SELE

Detailed Information

The SELE gene is located on human chromosome 1q24.2 and encodes a type I transmembrane glycoprotein known as E-selectin (also called CD62E). The gene spans approximately 13.8 kb, consisting of 14 exons and 13 introns, and produces a 4.3 kb mRNA transcript. Translation generates a precursor protein of 589 amino acids that is processed into a mature protein with a molecular weight of about 115 kDa. E-selectin belongs to the selectin family, which also includes P-selectin (encoded by SELP) and L-selectin (encoded by SELL). Members of this family share a conserved structural framework. The extracellular region of E-selectin comprises three major domains: an N-terminal C-type lectin domain responsible for carbohydrate recognition, an epidermal growth factor-like domain that maintains structural stability, and a short consensus repeat (SCR) domain containing six conserved cysteine residues that form disulfide bonds to stabilize tertiary structure.

Expression and regulation of E-selectin

E-selectin expression is highly cell type-specific and restricted to activated vascular endothelial cells. It is tightly regulated at the transcriptional level. In resting endothelial cells, expression is nearly absent, but exposure to pro-inflammatory cytokines such as TNF-α and IL-1β, or bacterial endotoxin (LPS), rapidly induces expression within 2–4 hours. This induction depends on transcription factors such as NF-κB binding to response elements in the SELE promoter. Expression is transient, peaking at 4–6 hours after activation and returning to baseline within 24 hours, reflecting precise inflammatory control to prevent excessive leukocyte infiltration and tissue damage.

Post-translational modifications of E-selectin are essential for its function. The protein undergoes complex glycosylation, critical for ligand binding, and its stability and activity also rely on correct disulfide bond formation and calcium ion binding. As a Ca²⁺-dependent adhesion molecule, E-selectin requires calcium to maintain its lectin domain conformation and mediate specific ligand interactions. These molecular features collectively enable E-selectin to act as a critical bridge between vascular endothelium and circulating leukocytes in inflammatory environments.

Biological functions and signaling mechanisms

The primary role of E-selectin is to mediate the adhesion of leukocytes to vascular endothelium, a central step in inflammation and immune surveillance. During the early phase of inflammation, endothelial cells upregulate E-selectin expression, enabling its extracellular domain to bind carbohydrate ligands on leukocytes, particularly sialyl Lewis X (sLeˣ). This interaction initiates leukocyte tethering and rolling along the vessel wall, slowing their movement and facilitating integrin-mediated firm adhesion and transendothelial migration. E-selectin preferentially supports adhesion of neutrophils, monocytes, and subsets of lymphocytes such as memory T cells, underscoring its role in both innate and adaptive immunity.

The interaction between E-selectin and its ligands is characterized by rapid on-and-off binding kinetics, producing the rolling behavior of leukocytes. Short-lived binding events exert drag forces that decelerate leukocytes, followed by quick dissociation that allows forward displacement, resulting in rolling motion. This dynamic requires precise spatial complementarity between the lectin domain and carbohydrate ligands, stabilized by calcium ions. Mutations that disrupt calcium binding or alter key residues such as Arg97 and His114 abolish adhesive function, emphasizing the structural precision necessary for activity.

Beyond adhesion, E-selectin also triggers intracellular signaling in leukocytes. Ligand engagement activates tyrosine kinases, increases intracellular calcium levels, and induces cytoskeletal reorganization. These events enhance integrin activation, transitioning leukocytes from rolling to firm adhesion, and can modulate functional responses such as neutrophil reactive oxygen species release or T cell migratory behavior. Thus, E-selectin contributes to bidirectional signaling between leukocytes and endothelial cells, shaping inflammatory microenvironments.

E-selectin regulation is multilayered. Transcriptionally, pathways involving NF-κB, AP-1, and Sp1 contribute to induction, while histone modifications at the SELE promoter affect gene responsiveness. At the protein level, membrane E-selectin can be cleaved to release soluble E-selectin (sE-selectin) into circulation. This soluble form retains ligand-binding capacity, potentially acting as a decoy to modulate inflammation and serving as a biomarker of endothelial activation. Together, these regulatory mechanisms ensure E-selectin’s precise functional control in both physiological and pathological contexts.

Disease associations and clinical significance

E-selectin plays a pivotal role in numerous inflammatory and vascular diseases, with a prominent role in atherosclerosis. In early stages, endothelial dysfunction induced by risk factors such as hypercholesterolemia or hypertension leads to aberrant upregulation of E-selectin. This enhances monocyte and T cell adhesion to the endothelium and transmigration into the intimal layer, where they differentiate into macrophages, engulf oxidized LDL, and form lipid-laden foam cells. Continued leukocyte infiltration amplifies inflammation and destabilizes plaques. Histological studies confirm high E-selectin expression in atherosclerotic endothelium, correlating with disease severity. Genetic studies also implicate SELE polymorphisms such as Ser128Arg and Leu554Phe in modulating susceptibility to atherosclerosis, possibly by altering protein function or expression levels.

In autoimmune diseases, E-selectin-mediated leukocyte infiltration is a key pathological hallmark. In rheumatoid arthritis, synovial microvascular endothelium expresses high levels of E-selectin under inflammatory cytokine stimulation, recruiting neutrophils and memory T cells into the joint. These cells release proteases and pro-inflammatory mediators, driving cartilage destruction and bone erosion. Circulating sE-selectin levels are elevated in rheumatoid arthritis patients and correlate with disease activity. Similar upregulation is observed in psoriatic skin lesions and the inflamed mucosa of inflammatory bowel disease patients, marking disease activity.

Figure 1. Model illustrating how E-selectin engagement of PSGL-1 and CD44 activates signaling pathways that promote neutrophil slow rolling via LFA-1 without inducing arrest. (Yago T, et al., 2010)

E-selectin is also implicated in tumor metastasis. Circulating tumor cells (CTCs) exploit E-selectin–ligand interactions to adhere to activated endothelium, facilitating extravasation and metastatic niche formation. Many cancer cells express sLeˣ and sLeᵃ ligands, and some tumors upregulate ligand expression to enhance metastatic potential. Blocking E-selectin or its ligands reduces metastasis in models of breast, colorectal, and pancreatic cancer, underscoring its role in tumor dissemination. Moreover, tumor-associated vasculature often shows abnormal E-selectin expression, likely influenced by chronic inflammation in the tumor microenvironment.

In infectious diseases, E-selectin participates in host defense. In bacterial sepsis, endotoxin-induced endothelial activation leads to widespread E-selectin expression, promoting neutrophil recruitment to infection sites. However, excessive or prolonged activation contributes to tissue injury and organ failure, playing a role in sepsis pathophysiology. Certain pathogens may even exploit E-selectin-mediated adhesion to facilitate dissemination or immune evasion, highlighting the complexity of host–pathogen interactions.