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L-selectin

L-selectin, also known as CD62L, is a type-I transmembrane glycoprotein and cell adhesion molecule expressed on the surface of most circulating leukocytes, including neutrophils, lymphocytes, and monocytes, where it mediates the initial tethering and rolling of these cells on vascular endothelium during immune responses.^[1] Its structure consists of an N-terminal C-type lectin domain responsible for carbohydrate-specific ligand binding, followed by an epidermal growth factor-like domain, two complement regulatory protein repeats, a transmembrane region, and a short 17-amino-acid cytoplasmic tail that lacks enzymatic activity but facilitates intracellular signaling.^[2] L-selectin binds to sialylated and fucosylated glycoproteins such as GlyCAM-1, CD34, and MAdCAM-1 on high endothelial venules, enabling lymphocyte homing to secondary lymphoid organs and neutrophil recruitment to inflammatory sites.^[3] Beyond adhesion, L-selectin exhibits signaling capabilities upon ligand engagement, triggering tyrosine phosphorylation of intracellular proteins, increases in cytosolic calcium, and activation of pathways like MAP kinase, which prime leukocytes for firm adhesion via integrins and subsequent transmigration.^[2] This process is tightly regulated by ectodomain shedding mediated by the metalloprotease ADAM17, which reduces surface expression and generates soluble L-selectin to modulate inflammatory responses and establish leukocyte polarity during migration.^[1] Expressed at high levels (approximately 50,000–70,000 molecules per cell) and preferentially localized to microvilli, L-selectin is downregulated upon leukocyte activation, ensuring directed trafficking.^[1] L-selectin plays essential roles in both innate and adaptive immunity, facilitating immune surveillance through lymphocyte recirculation, contributing to pathogen clearance, and influencing conditions like atherosclerosis and autoimmunity when dysregulated.^[1] As one of three selectin family members (alongside E-selectin and P-selectin), it operates in a calcium-dependent manner and is critical for the multi-step paradigm of leukocyte extravasation, with its ligands often sulfated to enhance binding affinity under shear flow.^[3]

Structure and Biochemistry

Gene and Protein Overview

L-selectin is encoded by the SELL gene, located on the long arm of human chromosome 1 at cytogenetic band 1q24.2.^[4] This gene spans approximately 21 kb and comprises 9 exons, producing a mature mRNA transcript that translates into a 372-amino-acid protein precursor.^[5] The SELL locus is positioned in tandem with the genes for the related E-selectin (SELE) and P-selectin (SELP), reflecting their shared evolutionary origins within the selectin family.^[6] The L-selectin protein, also known as CD62 antigen-like family member L (CD62L), is a type I transmembrane glycoprotein with a predicted core molecular weight of 42 kDa, though post-translational modifications such as N-linked glycosylation increase its apparent size to 74–100 kDa depending on the leukocyte subtype.^[5] It features a short cytoplasmic tail, a single transmembrane domain, and an extracellular region oriented toward the cell surface, enabling its role in cell-cell interactions.^[7] This structure positions L-selectin as a key mediator of leukocyte dynamics in the vasculature. L-selectin was initially discovered in the early 1980s as the MEL-14 antigen on murine lymphocytes, recognized for its involvement in lymph node homing.^[7] The murine cDNA encoding this antigen was cloned in 1989 through expression screening using the MEL-14 monoclonal antibody, revealing its homology to a novel family of calcium-dependent adhesion molecules.^[8] The human SELL homolog was isolated shortly afterward in 1989, confirming its conservation and functional parallels across species.^[7] Within the selectin family, L-selectin shares significant sequence similarity—approximately 60–70% identity in extracellular domains—with E- and P-selectins, underscoring their evolutionary divergence from a common ancestral gene cluster.^[6]

