Introduction 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 micro-environmental mediator, Secretory Leukocyte Protease Inhibitor (SLPI), governs this response.
Method Flow cytometry, immunohistochemistry and confocal imaging determined the phenotype, functional profile and tissue topography of MerTK+ monocytes/macrophages in human 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 WT and Mer−/− mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.
Results We demonstrate an expansion of prorestorative MerTK+HLA-DRhigh cells in circulatory/tissue compartments of ALF patients (Fig.A). Compared to WT mice which have an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF (Fig.B), APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells (KC) and increased number of neutrophils (Fig.C). Both in vitro and in APAP-treated mice (Fig.D), SLPI reprograms macrophages towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype that promotes neutrophil apoptosis and their subsequent clearance.
Conclusion 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.
Disclosure of Interest None Declared
- acute liver failure
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