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Kupffer cell

January 01, 1970

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.[2][3] They form part of the mononuclear phagocyte system.

Kupffer cell
Confocal microscopy picture showing the steady-state location and interactions between Kupffer cells (Red), hepatic stellate cells (green) and liver sinusoidal endothelial cells (blue). Cell nuclei are in grey.[1]
Basic liver structure
Details
LocationLiver
FunctionMacrophage
Identifiers
Latinmacrophagocytus stellatus
MeSHD007728
THH3.04.05.0.00016
FMA14656
Anatomical terms of microanatomy
[edit on Wikidata]

Location and structure edit

Kupffer cells can be found attached to sinusoidal endothelial cells in both the centrilobular and periportal 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. (Lipopolysaccharide (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.[4]

Development edit

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. Under normal conditions, these Kupffer cell populations are long-lived and self-renewing.[5]

However, if resident Kupffer cell populations are depleted, monocytes derived from hematopoietic stem cells in the bone marrow and 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.[6]

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.[4][7][3]

Function edit

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.[4] 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 the liver 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 produce inflammatory cytokines, TNF-alpha, oxygen radicals, and proteases. Excessive production of these mediators is linked to the development of liver injury.[4]

Apart from clearing bacteria, Kupffer cells are also responsible for recycling hemoglobin by destroying senescent red 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, and bilirubin, which is conjugated to glucuronic acid within hepatocytes and secreted into the bile.

Helmy et al. identified a receptor present in Kupffer cells, the complement receptor of the immunoglobulin family (CRIg). Mice without CRIg could not clear complement system-coated pathogens. CRIg is conserved in mice and humans and is a critical component of the innate immune system.[8]

Clinical significance edit

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.[9][4]

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 express ICAM-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 acute alcoholic 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 of lipopolysaccharide (endotoxin) from the intestine.

Ethanol increases permeability of the intestinal epithelium, resulting in endotoxin produced by the intestinal flora leaking from the intestinal lumen into the liver via the portal 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) and CD14, receptors on the Kupffer cell that internalize endotoxin. This in turn activates the transcription of pro-inflammatory cytokines and tumor necrosis factor-alpha (TNFα), with concurrent production of superoxides.

Cytokines and superoxides go on to cause inflammation and oxidizing damage respectively, while TNFα triggers the stellate cells in the liver to initiate collagen synthesis. These processes result in fibrosis, or scarring of the liver. Fibrosis will eventually cause cirrhosis, a loss of function of the liver due to extensive scarring.[10]

History edit

The cells were first observed by Karl Wilhelm von Kupffer in 1876.[11] 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.[12][13][14][15]

