Objective 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. Design 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. Results 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. Conclusions 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.

中文翻译：

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表达 MerTK 的肝巨噬细胞促进急性肝衰竭炎症的消退

目的急性肝衰竭（ALF）的特征是大量肝细胞死亡和肝脏炎症，坏死区域有大量骨髓细胞浸润。急性肝脏炎症消退的机制在很大程度上是未知的。在这里，我们旨在研究 ALF 期间 Mer 酪氨酸激酶 (MerTK) 的影响，并检查微环境介质、分泌性白细胞蛋白酶抑制剂 (SLPI) 如何控制这种反应。设计流式细胞术、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态。使用野生型 (WT) 和 Mer 缺陷型 (Mer-/-) 小鼠在 APAP 诱导的急性肝损伤中检查巨噬细胞 MerTK 表达的时间演变及其对分辨率的影响。使用 APAP 处理的 WT 小鼠在体外和体内测定 SLPI 对肝髓细胞的影响。结果我们证明了 ALF 患者循环和组织区室中分辨率样 MerTK+HLA-DRhigh 细胞的显着扩增。与在 ALF 消退阶段显示 MerTK+MHCIIhigh 巨噬细胞增加的 WT 小鼠相比，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 治疗的小鼠中，SLPI 通过诱导 MerTK+HLA-DRhigh 表型，促进中性粒细胞凋亡及其随后的清除，将骨髓细胞重新编程为解决反应。结论 我们确定了一种具有保肝作用的 MerTK+ 巨噬细胞表型，该表型在 ALF 后的消退阶段演变，代表了一种新的免疫治疗靶点，可促进急性肝损伤后的消退反应。