MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Abstract

ObjectiveAcute 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.DesignFlow 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.ResultsWe 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.ConclusionsWe 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.

Repair macrophages in acute liver failure

“…SLPI was found to induce the MerTK + HLA-DR + pro-resolution phenotype in human monocytes and hepatic macrophages, which is functionally characterised by reduced cytokine responses towards activating stimuli, suppression of neutrophils (NET formation) and enhanced clearance of apoptotic neutrophils 7. Finally, administration of exogenous SLPI in mice fostered MerTK + MHC-II + macrophage numbers and accelerated resolution from acetaminophen injury (figure 1).…”

“…Up to now, the ‘human counterpart’ of inflammatory versus restorative macrophages in ALF has been vague. In this issue of Gut , Dr. Antoniades and coworkers present compelling experimental evidence from human samples and a mouse model that restorative macrophages in ALF are characterised by the expression of the Mer tyrosine kinase (MerTK) 7. In addition, the authors identified secretory leucocyte protease inhibitor (SLPI) to induce MerTK+ macrophages prompting tissue-restoring responses (figure 1).…”

“…In addition, the authors identified secretory leucocyte protease inhibitor (SLPI) to induce MerTK+ macrophages prompting tissue-restoring responses (figure 1). 7 …”

“…By studying peripheral blood of 32 and liver samples of 8 patients with ALF, Antoniades and coworkers noted a distinct increase in MerTK expressing peripheral blood monocytes and hepatic macrophages, which formed ring-like structures around necrotic areas. Circulating MerTK + and HLA-DR + monocytes in patients with ALF were characterised by high phagocytic capacity for neutrophils, reduced inflammatory cytokine secretion as well as expression of survival and scavenging factors,7 indicating that these cells promote resolution from tissue injury. This hypothesis was investigated in Mer-deficient (Mer −/− ) mice.…”

“…This hypothesis was investigated in Mer-deficient (Mer −/− ) mice. In comparison to wild-type animals, Mer −/− mice that lack the MerTK +  major histocompatibility complex (MHC)-II + Ly-6C lo hepatic macrophages displayed prolonged liver injury and inflammation after experimental acetaminophen overdose 7. Unfortunately, direct experimental evidence linking the MerTK + phagocytes to resolution from injury in the acetaminophen poisoning model is currently lacking.…”