Kupffer cells (KCs) are liver resident macrophages with several key roles in maintaining healthy liver function. As phagocytes, their primary function is to engulf bacterial pathogens and endotoxins, dead cells, microbial debris, and other antigens in the liver. In doing so, they help to guard the liver against infection while preventing unnecessary immune activation against non-harmful antigens.
What is a Kupffer cell?
Kupffer cells (AKA hepatic macrophages) are a type of macrophage found in liver tissue. They account for 80-90% of the total number of macrophages in the immune system and play a vital role in maintaining healthy liver function.
Development of Kupffer Cells
The lifespan and renewal mechanisms of Kupffer cells is still under debate by scientists. One popular hypothesis is that, like other cells of the immune system, KCs develop from stem cells in the bone marrow before migrating to the liver. Other researchers believe that KCs are capable of self-renewal and develop from the division of cells in the liver.
KCs are thought to live for approximately 3.8 days, though some studies have shown that the lifespan of these cells in rats may be as long as 14 months.
Function of Kupffer Cells
Kupffer cells are macrophages, and a component of the innate immune system. They have a variety of functions in the liver, including phagocytosis of pathogens, antigen-presentation, and immune suppression.
Like all macrophages, KCs are phagocytes that engulf and digest pathogens, immune complexes, lysosomes, tumor cells, endotoxins, and more.
Their primary function is to protect the liver against infection, and KCs rapidly clear bacteria, endotoxins, and other microbial debris that arrive in the bloodstream from the gastrointestinal tract. They also engulf and destroy dead cells in the liver following inflammation or injury to the tissue, which helps to maintain liver homeostasis.
Kupffer cells act as antigen-presenting cells (APCs) in the liver and express low levels of both MHC I and MHC II complexes. Once they have engulfed a pathogen, they display its antigens as part of the MHC complex and present it to resident T cells. In doing so, KCs can induce the activation and proliferation of T cells in the liver, thereby inducing an adaptive immune response.
One of the most important functions of Kupffer cells is to promote immune tolerance in the liver. The liver is continuously exposed to a steady flow of antigens from the gut, as well as low levels of bacterial endotoxins. By engulfing and destroying non-threatening antigens, KCs help to prevent unnecessary immune activation.
KCs also secrete PGE2 and IL-10, two immunosuppressive products that downregulate the antigen-presenting functions of other immune cells in the liver. This helps to inhibit effector T cell activation and, therefore, suppresses the immune response against antigens.
Finally, KCs play an important role in the activation of regulatory T cells (Tregs). Tregs regulate and suppress immune function by helping to prevent the activation and proliferation of effector T cells (namely, helper T cells and cytotoxic T cells). They are also thought to suppress the functions of B cells and dendritic cells. In doing so, they put a damper on the immune response to antigens in the liver.
Kupffer Cells and Alcohol-Induced Liver Disease
Kupffer cells are known to play a role in the development of alcohol-induced liver disease, though the exact mechanism by which they do so is not fully understood. One theory suggests that excessive alcohol consumption reduces the ability of KCs to clear bacterial endotoxins from the liver, leading to higher circulating levels in the blood. Another proposed theory is that alcohol consumption increases the absorption of endotoxins through the intestinal wall, resulting in higher levels of endotoxins in the blood.
KCs are activated when they internalize these endotoxins, which results in the production of reactive oxygen species (ROS). These increase oxidative stress in the liver which results in liver damage and, eventually, loss of liver function.