Domains and Post-Translational Modifications

L-selectin is a type I transmembrane glycoprotein characterized by a modular extracellular domain, a single transmembrane helix, and a short cytoplasmic tail. The extracellular portion consists of an N-terminal calcium-dependent C-type lectin-like domain (CTLD), which mediates carbohydrate-based ligand recognition, an epidermal growth factor (EGF)-like domain that stabilizes the overall structure through interactions with the CTLD, and two short consensus repeats (SCRs), also known as complement control protein modules, which extend the molecule and position the CTLD for optimal binding.^[1] The transmembrane domain anchors L-selectin to the plasma membrane, preferentially localizing it to microvilli on leukocytes, while the cytoplasmic tail comprises 17 amino acids rich in serine and threonine residues that serve as sites for phosphorylation and mediate interactions with cytoskeletal elements such as ERM proteins and calmodulin.^[1] Post-translational modifications significantly influence L-selectin's adhesive function and stability. The protein undergoes extensive N-linked and O-linked glycosylation, with site-specific patterns varying by leukocyte type—resulting in apparent molecular weights of approximately 65 kDa on lymphocytes and 100 kDa on neutrophils—which contributes to its conformational integrity and ligand interaction potential.^[1] Sialylation, particularly the addition of sialic acid to form sialyl Lewis X (sLe^x) motifs on N-glycans, is essential for enhancing the affinity of L-selectin for endothelial ligands, as desialylation abolishes binding activity.^[9] Sulfation, including tyrosine sulfation in the CTLD and sulfation of GlcNAc residues within sLe^x glycans, further modulates binding specificity and avidity, with 6-sulfo sLe^x structures being particularly critical for high-affinity interactions.^[9] Phosphorylation of the cytoplasmic tail, notably at serine 364 (S364) and serine 367 (S367), regulates L-selectin's intracellular associations and membrane retention; for instance, PKC-mediated phosphorylation at S364 disrupts calmodulin binding, thereby promoting ectodomain release.^[1] Additionally, L-selectin is subject to regulated proteolytic shedding by the metalloprotease ADAM17 (also known as TACE), which cleaves the ectodomain at a site between lysine 321 and serine 322 (or equivalently Lys357/Ser358 in some numbering), generating a soluble form (sL-selectin) that circulates in plasma and may modulate inflammatory responses.^[10] This shedding process is calcium-dependent and triggered by cellular activation signals, ensuring rapid downregulation of surface expression during leukocyte emigration.^[11]

Expression Patterns

Cellular Distribution

L-selectin, also known as CD62L, is predominantly expressed on the surface of various leukocytes, playing a key role in their trafficking and immune surveillance. It is highly expressed on naive T and B lymphocytes, where it facilitates their recirculation through lymphoid tissues. Most monocytes and neutrophils also display significant levels of L-selectin, enabling these cells to interact with vascular endothelium during inflammation. Additionally, subsets of natural killer (NK) cells express L-selectin, particularly those with a more mature phenotype involved in immune regulation. Transient expression of L-selectin has been observed on hematopoietic stem cells (HSCs) under specific conditions, such as during their mobilization or homing to bone marrow niches, where it aids in their adhesive interactions. These patterns underscore L-selectin's role in dynamic cellular localization within the hematopoietic system. In contrast, mature erythrocytes and platelets exhibit absence or very low levels of L-selectin, consistent with their limited involvement in immune adhesion processes. Non-hematopoietic tissues generally do not express L-selectin, restricting its distribution primarily to cells of the immune lineage. Regarding quantitative aspects, L-selectin is expressed at high levels on central memory T cells, supporting their long-term surveillance functions, while expression is more variable on effector T cell subsets, often downregulated upon activation.

Regulation of Expression

The expression of L-selectin, encoded by the SELL gene, is tightly regulated at the transcriptional level by various cytokines and transcription factors to modulate leukocyte homing and trafficking. For instance, low doses of interleukin-2 (IL-2) promote the re-expression of L-selectin on activated T cells, facilitating the formation of central memory T cells that retain high surface levels for lymph node recirculation.^[12] Similarly, interleukin-6 (IL-6) enhances L-selectin function through gp130 signaling pathways, increasing adhesive interactions in response to inflammatory cues.^[13] Transcription factors such as NF-κB play a key role in upregulating SELL expression during inflammatory conditions, binding to promoter regions to drive gene activation.^[14] Other factors, including KLF2 and FOXO1, maintain constitutive expression in naive leukocytes, while PI3Kδ signaling downstream of cytokines like IL-2 can inhibit KLF2, leading to reduced transcription upon T cell activation.^[15] Post-translational downregulation primarily occurs through ectodomain shedding, a rapid mechanism that cleaves the extracellular domain to reduce surface L-selectin and terminate adhesion. Phorbol esters, such as phorbol 12-myristate 13-acetate (PMA), activate protein kinase C (PKC) pathways, triggering shedding within minutes on neutrophils and lymphocytes.^[16] Chemokine signaling, including from CXCL8 (IL-8) and CXCL12 (SDF-1), similarly induces shedding by mobilizing leukocytes and promoting protease activity, thereby shifting cells from rolling to firm adhesion.^[17] This process is modulated by phosphorylation at serine 364, which dissociates calmodulin from the cytoplasmic tail, exposing the cleavage site.^[18] Internalization and recycling dynamics further control L-selectin surface levels in response to activation signals. Upon stimulation with PMA or chemokines, L-selectin is internalized via clathrin-mediated endocytosis involving the μ1A subunit of the AP-1 adaptor complex, directing it to endosomes for potential degradation or recycling. In naive T cells, internalized L-selectin can be recycled back to the plasma membrane, helping sustain high expression for homing; however, sustained activation favors degradation, preventing reaccumulation.^[18] These dynamics ensure transient surface modulation during leukocyte activation without permanent loss of the protein pool. Developmentally, L-selectin expression is high on naive lymphocytes and central memory T cells (approximately 50,000–70,000 molecules per cell), enabling efficient entry into secondary lymphoid organs.^[19] Upon antigen-driven activation or maturation into effector cells, surface levels rapidly decline through shedding and transcriptional repression, adapting cells for peripheral tissue migration rather than lymphoid recirculation. This shift is reversible in some subsets, as re-expression occurs post-activation in memory cells to restore homing capacity.

