Hepatic inflammation and fibrosis: functional links and key pathways

Abstract

Inflammation is one of the most characteristic features of chronic liver disease of viral, alcoholic, fatty, and autoimmune origin. Inflammation is typically present in all disease stages and associated with the development of fibrosis, cirrhosis, and hepatocellular carcinoma. In the past decade, numerous studies have contributed to improved understanding of the links between hepatic inflammation and fibrosis. Here, we review mechanisms that link inflammation with the development of liver fibrosis, focusing on the role of inflammatory mediators in hepatic stellate cell (HSC) activation and HSC survival during fibrogenesis and fibrosis regression. We will summarize the contributions of different inflammatory cells, including hepatic macrophages, T and B lymphocytes, natural killer cells and platelets, as well as key effectors, such as cytokines, chemokines, and damage-associated molecular patterns. Furthermore, we will discuss the relevance of inflammatory signaling pathways for clinical liver disease and for the development of antifibrogenic strategies.

Figure 1. Interactions of hepatic stellate cells with inflammatory and liver resident cells during the hepatic wound healing responses

Numerous cell-cell interactions control both fibrogenesis and fibrosis regression. The activation of HSCs is promoted by interactions with hepatocytes, macrophages, innate lymphoid cells, B cells, NKT cells and CXCR4-positive endothelial cells. At the same time, HSC interaction with other cell types including NK cells, macrophages, platelets and endothelial cells results in decreased fibrogenesis and/or enhanced fibrosis regression.

Figure 2. Links between cell death, inflammation and fibrosis

In many disease settings, cell death and inflammation are intimately linked. Cell death triggers the infiltration of bone marrow-derived leukocytes and inflammation in the liver. Vice versa, inflammatory cells can amplify cell death through the release of cytotoxic cytokines or directly kill hepatocytes. Together, cell death and inflammation promote the development of fibrosis. HM, hepatic macrophages.