Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. Kupffer cells comprise the largest population of tissue-resident macrophages in the body. Gut bacteria, bacterial endotoxins, and microbial debris transported to the liver from the gastrointestinal tract via the portal vein will first come in contact with Kupffer cells, the first immune cells in the liver. It is because of this that any change to Kupffer cell functions can be connected to various liver diseases such as alcoholic liver disease, viral hepatitis, intrahepatic cholestasis, steatohepatitis, activation or rejection of the liver during liver transplantation and liver fibrosis. They form part of the mononuclear phagocyte system.
Location and structure Kupffer cells can be found in the sinusoidal space attached to the luminal side of sinusoidal endothelial cells. They are more numerous in the periportal regions than the pericentral regions of the hepatic lobules. Kupffer cell function and structures are specialized depending on their location. Periportal Kupffer cells tend to be larger and have more lysosomal enzyme and phagocytic activity, whereas centrilobular Kupffer cells create more superoxide radical. Kupffer cells are amoeboid in character, with surface features including microvilli, pseudopodia and lamellipodia, which project in every direction. The microvilli and pseudopodia play a role in the endocytosis of particles. The nucleus is indented and ovoid, and can be lobulated. Notable cytoplasmic elements include ribosomes, Golgi complexes, centrioles, microtubules and microfilaments. Kupffer cells also contain rough endoplasmic reticulum, a nuclear envelope, and annulate lamellae, all of which demonstrate peroxidase activity. Importantly, Kupffer cells express the SR-AI/II scavenger receptor. This receptor is involved in recognising and binding the lipid A domain of lipopolysaccharide (LPS) and lipoteichoic acid. (LPS is a bacterial endotoxin which is found in the cell wall gram-negative bacteria, whereas lipoteichoic acid is present in gram-positive bacteria.) Because of this detection system, Kupffer cells play a critical role in initiating and mediating immune responses to bacterial infection of the liver.
Development Development of an initial population of Kupffer cells begins in the embryonic yolk sac where precursor cells differentiate into fetal macrophages. Once they enter the blood stream, they migrate to the fetal liver where they stay. There they complete their differentiation into Kupffer cells, which is dependent on the induction of the transcription factor Id3. Other transcription factors that maintain Kupffer cell identity are Id1 and Nr1h3 (Lxr). Under normal conditions, these Kupffer cell populations are long-lived and self-renewing. However, if resident Kupffer cell populations are depleted, monocytes derived from hematopoietic stem cells in the bone marrow transported through blood circulation to the liver can also fully differentiate into true Kupffer cells. Unlike other tissue macrophages, which must be continually renewed by circulating monocytes, these monocyte-derived Kupffer cells are capable of self-renewal once a population is established. Development of mature Kupffer cells is regulated by numerous growth factors, with macrophage colony-stimulating factor (CSF1) playing a key role. Cytokines involved in type 2 inflammation, such as IL-4, may also stimulate Kupffer cell proliferation. A time frame of 14 to 21 days for complete replenishment of Kupffer cell populations has been demonstrated in animal studies. Despite high monocyte influx and maturation rates, hepatic Kupffer cell populations are tightly maintained. Evidently, there is a high rate of turnover, with the average lifespan of a Kupffer cell estimated at 3.8 days. However, the ultimate fate of Kupffer cells in vivo is not yet fully understood.
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