Ligands and Binding

Primary Ligands

L-selectin's primary ligands are predominantly sialomucins expressed on high endothelial venules (HEVs) of secondary lymphoid organs and mucosal tissues, as well as on leukocytes, featuring sulfated sialyl Lewis X (sLeX) carbohydrate motifs that enable recognition by the selectin's C-type lectin domain. These ligands facilitate initial leukocyte-endothelial interactions through specific glycosylation patterns, including tyrosine sulfation and fucosylation.^[20] GlyCAM-1 (glycosylation-dependent cell adhesion molecule-1) is a secreted mucin-like glycoprotein prominently expressed on the luminal surface of HEVs in peripheral lymph nodes, serving as a key ligand for naïve lymphocyte homing. It bears O-linked sulfated sLeX structures essential for L-selectin binding.^[21] CD34, a transmembrane sialomucin, is widely expressed on HEVs across lymphoid tissues and acts as a major L-selectin ligand, particularly in human tonsils, where its glycosylated forms support lymphocyte recirculation. Its activity depends on peripheral O-linked sLeX moieties. MAdCAM-1 (mucosal vascular addressin cell adhesion molecule-1), an immunoglobulin superfamily member with a mucin-like domain, is expressed on HEVs in mucosal lymphoid tissues such as Peyer's patches and contributes to L-selectin-dependent lymphocyte trafficking. It presents O-linked sLeX carbohydrates on its mucin domain for ligand function.^[22] PSGL-1 (P-selectin glycoprotein ligand-1, also known as CD162) is a mucin-type glycoprotein expressed on most leukocytes, functioning as an L-selectin ligand in homotypic leukocyte-leukocyte interactions during inflammation. Its N-terminal region, modified with sulfated tyrosines and core-2 O-glycans bearing sLeX, is critical for binding.^[23] Sulfated sLeX motifs represent the minimal carbohydrate recognition units for L-selectin across multiple glycoprotein scaffolds, with 6-sulfo-sLeX on core-2 branches enhancing affinity through interactions with the lectin's binding site. These structures are prevalent on HEV ligands and require specific sulfotransferases for biosynthesis. Tissue-specific ligands include podocalyxin, a sialomucin expressed on HEVs and bone marrow endothelium, where it supports hematopoietic progenitor adhesion via L-selectin engagement with its sulfated sLeX-bearing O-glycans. CLA (cutaneous lymphocyte antigen), a glycosylated epitope primarily on PSGL-1 variants but also on vascular endothelia, functions as a carbohydrate component of L-selectin ligands, defined by HECA-452 reactivity and sulfated sLeX modifications that direct skin-homing interactions.

