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Reticuloendothelial system

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In anatomy the term "reticuloendothelial system" (abbreviated RES), often associated nowadays with the mononuclear phagocyte system (MPS), was employed by the beginning of the 20th century to denote a system of specialised cells that effectively clear colloidal vital stains (so called because they stain living cells) from the blood circulation. The term is still used today, but its meaning has changed over the years, and is used inconsistently in present-day literature. Although RES is commonly associated exclusively with macrophages, recent research has revealed that the cells that accumulate intravenously administered vital stain belong to a highly specialised group of cells called scavenger endothelial cells (SECs), that are not macrophages.[1][2][3]


In the 1920s, the originator of the term RES, Ludwig Aschoff, reviewed the field of vital staining, and concluded that the cells lining the hepatic sinusoids are by far the most numerous and important cells accumulating intravenously administered vital stains in mammals and other vertebrates. Cells lining the lymph sinuses, and the capillaries of the adrenals, pituitary and bone marrow also accumulated vital stains, yet to a lower extent. Based on these observations Aschoff in his review concluded that these were the organs housing the cells of the RES, in the narrow sense of the term.[4] At the time when the notion of RES was launched, the understanding of concepts like endothelium, macrophages and phagocytosis were immature compared to what we know today, and during the centennium that followed there has been a considerable change in the way we understand these terms today.

The RES – MPS confusion[edit]

During the years that followed after Aschoff had originated the concept of RES, research on macrophages and their role as phagocytes steadily increased, and in 1960 the concept of the mononuclear phagocyte system was proposed to denote all cells identified as macrophages. The cells of MPS, by way of their common functional signature as professional phagocytes, clear particulate matter such as bacteria, fungi, viruses, and dying cells from the circulation. Since blood clearance is also a characteristic function of cells of RES, it was suggested in the late 1960s that RES is identical to MPS, and it was proposed that the term RES be replaced with MPS.[5]

During the 1980s and 1990s some laboratories noted that specialized endothelial cells (called scavenger endothelial cells), but not macrophages, were responsible for the avid clearance of macromolecules and nanoparticles from the blood circulation. This triggered a re-evaluation of the well-established notion that RES = MPS. In 1998 experiments were carried out to repeat the studies of Aschoff, following exactly the original methods description, and using modern ways of identifying the cells that were responsible for clearance of intravascularly injected colloidal lithium carmine, the most commonly used vital stain. The studies showed that the cell system that Aschoff described as RES in the liver were liver sinusoidal endothelial cells (LSECs), but not liver macrophages (Kupffer cells).[6]

In most present-day text books and articles the term RES is used synonymously with MPS.[7][8] This is especially unfortunate when discussing e.g. blood clearance of nano formulations. Refraining from including the highly active LSEC when discussing blood clearance may lead to failure to understand the mechanisms of clearance of several substances from the circulation.[9][10][11]

See also[edit]


  1. ^ Smedsrød, B (14 January 2004). "Clearance function of scavenger endothelial cells". Comparative Hepatology. 3 (Suppl 1): S22. doi:10.1186/1476-5926-2-S1-S22. PMC 2409441. PMID 14960174.
  2. ^ Wake, K; Kawai, Y; Smedsrød, B (2001). "Re-evaluation of the reticulo-endothelial system". Italian Journal of Anatomy and Embryology. 106 (2 Suppl 1): 261–9. PMID 11729964.
  3. ^ Campbell, Frederick; Bos, Frank L.; Sieber, Sandro; Arias-Alpizar, Gabriela; Koch, Bjørn E.; Huwyler, Jörg; Kros, Alexander; Bussmann, Jeroen (10 January 2018). "Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake". ACS Nano. 12 (3): 2138–2150. doi:10.1021/acsnano.7b06995. PMC 5876619. PMID 29320626.
  4. ^ Aschoff, L. (1924). "Das reticulo-endotheliale System". Ergebnisse der Inneren Medizin und Kinderheilkunde (in German). Springer Berlin Heidelberg. pp. 1–118. doi:10.1007/978-3-642-90639-8_1. ISBN 978-3-642-88784-0. {{cite book}}: |journal= ignored (help)
  5. ^ van Furth, R; Cohn, ZA; Hirsch, JG; Humphrey, JH; Spector, WG; Langevoort, HL (1972). "The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells". Bulletin of the World Health Organization. 46 (6): 845–52. PMC 2480884. PMID 4538544.
  6. ^ Kawai, Y; Smedsrød, B; Elvevold, K; Wake, K (May 1998). "Uptake of lithium carmine by sinusoidal endothelial and Kupffer cells of the rat liver: new insights into the classical vital staining and the reticulo-endothelial system". Cell and Tissue Research. 292 (2): 395–410. doi:10.1007/s004410051069. PMID 9560481. S2CID 13183775.
  7. ^ Tartaro, K; VanVolkenburg, M; Wilkie, D; Coskran, TM; Kreeger, JM; Kawabata, TT; Casinghino, S (2015). "Development of a fluorescence-based in vivo phagocytosis assay to measure mononuclear phagocyte system function in the rat". Journal of Immunotoxicology. 12 (3): 239–46. doi:10.3109/1547691X.2014.934976. PMID 25027674.
  8. ^ Dictionary of medical terms (6th ed.). Barron's Educational Series. 2012-11-01. ISBN 9780764147586.
  9. ^ Praaning-van Dalen, DP; Brouwer, A; Knook, DL (December 1981). "Clearance capacity of rat liver Kupffer, Endothelial, and parenchymal cells". Gastroenterology. 81 (6): 1036–44. doi:10.1016/s0016-5085(81)80009-1. PMID 7286581.
  10. ^ Anderson, CL (December 2015). "The liver sinusoidal endothelium reappears after being eclipsed by the Kupffer cell: a 20th century biological delusion corrected". Journal of Leukocyte Biology. 98 (6): 875–6. doi:10.1189/jlb.4VMLT0215-054R. PMID 26628636.
  11. ^ Ganesan, LP; Mohanty, S; Kim, J; Clark, KR; Robinson, JM; Anderson, CL (September 2011). "Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium". PLOS Pathogens. 7 (9): e1002281. doi:10.1371/journal.ppat.1002281. PMC 3182912. PMID 21980295.