Blood, Bugs, Clathrin, Lipopolysaccharide
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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

In anatomy the term “reticuloendothelial system” (abbreviated RES), often associated nowadays with the mononuclear phagocyte system (MPS), was originally launched 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.

History

In the 1920s, the founder 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. 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.

  • 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)

The RES – MPS confusion

During the years that followed after Aschoff had launched the concept of RES, research on macrophages and their feature as professional 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.

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).

  • 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.

In most present-day text books and articles the term RES is used synonymously with MPS. 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.

See also

Scavenger Endothelial Cells (SECs)

The term scavenger endothelial cell (SEC) was initially coined to describe a specialized sub-group of endothelial cells in vertebrates that express a remarkably high blood clearance activity. The term SEC has now been adopted by several scientists.

In vertebrates

The term “scavenger endothelial cell”, first appearing in the scientific literature in 1999, was coined to distinguish a highly specialized subclass of endothelium in vertebrates that was observed to express a remarkably avid blood clearance activity. Blood borne waste macromolecules are known to be efficiently cleared from the blood circulation via scavenger receptors (stabilin-1, stabilin-2), the mannose receptor, and the Fc gamma receptor IIb2 of the mammalian liver sinusoidal endothelial cells. Ligands that are efficiently cleared from blood by receptor-mediated endocytosis in liver sinusoidal endothelial cells in mammals, are also avidly cleared by liver sinusoidal endothelial cells in birds, reptiles and amphibia, as in mammals. However, in bony fish (teleosts) the same macromolecules accumulate in either heart endocardium (e.g. in the Atlantic cod) or kidney sinusoids (e.g. in carp and salmonid fishes), but not in liver. Furthermore, in animal species of phylogenetically older vertebrate classes, i.e. cartilaginous (e.g. ray) and jawless (lamprey and hagfish) fishes, only specialized endothelial cells in gills exhibit the same active blood clearance capability as observed in liver sinusoidal endothelial cells in the four land-based vertebrate classes. In all these cases the clearance cells are not macrophages, but a special type of endothelial cells that have been named scavenger endothelial cells to distinguish them functionally from other types of vertebrate endothelia. Recently it was shown that the endothelial cells in the caudal vein plexus of the embryonic zebrafish, also exhibit characteristic scavenger functions. These SECs, but not macrophages, avidly and preferentially clear colloidal waste and viral particles, as well as endogenous exosomes that are specifically internalized in a dynamin- and scavenger receptor dependent pathway to be targeted to lysosomes for degradation. Anionic nanoparticles are primarily taken up by these zebrafish SECs by the scavenger receptor, stabilin-2 in this process, which is also a signature scavenger receptor of mammalian liver sinusoidal endothelial cells.

Analogues in invertebrates

Although true endothelial cells are only found in vertebrates, insect hemocytes and nephrocytes have similar scavenger functions to vertebrate macrophages and SECs, sharing the task of waste clearance and defense against foreign intruders. Colloidal vital dyes, such as ammonia carmine and trypan blue, are rapidly and preferentially taken up by insect pericardial and garland nephrocytes. Nephrocytes, but not hemocytes of the common blow fly (Calliphora) avidly endocytose and degrade ligands that are also recognized by stabilin-2 of mammalian scavenger endothelial cells. In Drosophila, nephrocytes remove microbiota-derived peptidoglycan from systemic circulation to maintain immune homeostasis. Nephrocytes that strongly resemble insect nephrocytes are found in several other major invertebrate classes.

  • Das, D; Aradhya, R; Ashoka, D; Inamdar, M (1 May 2008). “Macromolecular uptake in Drosophila pericardial cells requires rudhira function”. Experimental Cell Research. 314 (8): 1804–10. doi:10.1016/j.yexcr.2008.02.009. PMID 18355807.
  • Palm, NB (1952). Storage and excretion of vital dyes in insects. With special regard to trypan blue (Almqvist Wiksell ed.). Stockholm: Arkiv für Zoologi. pp. 195–272.
  • Sørensen, KK; McCourt, P; Berg, T; Crossley, C; Le Couteur, D; Wake, K; Smedsrød, B (15 December 2012). “The scavenger endothelial cell: a new player in homeostasis and immunity”. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 303 (12): R1217-30. doi:10.1152/ajpregu.00686.2011. PMID 23076875.

The dual-cell principle of waste clearance

It appears that the major scavenger cell systems of vertebrates and invertebrates are based on a dual-cell principle of waste clearance. In vertebrates, distinct populations of scavenger endothelial cells represent the professional pinocyte, clearing the blood of a wide range of soluble macromolecules and small particles (<200 nm) by clathrin-mediated endocytosis, while the macrophage represents the professional phagocyte, eliminating larger particles (>200 nm).

See also

References

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