Kupffer cell

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. == Function ==

The primary function of the Kupffer cell is to remove foreign debris and particles that have come from the hepatic portal system when passing through the liver. It is possible for the Kupffer cells to take in large particles by phagocytosis and smaller particles via pinocytosis. Kupffer cells are one of the main sources of plasma Cholesteryl ester transfer protein (CETP), which regulates plasma levels of High-density lipoprotein and Very low-density lipoprotein. Kupffer cells also perform arachidonic acid metabolism and are a major source of prostanoids in the liver. ==Clinical significance==

Kupffer cells are incredibly plastic cells that have the capability to polarize specific activation states and can perform different functions in different microenvironments. M1 (classical activation) and M2 (alternative activation) designate the two extremes of macrophage polarization. M1-polarized Kupffer cells produce a large amount of pro-inflammatory cytokines like TNF-alpha. On the other hand, M2-polarized Kupffer cells produce a large quantity of anti-inflammatory mediators, for example, IL-10. == Phylogenetic distribution ==

Kupffer cells have been described in the liver of adult lamprey, indicating the possibility of vertebrate-wide distribution. Kupffer cells in lamprey liver are not as abundant as in mammalian liver. In the adult lamprey, the liver is not the main site of clearance of senescent erythrocytes (a function performed by mammalian Kupffer cells), and lamprey Kupffer cells seem to have a limited role in iron storage. Kupffer cells in lamprey as well as in amphibians contain melanin granules. ==History==

The cells were first observed by Karl Wilhelm von Kupffer in 1876. The scientist called them "Sternzellen" (star cells or hepatic stellate cell) but thought, inaccurately, that they were an integral part of the endothelium of the liver blood vessels and that they originated from it. In 1898, after several years of research, Tadeusz Browicz identified them, correctly, as macrophages. == References ==