A novel mechanism of erythrocyte capture from circulation in humans

Kerfoot, Steven M., McRae, Krista, Lam, Florence, McAvoy, Erin F., Clark, Stephen Robert ORCID: https://orcid.org/0000-0001-5907-9671, Brain, Michael, Lalor, Patricia F., Adams, David H. and Kubes, Paul 2008. A novel mechanism of erythrocyte capture from circulation in humans. Experimental Hematology 36 (2) , pp. 111-118. 10.1016/j.exphem.2007.08.029

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Abstract

Objective The capture of blood cells from the circulation is mediated by highly specialized adhesion molecules. These molecules contribute to the specificity of recruitment for various subsets. Here, we used a simple substrate of hyaluronic acid to investigate the specificity of CD44-mediated recruitment from human whole blood under shear conditions. Materials and Methods Human whole blood was perfused through a parallel-plate flow chamber, which mimics intravascular conditions. Microscopy was used to directly observe blood-cell interactions with adhesion molecule substrates. Results Erythrocytes, but not leukocytes, efficiently tethered to and rolled on the hyaluronic acid substrate. These interactions were demonstrated to be mediated by CD44 and regulated by the sialic acid content of the cells. Inflammatory stimuli did not result in enhanced erythrocyte rolling. Rather, interactions were restricted to aged erythrocytes approaching senescence. This mechanism of erythrocyte capture from the blood flow was found to be restricted to primates and not conserved across mammalian species. Conclusion This is the first report of erythrocyte tethering and rolling under shear conditions, a behavior, until now, thought to be exclusive to leukocytes. It may represent an important mechanism to identify, capture, and clear old erythrocytes during normal homeostasis or clot formation. The mechanisms behind leukocyte capture from the circulation are relatively well-known. This process is dependent on interactions between specialized molecules with high affinities and short binding kinetics for their ligands [1]. These are required to overcome shear forces caused by flowing blood in the circulation. Selectins and their ligands mediate the initial capture, or tethering, of leukocytes, followed by subsequent rolling. Integrins and their ligands predominantly mediate adhesion, although α4-integrin/vascular cell adhesion molecule-1 (VCAM-1) interactions can also mediate tethering and rolling under some circumstances. In addition to these primary players, a number of other molecules have been shown to play a role in the process of leukocyte recruitment, although the extent of their contribution is less well-understood. One example is CD44, which has been shown to be involved in the rolling of some subsets of activated leukocytes in some circumstances [2], [3], [4], [5], [6] and [7]. While CD44 is ubiquitously expressed by nearly all blood cells, including leukocytes and erythrocytes, only a very limited set of leukocytes have been shown to interact with its ligand, hyaluronic acid (HA). HA is produced by endothelial cells and is an important glycosaminoglycan component of the extracellular matrix. CD44 affinity for HA has been shown to be regulated via various posttranslational modifications, including glycosylation and sialic acid content [6], [7] and [8]. Despite this, very little is known about the relative contribution of CD44 to the capture of the different blood cell subsets under physiological conditions. In addition to leukocytes, erythrocytes are also known to express significant amounts of CD44. However, adhesion to endothelium is not normally associated with these cells. Nevertheless, human erythrocytes have a life span of approximately 120 days [9] and [10], after which they must be cleared from the circulation. To date, no mechanism capable of capturing erythrocytes from flowing blood has been described. While erythrocytes do not express most of the adhesion molecules involved in leukocyte capture, they do express CD44. Loss of sialic acid from membrane proteins has been associated with erythrocyte senescence, and this has been hypothesized to contribute to their clearance [11] and [12]. However, to date, no endogenous mechanism or receptor to recognize the loss of sialic acid has been described. Indeed, despite a great deal of effort to characterize the erythrocyte lifecycle, the mechanisms of senescence and clearance remain largely unknown. We used an unbiased, flow-based, screen assay to identify all blood cell subsets recruited by the specific adhesion molecule HA. Unlike other adhesion molecules that we tested, no leukocytes were observed to interact with HA under baseline conditions. To our surprise, however, large numbers of erythrocytes tethered and rolled in a fashion reminiscent of typical leukocyte interactions. These interactions were mediated by CD44 and regulated by sialic acid. Erythrocyte affinity for HA was not increased by inflammatory signals, but instead increased over the lifespan of the cell. Therefore, this may represent the in vivo mechanism by which erythrocyte clearance is accomplished and homeostasis is maintained.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Elsevier
ISSN:	0301-472X
Last Modified:	19 Oct 2022 10:39
URI:	https://orca.cardiff.ac.uk/id/eprint/25099

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