Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials

Abstract

Alcoholic liver disease (ALD) encompasses a spectrum of liver injury ranging from steatosis to steatohepatitis, fibrosis, and finally cirrhosis. Accumulating evidences have demonstrated that Kupffer cells (KCs) play critical roles in the pathogenesis of both chronic and acute ALD. It has become clear that alcohol exposure can result in increased hepatic translocation of gut-sourced endotoxin/lipopolysaccharide, which is a strong M1 polarization inducer of KCs. The activated KCs then produce a large amount of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, which finally lead to liver injury. The critical roles of KCs and related inflammatory cascade in the pathogenesis of ALD make it a promising target in pharmaceutical drug developments for ALD treatment. Several drugs (such as rifaximin, pentoxifylline, and infliximab) have been evaluated or are under evaluation for ALD treatment in randomized clinical trials. Furthermore, screening pharmacological regulators for KCs toward M2 polarization may provide additional therapeutic agents. The combination of these potentially therapeutic drugs with hepatoprotective agents (such as zinc, melatonin, and silymarin) may bring encouraging results.

Keywords: Kupffer cells; alcoholic liver disease; cytochrome P4502E1; lipopolysaccharide; polarization; tumor necrosis factor α.

Figure 1

A schema graph for the critical roles of KCs in the pathogenesis of ALD. Chronic ethanol exposure increases the gut permeability, resulting in translocation of gut endotoxin/LPS to liver. In liver, LPS leads to KCs activation via activating NOX and the TLR-4 pathway. Activated KCs produce a large amount of ROS, pro-inflammatory cytokines, and chemokines and induce the infiltration of other inflammatory cells. The ROS, pro-inflammatory cytokines, and the infiltration of other inflammatory cells finally cause liver injury. DPI, a NOX inhibitor, can significantly block ethanol-induced oxidative stress and the liver injury. In addition, chronic ethanol exposure can also sensitize the LPS-induced toxicity by increasing the half-life and cell surface receptor number of TNF-α, the expression of TLR-related co-receptors, and forming oxidative stress-related pro-inflammatory adducts, such as MAA adducts (MDA reacts with acetaldehyde and proteins to form hybrid protein adducts).

Figure 2

Overview of TLR-4/LPS signaling pathway activated by LPS in ALD. Chronic ethanol exposure leads to increased translocation of LPS to liver. In liver, LBP (the shuttle protein) transfers LPS to CD14, which facilitates the binding of LPS to TLR-4/MD-2 complex. TLR4 undergoes dimerization and transduces signal by two different pathways, i.e., MyD88-dependent and TRIF-dependent pathways. The former pathway included the recruitment of IRAK4, IRAK1, and TRAF-6, which ultimately leads to the production of pro-inflammatory cytokines by the activation of NF-κB and MAPK. In the second scenario, TRIF triggers a signaling pathway which controls the production of type I interferon and some other cytokines, as well as the late-phase activation of NF-κB and MAPK.

Figure 3

Interactions between CYP2E1 and LPS/TNF-α. CYP2E1 has been demonstrated to be expressed in hepatocytes, KCs, and also in small intestines. Intestinal CYP2E1 activation promotes ethanol-induced gut hyperpermeability, while CYP2E1 in KCs potentiates LPS-induced production of TNF-α. Furthermore, CYP2E1 can sensitize the hepatocytes to LPS/TNF-α toxicity from proliferation to apoptotic and necrotic cell death. All these adverse effects of CYP2E1 can be suppressed by CMZ, a specific inhibitor of CYP2E1.

Figure 4

Maturation and polarization of KCs. KCs, the resident macrophage in the liver, originate from the precursor cells in the bone marrow, which give rise to blood monocytes. Blood monocytes migrate into liver and develop in to liver macrophage, namely KCs. In the liver, KCs can polarize in two ways: classical activation/M1 polarization and alternative activation/M2 polarization, which exhibit pro-inflammatory and anti-inflammatory effects, respectively. The imbalance between M1 and M2 polarization of KCs contributes to the pathogenesis of ALD.