| Kupffer cell | |
|---|---|
 Confocal microscopy picture showing the steady-state location and interactions betweenKupffer cells (Red),hepatic stellate cells (green) andliver sinusoidal endothelial cells (blue). Cell nuclei are in grey.[1] | |
 Basic liver structure | |
| Details | |
| Location | Liver |
| Function | Macrophage |
| Identifiers | |
| Latin | macrophagocytus stellatus |
| MeSH | D007728 |
| TH | H3.04.05.0.00016 |
| FMA | 14656 |
| Anatomical terms of microanatomy | |
Kupffer cells, also known asstellate macrophages andKupffer–Browicz cells, are specialized cells localized in theliver 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-residentmacrophages in the body. Gut bacteria, bacterial endotoxins, and microbial debris transported to the liver from thegastrointestinal tract via theportal 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.[2][3] They form part of themononuclear phagocyte system.
Kupffer cells can be found in the sinusoidal space attached to the luminal side ofsinusoidal endothelial cells. They are more numerous in the periportal regions than the pericentral regions of thehepatic lobules[4]. 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 includingmicrovilli,pseudopodia andlamellipodia, 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 includeribosomes,Golgi complexes,centrioles,microtubules andmicrofilaments. Kupffer cells also containrough endoplasmic reticulum, anuclear envelope, andannulate lamellae, all of which demonstrateperoxidase activity.
Importantly, Kupffer cells express the SR-AI/IIscavenger receptor. This receptor is involved in recognising and binding the lipid A domain oflipopolysaccharide (LPS) andlipoteichoic acid. (LPS is a bacterial endotoxin which is found in the cell wallgram-negative bacteria, whereas lipoteichoic acid is present ingram-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.[5]
Development of an initial population of Kupffer cells begins in the embryonicyolk sac whereprecursor cells differentiate into fetalmacrophages. Once they enter the blood stream, they migrate to thefetal liver where they stay. There they complete their differentiation into Kupffer cells, which is dependent on the induction of the transcription factorId3[6]. Other transcription factors that maintain Kupffer cell identity areId1 andNr1h3 (Lxr)[7].
Under normal conditions, these Kupffer cell populations are long-lived and self-renewing.[8] However, if resident Kupffer cell populations are depleted, monocytes derived fromhematopoietic 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.[9]
Development of mature Kupffer cells is regulated by numerous growth factors, with macrophage colony-stimulating factor (CSF1) playing a key role. Cytokines involved intype 2 inflammation, such asIL-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.[5][10][3]
The primary function of the Kupffer cell is to remove foreign debris and particles that have come from thehepatic portal system when passing through the liver. It is possible for the Kupffer cells to take in large particles byphagocytosis and smaller particles viapinocytosis.[5] Kupffer cells are integral in the innate responses of the immune system. They are important for host defense and play a role in the metabolism of many different compounds including, lipids, protein complexes and small particles. They are also useful in removing apoptotic cells from circulation.[2][3]
The amount of Kupffer cells in the liver is held constant. Kupffer cells have a proliferative capacity, allowing for cell populations to replenish themselves: this is in complete contrast to monocyte-derived macrophages that have no proliferative potential. Old or defective cells are removed through apoptosis, as well as through being phagocytized by neighbouring Kupffer cells.
Kupffer cells are heterogeneous in their function, dependent on their location in theliver lobules. Cells in the periportal zone are directly exposed to bloodflow, and express greater lysosomal activity to more efficiently process incoming foreign substances. In contrast, cells in the centrilobular zone experience less perfusion, and are equipped with greater stores of superoxide to combat deeply-penetrating injuries and infections.
In response to infection or irritation, Kupffer cells can produceinflammatory cytokines,TNF-alpha,oxygen radicals, andproteases. Excessive production of these mediators is linked to the development of liver injury.[5]
Apart fromclearing bacteria, Kupffer cells are also responsible for recyclinghemoglobin by destroyingsenescentred blood cells through phagocytic action. The globin chains are re-used, while the iron-containing portion,heme, is further broken down into iron, which is re-used, andbilirubin, which is conjugated toglucuronic acid withinhepatocytes and secreted into thebile.
Helmy et al. identified a receptor present in Kupffer cells, thecomplement receptor of the immunoglobulin family (CRIg). Mice without CRIg could not clearcomplement system-coated pathogens. CRIg is conserved in mice and humans and is a critical component of the innate immune system.[11]
Kupffer cells are one of the main sources of plasmaCholesteryl ester transfer protein (CETP), which regulates plasma levels ofHigh-density lipoprotein andVery low-density lipoprotein[12]. Kupffer cells also performarachidonic acid metabolism and are a major source ofprostanoids in the liver[13].
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 ofmacrophage 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.[14][5]
Kupffer cells play a role in the pathogenesis of a damaged liver in response to sepsis. The macrophages in the liver activate and release both IL-1 and TNF-alpha. In turn, this activates leukocytes and sinusoidal endothelial cells to expressICAM-1. This results in tissue damage to the endothelium because of proteases, oxygen radicals,prostanoids and other substances from leukocytes.
Kupffer cell activation contributes to pathogenesis of both chronic and acutealcoholic liver disease in response to ethanol-induced liver injury, common in chronic alcoholics. Chronic alcoholism and liver injury deal with a two-hit system. While the first hit is direct, mediated by the direct toxicity of ethanol and its metabolic byproducts, the second hit is indirect, mediated by increased uptake oflipopolysaccharide (endotoxin) from the intestine.
Ethanol increases permeability of the intestinal epithelium, resulting in endotoxin produced by theintestinal flora leaking from theintestinal lumen into the liver via theportal vein. The presence of endotoxin induces a strong M1 polarization of Kupffer cells. A large amount of reactive oxygen species, pro-inflammatory cytokines and chemokines are produced by the activated Kupffer cells which lead to liver injury.
The cascade begins with endotoxin-mediated activation of the Toll-like receptor 4 (TLR4) andCD14, receptors on the Kupffer cell that internalize endotoxin. This in turn activates the transcription of pro-inflammatorycytokines andtumor necrosis factor-alpha (TNFα), with concurrent production ofsuperoxides.
Cytokines and superoxides go on to cause inflammation and oxidizing damage respectively, while TNFα triggers thestellate cells in the liver to initiatecollagen synthesis. These processes result infibrosis, or scarring of the liver. Fibrosis will eventually causecirrhosis, a loss of function of the liver due to extensive scarring.[15]
Kupffer cells have been described in the liver of adultlamprey[16], 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 inamphibians containmelanin granules[17][16].
The cells were first observed byKarl Wilhelm von Kupffer in 1876.[18] The scientist called them "Sternzellen" (star cells orhepatic stellate cell) but thought, inaccurately, that they were an integral part of theendothelium of the liver blood vessels and that they originated from it. In 1898, after several years of research,Tadeusz Browicz identified them, correctly, asmacrophages.[19][20][21][22]