：
2018-11-01
影响因子：
3.3
作者：
Cheng, G-Y;Jiang, Q.;Li, Y-Y
通讯作者：
Li, Y-Y
影响因子：
4.6
作者：
Kojo K;Ito Y;Eshima K;Nishizawa N;Ohkubo H;Yokomizo T;Shimizu T;Watanabe M;Majima M
通讯作者：
Majima M
影响因子：
3.8
作者：
Harrill, Alison H.;Ross, Pamela K.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
影响因子：
3.8
作者：
Cover, Cathleen;Liu, Jie;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut
肝线粒体 DNA/Toll 样受体 9/MicroRNA-223 形成负反馈环，限制小鼠中性粒细胞过度激活和对乙酰氨基酚肝毒性
DOI：
10.1002/hep.29153
发表时间：
2017-07
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
He Y;Feng D;Li M;Gao Y;Ramirez T;Cao H;Kim SJ;Yang Y;Cai Y;Ju C;Wang H;Li J;Gao B
通讯作者：
Gao B