Targeting hepatic macrophages to treat liver diseases

Summary

Our view on liver macrophages in the context of health and disease has been reformed by the recognition of a remarkable heterogeneity of phagocytes in the liver. Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Kupffer cells are self-renewing, resident and principally non-migratory phagocytes, serving as sentinels for liver homeostasis. Liver injury triggers Kupffer cell activation, leading to inflammatory cytokine and chemokine release. This fosters the infiltration of monocytes into the liver, which give rise to large numbers of inflammatory monocyte-derived macrophages. Liver macrophages are very plastic and adapt their phenotype according to signals derived from the hepatic microenvironment (e.g. danger signals, fatty acids, phagocytosis of cellular debris), which explains their manifold and even opposing functions during disease. These central functions include the perpetuation of inflammation and hepatocyte injury, activation of hepatic stellate cells with subsequent fibrogenesis, and support of tumor development by angiogenesis and T cell suppression. If liver injury ceases, specific molecular signals trigger hepatic macrophages to switch their phenotype towards reparative phagocytes that promote tissue repair and regression of fibrosis. Novel strategies to treat liver disease aim at targeting macrophages. These interventions modulate Kupffer cell activation (e.g. via gut-liver axis or inflammasome formation), monocyte recruitment (e.g. via inhibiting chemokine pathways like CCR2 or CCL2) or macrophage polarization and differentiation (e.g. by nanoparticles). Evidence from mouse models and early clinical studies in patients with non-alcoholic steatohepatitis and fibrosis support the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with liver disease.

Lay summary

Macrophages (Greek for “big eaters”) are a frequent non-parenchymal cell type of the liver that ensures homeostasis, antimicrobial defense and proper metabolism. However, liver macrophages consist of different subtypes regarding their ontogeny (developmental origin), differentiation and function. Understanding this heterogeneity and the critical regulation of inflammation, fibrosis and cancer by macrophage subsets opens promising new options for treating liver diseases.

Introduction

Some of the most pressing unresolved challenges in hepatology today can be related to an imbalance of inflammatory processes: (i) functional or biological cure from hepatitis B virus (HBV) infections can probably not be achieved without an effective antiviral immune response; (ii) the progression from non-alcoholic fatty liver to non-alcoholic steatohepatitis (NASH) with fibrosis is fuelled by chronic hepatic inflammation; (iii) patients with end-stage cirrhosis are prone to life-threatening bacterial infections indicating insufficient antimicrobial responses in the liver; finally, (iv) development and progression of hepatocellular carcinoma (HCC) is the result of inadequate tumor clearance and/or suppression of anti-tumor immunity [1]. During the past decades, it has become apparent that hepatic macrophages hold central functions in initiating, perpetuating and even restricting inflammation in the liver. The tremendous progress in understanding their heterogeneity and various functions will be reviewed here and opens new perspectives for the treatment of liver diseases.

Liver macrophages display a remarkable heterogeneity, reflecting their developmental origin (resident Kupffer cells and infiltrating monocytes) and their differentiation (e.g. inflammatory or anti-inflammatory) in response to microenvironmental signals (e.g. danger signals, phagocytosis of cellular debris)