L-selectin

L-selectin, also known as CD62L, is a

While L-selectin ligands on the apical side of the endothelium have long been characterized as receptors for binding and rolling, glycans enriched on the basolateral side and in the basement membrane likely control quite different signals. The binding lifetime of L-selectin with apical ligands will be on the order of milliseconds, so in contrast, L-selectin-dependent adhesion in a microenvironment without hydrodynamic shear stress (e.g., within transmigrating pseudopods) will take seconds to minutes.

• high endothelial venules of the lymph nodes
  .
• CD34, found on endothelial cells.
• MadCAM-1, found on endothelial cells of gut-associated lymphoid tissue
  .
• PSGL-1
  , binds with low affinity.

L-selectin is expressed constitutively on most circulating leukocytes.[6] Over time, these molecules are released through the process of ectodomain shedding and are replaced by newly synthesized L-selectin proteins. Ectodomain shedding is largely accomplished through cleavage by ADAM17.

The human L-selectin gene (sell) is located on the long arm of chromosome 1 (1q24.2), and is arranged in tandem with its family members (in the order: L-, P-, and E-selectin). Human sell consists of 10 exons and its transcription factor is FOXO 1,^[9] on the other hand the mouse sell gene is composed of 9 exons. ^[6]

Subsequent splicing of exons into mature mRNA translates to a protein product with a predicted molecular mass of 30 kDa. L-selectin varies between cell types, has ranging molecular weight from 65 kDa in lymphocytes to 100 kDa in neutrophils, and is due to cell type-specific glycosylation. Most glycoproteins undergo either N- or O-linked glycosylation, and it is very likely that the type of L-selectin glycosylation determines the specific functions of individual cells, but this has not yet been investigated in detail. ^[6]

L-selectin is expressed on naive T cells and is rapidly shed following T cell priming.^[6] L-selectin expression is re-activated in cytotoxic T cells once they exit the lymph node.  Mature central memory T cells express L-selectin while effector memory cells do not. L-selectin is also expressed by naive B cells, with the loss of L-selectin distinguishing activated B cells destined to differentiate to antibody-secreting cells

L-selectin is expressed on circulating neutrophils and is shed following neutrophil priming.^[6] Expression of L-selectin in neutrophils decreases with neutrophil aging. Classical monocytes express high levels of L-selectin while in circulation. Shedding of L-selectin from monocytes occurs during trans-endothelial migration.

L-selectin expression is also observed on oocytes and early-stage embryos. Blastocysts express L-selectin following, but not prior to emergence from the zona pellucida. An increase in L-selectin expression is observed when both the blastocyst and cytotrophoblast attach to the endometrium.  L-selectin expression decreases by the 17th week of pregnancy, and remains low or non-existent until term (2017).^[7]

Function

Lymphocytes

L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules.

Similar to its role in homing lymphocytes to secondary lymphoid tissues, L-selectin expressed on the surface of monocytes and neutrophils is essential for facilitating the first stage of adhesion to venule epithelial cells (known as the “rolling stage”).[6]^[5] Adhesion to activated epithelial cells is a critical step in the immune response as it allows these immune cells to emigrate from the bloodstream into inflamed tissue. Prolonged rolling and transmigration of neutrophils can trigger shedding of L-selectin from the neutrophil plasma membrane.^[5] The membrane-bound fragment left behind following cleavage of L-selectin has also been suggested to play a critical role in the interstitial chemotaxis of neutrophils along a cytokine gradient.^[6] L-selectin on neutrophils can result in its own ectodomain shedding, drived by activation of p38 MAPK followed by antibody-mediated clustering (AMC), after which L-selectin can behave as a cell adhesion molecule and signaling receptor. L-selectin shedding is not strictly consequence of neutrohpil transmigration, because it was observed that there is differences between neutrophil migration toward acute or chronic inflammation could differ in the expression and turnover of adhesion molecules.^[12]

L-selectin shedding also occurs in monocytes; however, in these cells shedding is triggered only during trans-endothelial and not by earlier stages of the adhesion process.^[6] The specific shedding of L-selectin from the leading migratory fronts of transmigrating monocytes suggests that this process plays a role in facilitating the directional migration of these cells (2019).^[6]

Embryo

L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor,

The binding of L-selectin to its ligands plays an important role in embryo implantation during human pregnancy. Deficiency epithelial expression of L-selectin ligands has been associated with infertility, while increased expression has been implicated in ectopic pregnancies^[7]

Cancer

The adhesive properties of L-selectin have been shown to contribute to cancer progression. L-selectin interactions participate in trafficking of chronic lymphocytic leukemia cells to the lymph nodes where they are able to proliferate and evolve. Additionally, L-selectin interactions may play a role in metastasis.^[15]

References