MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.
MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.
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DOI：
10.1136/gutjnl-2016-313615
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发表时间：
2018-03
期刊：
影响因子：
24.5
通讯作者：
Antoniades CG
中科院分区：
文献类型：
--
作者：
Triantafyllou E;Pop OT;Possamai LA;Wilhelm A;Liaskou E;Singanayagam A;Bernsmeier C;Khamri W;Petts G;Dargue R;Davies SP;Tickle J;Yuksel M;Patel VC;Abeles RD;Stamataki Z;Curbishley SM;Ma Y;Wilson ID;Coen M;Woollard KJ;Quaglia A;Wendon J;Thursz MR;Adams DH;Weston CJ;Antoniades CG
急性肝衰竭（ALF）的特征是压倒性的肝细胞死亡和肝脏炎症，坏死区域有大量髓样细胞浸润。急性肝脏炎症消退的机制在很大程度上是未知的。在这里，我们的目的是调查的影响，Mer酪氨酸激酶（MerTK）在ALF，也研究如何微环境介质，分泌性白细胞蛋白酶抑制剂（SLPI），支配这种反应。流式细胞术、免疫组织化学、共聚焦成像和基因表达分析确定了ALF、健康和疾病对照中MerTK+单核细胞/巨噬细胞的表型、功能/转录组学特征和组织形貌。在APAP诱导的急性肝损伤中，使用野生型（WT）和Mer缺陷型（Mer−/−）小鼠检查巨噬细胞MerTK表达的时间演变及其对消退的影响。使用APAP处理的WT小鼠在体外和体内测定SLPI对肝骨髓细胞的作用。我们证明了在ALF患者的循环和组织隔室中，消退样MerTK+ HLA-DR高细胞显著扩增。WT小鼠在ALF消退期表现出MerTK+MHCIIhigh巨噬细胞增加，与之相比，APAP处理的Mer−/−小鼠表现出持续性肝损伤和炎症，其特征是常驻库普弗细胞比例降低和中性粒细胞数量增加。在体外和APAP处理的小鼠中，SLPI通过诱导MerTK+ HLA-DR高表型将骨髓细胞重编程为消退反应，这促进了中性粒细胞凋亡及其随后的清除。我们确定了一种肝保护性的MerTK+巨噬细胞表型，该表型在ALF后的消退阶段演变，并代表了一种新的免疫靶点，以促进急性肝损伤后的消退反应。
Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
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影响因子：
168.9
作者：
Bernal, W;Donaldson, N;Wendon, J
通讯作者：
Wendon, J
分泌白细胞抑制剂（SLPI）缺陷小鼠对LPS诱导的内毒素休克的敏感性增加。
影响因子：
15.3
作者：
Nakamura, A;Mori, Y;Hagiwara, K;Suzuki, T;Sakakibara, T;Kikuchi, T;Igarashi, T;Ebina, M;Miyazaki, J;Takai, T;Nukiwa, T;Nukiwa, T
通讯作者：
Nukiwa, T
DOI：
10.1084/jem.20141539
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dal-Secco D;Wang J;Zeng Z;Kolaczkowska E;Wong CH;Petri B;Ransohoff RM;Charo IF;Jenne CN;Kubes P
通讯作者：
Kubes P
影响因子：
4.1
作者：
Ju, C;Reilly, TP;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
6.1
作者：
Choi, Dong-Young;Ban, Jung-Ok;Hong, Jin Tae
通讯作者：
Hong, Jin Tae