Liver inflammation and fibrosis

Abstract

Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation. The inflammatory cells activate hepatic stellate cells, which are the major source of myofibroblasts in the liver. Here we review the initiation of inflammation in the liver, the liver inflammatory cells, and their crosstalk with myofibroblasts.

Figure 1. An overview of lipid metabolism in hepatocytes.

Hepatocytes become steatotic as a result of increased de novo lipogenesis, decreased β oxidation, and decreased VLDL secretion. Free fatty acids (FFAs) such as palmitate can induce the formation of both ceramide and lysophosphatidylcholine (LPC). LPC can activate proapoptotic signaling and lead to extracellular vesicle (EV) release. Palmitate-derived ceramide also induce EV release. HMGB1 and IL-33 are alarmins that are released from hepatocytes in the pathogenesis of chronic liver diseases, including nonalcoholic fatty liver disease. PPAR stimulation facilitates oxidation of lipids by upregulating acyl-CoA-oxidase and MCAD. Thus, PPARs are possible therapeutic targets in nonalcoholic steatohepatitis. FXR signaling facilitates secretion of bile acids and decreases hepatic lipid synthesis and enhances peripheral clearance of VLDL. AOX, acyl-CoA oxidase.

Figure 2. Interaction of immune cells and the liver.

The initiation of inflammation results in the trafficking and localization of immune cells to the site of injury, including neutrophils, recruited macrophages, and Tregs. Generation of an intravascular chemokine gradient (e.g., CXCL12) directs neutrophil migration toward damage foci. HMGB1 released by necrotic hepatocytes also mediates the recruitment of neutrophils through interaction with the HMGB1 receptor RAGE. Monocyte infiltration into the liver is primarily controlled by CCR2 and its ligand CCL2, which may serve as therapeutic targets in nonalcoholic steatohepatitis (NASH). Serum amyloid P binds to neutrophils and decreases TNF-α– and IL-8–induced neutrophil adhesion to extracellular matrix proteins, attenuates profibrotic macrophages, activates the complement pathway, and promotes phagocytosis of cell debris. Oral administration of an anti-CD3 mAb induces Tregs and has been shown to be effective in a NASH animal model; this antibody is currently in clinical trials. The CCR2/5 antagonist cenicriviroc is now in clinical trials.