摘要：

Background: Acute liver failure (ALF) is characterized by overwhelming hepatocyte death and liver inflammation where the infiltration of myeloid cells in areas of necrosis is contrasted by immune cell depletion and dysregulation in the systemic circulation. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown to date. In this thesis, I used both human and murine experimental models in order to investigate the impact of Mer Tyrosine Kinase (MerTK) during ALF and examine how the micro-environmental mediator, Secretory Leukocyte Protease Inhibitor (SLPI), governs this immunological response. Methods: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotypic, functional and transcriptomic profile and tissue topography of MerTK+ monocytes and macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on hepatic resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer/) mice. Furthermore, SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results: I demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in both circulatory and tissue compartments of ALF patients. Compared to WT mice, that show an increase of MerTK+MHCIIhigh hepatic macrophages during the resolution phase in ALF, APAP-treated Mer/ mice exhibit persistent liver injury and inflammation, characterized by a decreased proportion of liver-resident Kupffer cells and increased number of hepatic neutrophils. Both in vitro and in APAPtreated mice, SLPI reprograms macrophages towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions: The work presented in this thesis has identified a prorestorative, MerTK+, macrophage phenotype that evolves during the resolution phase of APAP-induced ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.

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