Macrophages as key regulators of liver health and disease.

Macrophages are a heterogeneous population of innate immune cells and key cellular components of the liver. Hepatic macrophages consist of embryologically-derived resident Kupffer cells (KC), recruited monocyte-derived macrophages (MDM) and capsular macrophages. Both the diversity and plasticity of hepatic macrophage subsets explain their different functions in the maintenance of hepatic homeostasis and in injury processes in acute and chronic liver diseases. In this review, we assess the evidence for macrophage involvement in regulating both liver health and injury responses in liver diseases including acute liver injury (ALI), chronic liver disease (CLD) (including liver fibrosis) and hepatocellular carcinoma (HCC). In healthy livers, KC display critical functions such as phagocytosis, danger signal recognition, cytokine release, antigen processing and the ability to orchestrate immune responses and maintain immunological tolerance. However, in most liver diseases there is a striking hepatic MDM expansion, which orchestrate both disease progression and regression. Single-cell approaches have transformed our understanding of liver macrophage heterogeneity, dynamics, and functions in both human samples and preclinical models. We will further discuss the new insights provided by these approaches and how they are enabling high-fidelity work to specifically identify pathogenic macrophage subpopulations. Given the important role of macrophages in regulating injury responses in a broad range of settings, there is now a huge interest in developing new therapeutic strategies aimed at targeting macrophages. Therefore, we also review the current approaches being used to modulate macrophage function in liver diseases and discuss the therapeutic potential of targeting macrophage subpopulations as a novel treatment strategy for patients with liver disorders.

CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.