References edit

  1. ^ Bonnardel J, T'Jonck W, Gaublomme D, Browaeys R, Scott CL, Martens L, et al. (October 2019). "Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche". Immunity. 51 (4): 638–654.e9. doi:10.1016/j.immuni.2019.08.017. PMC 6876284. PMID 31561945.
  2. ^ a b Nguyen-Lefebvre, Anh Thu; Horuzsko, Anatolij (2015). "Kupffer Cell Metabolism and Function". Journal of Enzymology and Metabolism. 1 (1). PMC 4771376. PMID 26937490.
  3. ^ a b c Dixon, Laura J.; Barnes, Mark; Tang, Hui; Pritchard, Michele T.; Nagy, Laura E. (April 2013). "Kupffer Cells in the Liver". Comprehensive Physiology. 3 (2): 785–797. doi:10.1002/cphy.c120026. ISSN 2040-4603. PMC 4748178. PMID 23720329.
  4. ^ a b c d e Basit, Hajira; Tan, Michael L.; Webster, Daniel R. (2020), "Histology, Kupffer Cell", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29630278, retrieved 2020-08-25
  5. ^ Naito M, Hasegawa G, Takahashi K (November 1997). "Development, differentiation, and maturation of Kupffer cells". Microscopy Research and Technique. 39 (4): 350–64. doi:10.1002/(SICI)1097-0029(19971115)39:4<350::AID-JEMT5>3.0.CO;2-L. PMID 9407545. S2CID 21193303.
  6. ^ Scott C, Zheng F, De Baetselier P, et al. (27 January 2016). "Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells". Nature Communications. 7, 10321 (2016): 10321. Bibcode:2016NatCo...710321S. doi:10.1038/ncomms10321. PMC 4737801. PMID 26813785.
  7. ^ Chen, Jiajia; Deng, Xiaoyi; Liu, Yongjian; Tan, Qiuhua; Huang, Guidong; Che, Qishi; Guo, Jiao; Su, Zhengquan (2020). "Kupffer Cells in Non-alcoholic Fatty Liver Disease: Friend or Foe?". International Journal of Biological Sciences. 16 (13): 2367–2378. doi:10.7150/ijbs.47143. PMC 7378652. PMID 32760204. Retrieved 2020-08-31.
  8. ^ Helmy KY, Katschke KJ, Gorgani NN, Kljavin NM, Elliott JM, Diehl L, et al. (March 2006). "CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens". Cell. 124 (5): 915–27. doi:10.1016/j.cell.2005.12.039. PMID 16530040. S2CID 15525209.
  9. ^ Zeng, Tao; Zhang, Cui-Li; Xiao, Mo; Yang, Rui; Xie, Ke-Qin (2016). "Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials". Frontiers in Immunology. 7: 538. doi:10.3389/fimmu.2016.00538. ISSN 1664-3224. PMC 5126119. PMID 27965666.
  10. ^ Wheeler MD (2003). "Endotoxin and Kupffer cell activation in alcoholic liver disease". Alcohol Research & Health. 27 (4): 300–6. PMC 6668869. PMID 15540801.
  11. ^ Haubrich WS (July 2004). "Kupffer of Kupffer cells". Gastroenterology. 127 (1): 16. doi:10.1053/j.gastro.2004.05.041. PMID 15236167.
  12. ^ Szymańska R, Schmidt-Pospuła M (1979). "[Studies of liver's reticuloendothelial cells by Tadeusz Browicz and Karl Kupffer. A historical outline]". Archiwum Historii Medycyny. 42 (3): 331–6. PMID 386989.
  13. ^ Stachura J, Gałązka K (December 2003). "History and current status of Polish gastroenterological pathology". Journal of Physiology and Pharmacology. 54 Suppl 3: 183–92. PMID 15075472.
  14. ^ Śródka A, Gryglewski RW, Szczepański W (2006). "Browicz or Kupffer cells?". Polish Journal of Pathology. 57 (4): 183–5. PMID 17285760.
  15. ^ Wake K (2009). "[Browicz's phagocytic cells and Kupffer's 'so-called stellate cells']". Kaibogaku Zasshi. 84 (1): 17–21. PMID 19413196.

External links edit

  • - Comparative Organology at University of California, Davis - "Mammal, liver (EM, Low)"
  • Histology image: 15508loa – Histology Learning System at Boston University

