The Multifaceted Roles of Macrophages in NAFLD Pathogenesis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome. NAFLD constitutes a spectrum of pathologies ranging from simple hepatic steatosis (nonalcoholic fatty liver) to the more progressive form of steatohepatitis and fibrosis, which can culminate in liver cirrhosis and hepatocellular carcinoma. Macrophages play multiple roles in the context of NAFLD pathogenesis by regulating inflammatory responses and metabolic homeostasis in the liver and thereby may represent an attractive therapeutic target. Advances in high-resolution methods have highlighted the extraordinary heterogeneity and plasticity of hepatic macrophage populations and activation states thereof. Harmful/disease-promoting as well as beneficial/restorative macrophage phenotypes co-exist and are dynamically regulated, thus this complexity must be taken into consideration in strategies concerning therapeutic targeting. Macrophage heterogeneity in NAFLD includes their distinct ontogeny (embryonic Kupffer cells vs bone marrow-/monocyte-derived macrophages) as well as their functional phenotype, for example, inflammatory phagocytes, lipid- and scar-associated macrophages, or restorative macrophages. Here, we discuss the multifaceted role of macrophages in the pathogenesis of NAFLD in steatosis, steatohepatitis, and transition to fibrosis and hepatocellular carcinoma, focusing on both their beneficial and maladaptive functions at different disease stages. We also highlight the systemic aspect of metabolic dysregulation and illustrate the contribution of macrophages in the reciprocal crosstalk between organs and compartments (eg, the gut-liver axis, adipose tissue, and cardiohepatic metabolic interactions). Furthermore, we discuss the current state of development of pharmacologic treatment options targeting macrophage biology.

Keywords: HCC; NASH; liver fibrosis; macrophage; obesity; type 2 diabetes.

Figure 1

Macrophages foster progression from nonalcoholic fatty liver to NASH and fibrosis. (A) Kupffer cells are activated upon ingestion of apoptotic fat-laden hepatocytes and free cholesterol, triggering proinflammatory activation. (B) The inflammatory microenvironment recruits monocytes that differentiate in heterogeneous monocyte-derived macrophage populations (Kupffer cell-like, inflammatory macrophages, and lipid-associated macrophages [LAMs]) based on signals from the environment. (C) Macrophage populations shape both profibrotic (red) and antifibrotic (green) processes within the fibrotic niche. Important phenotypic markers of the macrophage populations identified in mouse models are shown in the figure. CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1; CLEC4F, C-Type Lectin Domain Family 4 Member F; Mac1, macrophage-1 antigen; MMP, matrix metalloproteinase; Msr1, macrophage scavenger receptor 1; SAM, scar-associated macrophages; SatM, segregated-nucleus-containing atypical monocytes; Tgfb3, transforming growth factor β; VSIG4, V-set and immunoglobulin domain containing 4. (Figure was created with BioRender).

Figure 2

Hepatic inflammation and organ crosstalk. Stress-induced signals from the liver shape metabolic processes and immune cell phenotypes in remote organs and vice versa. (A) NAFLD is associated with a proinflammatory signature of progenitor cells in the bone marrow. (B) Lipid-associated macrophages in visceral adipose tissue that promote liver inflammation. (C) Cardiovascular disease is related to alteration of hepatic lipid metabolism. (D) Intestinal bacterial translocation and endotoxemia promote liver inflammation in NAFLD. LDL, low-density lipoprotein. (Figure was created with BioRender)