Liver immunology and its role in inflammation and homeostasis

Abstract

The human liver is usually perceived as a non-immunological organ engaged primarily in metabolic, nutrient storage and detoxification activities. However, we now know that the healthy liver is also a site of complex immunological activity mediated by a diverse immune cell repertoire as well as non-hematopoietic cell populations. In the non-diseased liver, metabolic and tissue remodeling functions require elements of inflammation. This inflammation, in combination with regular exposure to dietary and microbial products, creates the potential for excessive immune activation. In this complex microenvironment, the hepatic immune system tolerates harmless molecules while at the same time remaining alert to possible infectious agents, malignant cells or tissue damage. Upon appropriate immune activation to challenge by pathogens or tissue damage, mechanisms to resolve inflammation are essential to maintain liver homeostasis. Failure to clear 'dangerous' stimuli or regulate appropriately activated immune mechanisms leads to pathological inflammation and disrupted tissue homeostasis characterized by the progressive development of fibrosis, cirrhosis and eventual liver failure. Hepatic inflammatory mechanisms therefore have a spectrum of roles in the healthy adult liver; they are essential to maintain tissue and organ homeostasis and, when dysregulated, are key drivers of the liver pathology associated with chronic infection, autoimmunity and malignancy. In this review, we explore the changing perception of inflammation and inflammatory mediators in normal liver homeostasis and propose targeting of liver-specific immune regulation pathways as a therapeutic approach to treat liver disease.

Figure 1

The role of inflammatory processes in liver homeostasis and pathology. Inflammatory processes in the liver are involved in both homeostasis (organ and systemic) and pathology. Homeostatic inflammation is tightly regulated by mechanisms that act to resolve inflammation in order to avoid the pathological consequences of excessive inflammation.

Figure 2

Immunological and metabolic roles of hepatocytes. Hepatocytes perform a number of important immunological roles, in addition to their essential metabolic roles. These include: the production of plasma proteins such as clotting factors, complement and antimicrobial proteins; the production of acute phase proteins upon local or systemic infection; and antigen presentation to T cells within the liver.

Figure 3

Regulation of systemic homeostasis by the liver. In a healthy individual, the liver produces a range of serum proteins including albumin, clotting factors and complement. During acute infection hepatocytes are induced to produce a range of antimicrobial proteins, inflammatory mediators, coagulation factors and opsonins, collectively known as the acute phase response. Inflammatory cytokines produced in the liver (for example, IL-6) enhance the acute phase response, alter thermoregulation and induce leukocytosis.

Figure 4

Maintenance of local homeostasis in the liver in response to liver damage. Inflammatory processes are vital to maintain liver homeostasis following cell death or infection. Upon acute injury, cell death or infection, apoptotic hepatocytes release a variety of DAMPs and/or MAMPs (1) that are recognized by and activate neighboring hepatocytes, HSCs, and liver-resident immune cell populations. Activated cells secrete inflammatory mediators leading to leukocyte recruitment and HSC trans-differentiation into myofibroblasts, which initiate fibrosis through the synthesis of extra-cellular matrix components (2). The initiation of inflammation leads to the expression of pro-resolving factors from recruited leukocytes and myofibroblast apoptosis (3), enabling tissue regeneration and a return to homeostasis (4). If this resolution phase does not occur persistent inflammation results in the progressive development of liver fibrosis and eventual cirrhosis. Abbreviations: DAMPs, damage-associated molecular patterns; ECM, extra-cellular matrix components; HSCs, hepatic stellate cells; MAMPs, microbial associated molecular patterns.