January 01, 1970
kupffer, cell, also, known, stellate, macrophages, kupffer, browicz, cells, specialized, cells, localized, liver, within, lumen, liver, sinusoids, adhesive, their, endothelial, cells, which, make, blood, vessel, walls, comprise, largest, population, tissue, re. 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 2 3 They form part of the mononuclear phagocyte system Kupffer cellConfocal microscopy picture showing the steady state location and interactions between Kupffer cells Red hepatic stellate cells green and liver sinusoidal endothelial cells blue Cell nuclei are in grey 1 Basic liver structureDetailsLocationLiverFunctionMacrophageIdentifiersLatinmacrophagocytus stellatusMeSHD007728THH3 04 05 0 00016FMA14656Anatomical terms of microanatomy edit on Wikidata Contents 1 Location and structure 2 Development 3 Function 4 Clinical significance 5 History 6 References 7 External linksLocation and structure editKupffer cells can be found attached to sinusoidal endothelial cells in both the centrilobular and periportal 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 Lipopolysaccharide 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 4 Development editDevelopment 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 Under normal conditions these Kupffer cell populations are long lived and self renewing 5 However if resident Kupffer cell populations are depleted monocytes derived from hematopoietic stem cells in the bone marrow and 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 6 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 4 7 3 Function editThe 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 4 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 the liver 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 produce inflammatory cytokines TNF alpha oxygen radicals and proteases Excessive production of these mediators is linked to the development of liver injury 4 Apart from clearing bacteria Kupffer cells are also responsible for recycling hemoglobin by destroying senescent red 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 and bilirubin which is conjugated to glucuronic acid within hepatocytes and secreted into the bile Helmy et al identified a receptor present in Kupffer cells the complement receptor of the immunoglobulin family CRIg Mice without CRIg could not clear complement system coated pathogens CRIg is conserved in mice and humans and is a critical component of the innate immune system 8 Clinical significance editKupffer 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 9 4 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 express ICAM 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 acute alcoholic 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 of lipopolysaccharide endotoxin from the intestine Ethanol increases permeability of the intestinal epithelium resulting in endotoxin produced by the intestinal flora leaking from the intestinal lumen into the liver via the portal 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 and CD14 receptors on the Kupffer cell that internalize endotoxin This in turn activates the transcription of pro inflammatory cytokines and tumor necrosis factor alpha TNFa with concurrent production of superoxides Cytokines and superoxides go on to cause inflammation and oxidizing damage respectively while TNFa triggers the stellate cells in the liver to initiate collagen synthesis These processes result in fibrosis or scarring of the liver Fibrosis will eventually cause cirrhosis a loss of function of the liver due to extensive scarring 10 History editThe cells were first observed by Karl Wilhelm von Kupffer in 1876 11 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 12 13 14 15 References edit Bonnardel J T Jonck W Gaublomme D Browaeys R Scott CL Martens L et al October 2019 Stellate Cells Hepatocytes and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche Immunity 51 4 638 654 e9 doi 10 1016 j immuni 2019 08 017 PMC 6876284 PMID 31561945 a b Nguyen Lefebvre Anh Thu Horuzsko Anatolij 2015 Kupffer Cell Metabolism and Function Journal of Enzymology and Metabolism 1 1 PMC 4771376 PMID 26937490 a b c Dixon Laura J Barnes Mark Tang Hui Pritchard Michele T Nagy Laura E April 2013 Kupffer Cells in the Liver Comprehensive Physiology 3 2 785 797 doi 10 1002 cphy c120026 ISSN 2040 4603 PMC 4748178 PMID 23720329 a b c d e Basit Hajira Tan Michael L Webster Daniel R 2020 Histology Kupffer Cell StatPearls Treasure Island FL StatPearls Publishing PMID 29630278 retrieved 2020 08 25 Naito M Hasegawa G Takahashi K November 1997 Development differentiation and maturation of Kupffer cells Microscopy Research and Technique 39 4 350 64 doi 10 1002 SICI 1097 0029 19971115 39 4 lt 350 AID JEMT5 gt 3 0 CO 2 L PMID 9407545 S2CID 21193303 Scott C Zheng F De Baetselier P et al 27 January 2016 Bone marrow derived monocytes give rise to self renewing and fully differentiated Kupffer cells Nature Communications 7 10321 2016 10321 Bibcode 2016NatCo 710321S doi 10 1038 ncomms10321 PMC 4737801 PMID 26813785 Chen Jiajia Deng Xiaoyi Liu Yongjian Tan Qiuhua Huang Guidong Che Qishi Guo Jiao Su Zhengquan 2020 Kupffer Cells in Non alcoholic Fatty Liver Disease Friend or Foe International Journal of Biological Sciences 16 13 2367 2378 doi 10 7150 ijbs 47143 PMC 7378652 PMID 32760204 Retrieved 2020 08 31 Helmy KY Katschke KJ Gorgani NN Kljavin NM Elliott JM Diehl L et al March 2006 CRIg a macrophage complement receptor required for phagocytosis of circulating pathogens Cell 124 5 915 27 doi 10 1016 j cell 2005 12 039 PMID 16530040 S2CID 15525209 Zeng Tao Zhang Cui Li Xiao Mo Yang Rui Xie Ke Qin 2016 Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease From Basic Science to Clinical Trials Frontiers in Immunology 7 538 doi 10 3389 fimmu 2016 00538 ISSN 1664 3224 PMC 5126119 PMID 27965666 Wheeler MD 2003 Endotoxin and Kupffer cell activation in alcoholic liver disease Alcohol Research amp Health 27 4 300 6 PMC 6668869 PMID 15540801 Haubrich WS July 2004 Kupffer of Kupffer cells Gastroenterology 127 1 16 doi 10 1053 j gastro 2004 05 041 PMID 15236167 Szymanska R Schmidt Pospula M 1979 Studies of liver s reticuloendothelial cells by Tadeusz Browicz and Karl Kupffer A historical outline Archiwum Historii Medycyny 42 3 331 6 PMID 386989 Stachura J Galazka K December 2003 History and current status of Polish gastroenterological pathology Journal of Physiology and Pharmacology 54 Suppl 3 183 92 PMID 15075472 Srodka A Gryglewski RW Szczepanski W 2006 Browicz or Kupffer cells Polish Journal of Pathology 57 4 183 5 PMID 17285760 Wake K 2009 Browicz s phagocytic cells and Kupffer s so called stellate cells Kaibogaku Zasshi 84 1 17 21 PMID 19413196 External links editAnatomy photo digestive mammal liver5 liver4 Comparative Organology at University of California Davis Mammal liver EM Low Histology image 15508loa Histology Learning System at Boston University Retrieved from https en wikipedia org w index php title Kupffer cell amp oldid 1182756377, wikipedia, wiki, book, books, library,

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