Binding Mechanisms

L-selectin mediates calcium-dependent binding through its N-terminal C-type lectin domain, which recognizes sulfated and sialylated carbohydrate structures on endothelial ligands. This interaction requires the presence of calcium ions, as chelation with agents like EDTA abolishes binding affinity. The lectin domain coordinates Ca²⁺ ions via conserved amino acid residues, enabling specific recognition of glycan hydroxyl groups, particularly those modified by sulfate and sialic acid.^[1]^[24]^[25] In the tethering and rolling model, L-selectin facilitates leukocyte capture from free flow by forming transient bonds with rapid association and dissociation kinetics, characterized by an off-rate of approximately 1–10 s⁻¹ under physiological shear stress. This fast dissociation rate, which is 7–10-fold higher than that of E- or P-selectins, allows leukocytes to roll along the endothelium without firm arrest, with bond lifetime decreasing exponentially with applied force according to the Bell model. Shear flow paradoxically enhances tether formation and rolling stability by promoting catch-slip bond behavior, where initial force strengthens bonds before rapid dissociation at higher stresses.^[26]^[27]^[28] Multivalency plays a critical role in enhancing the avidity of L-selectin interactions with densely glycosylated surfaces, where multiple lectin domains bind clustered sulfated glycans simultaneously, overcoming the low affinity of individual bonds (K_d ~ μM range). This cooperative binding increases overall adhesion strength, enabling effective leukocyte rolling even at low ligand densities on endothelial cells.^[29]^[30] L-selectin binding exhibits sensitivity to environmental factors, including pH and temperature, with optimal activity at physiological conditions (pH 7.4 and 37°C); deviations, such as acidification during inflammation, can reduce affinity by altering glycan conformation or Ca²⁺ coordination. Fucosylation is essential for ligand specificity, as α1,3-linked fucose residues in structures like sialyl Lewis X (sLe^x) form the core recognition motif, with defucosylated glycans showing negligible binding. For instance, L-selectin binds avidly to fucosylated, sulfated sLe^x on glycoproteins such as GlyCAM-1.^[31]^[25]^[32]

Physiological Roles

Leukocyte Adhesion and Rolling

L-selectin plays a pivotal role in the initial capture and rolling of leukocytes on the activated endothelium during the early stages of inflammation and immune surveillance. Expressed on the microvilli of most leukocytes, L-selectin facilitates tethering from the free-flowing bloodstream to the vessel wall under hydrodynamic shear stress, typically ranging from 0.3 to 1.0 dyn/cm² in postcapillary venules. This interaction occurs through the C-type lectin domain of L-selectin binding to sialylated, sulfated glycoprotein ligands on endothelial cells, such as CD34 and GlyCAM-1, enabling rapid, reversible adhesion that slows leukocytes from bulk flow velocities of approximately 1000 μm/s to rolling speeds of 10–50 μm/s.^[1]^[33] The rolling mediated by L-selectin exhibits catch-slip bond kinetics, where increasing shear force initially strengthens bonds (catch phase) before dissociation at higher stresses (slip phase), optimizing adhesion under physiological flow conditions. This mechanism ensures efficient leukocyte margination, positioning cells near the endothelium for subsequent activation steps. In vivo studies demonstrate that L-selectin supports leukocyte rolling independent of other selectins in untreated venules, with microvillar distribution enhancing tethering efficiency by up to 4-fold in larger vessels.^[1]^[34] L-selectin synergizes with P-selectin and E-selectin in the multi-step adhesion cascade, where initial P-selectin-mediated capture transitions to cooperative rolling involving all three selectins, amplifying leukocyte recruitment efficiency. For instance, L-selectin can mediate secondary tethering to adherent leukocytes via interactions with PSGL-1, bridging to downstream endothelial sites. This synergy is evident in inflammatory models, where combined selectin blockade abolishes rolling more effectively than single targeting.^[1]^[35] By facilitating rapid neutrophil margination and rolling, L-selectin contributes critically to the innate immune response, enabling swift recruitment to sites of infection or injury. In L-selectin-deficient mice, neutrophil emigration is reduced by up to 50% in thioglycollate-induced peritonitis, underscoring its role in positioning innate effectors for transmigration. This process supports host defense without relying on adaptive immunity-specific mechanisms.^[1]^[36]

Lymphocyte Homing and Trafficking

L-selectin plays a pivotal role in the homing of naive lymphocytes to secondary lymphoid organs, such as lymph nodes and Peyer's patches, by mediating their initial tethering and rolling on high endothelial venules (HEVs). These specialized post-capillary venules express sulfated glycoprotein ligands, including glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1) and CD34, which are recognized by L-selectin on the surface of circulating naive T and B cells. This interaction enables the selective recruitment of lymphocytes from the bloodstream into lymphoid tissues, facilitating antigen surveillance without broad inflammatory involvement.^[37]^[38]^[29] The recirculation pathway of lymphocytes, orchestrated in part by L-selectin, ensures continuous immune surveillance by allowing naive cells to exit the blood, traverse lymphoid organs, enter the lymphatic system, and return to circulation via the thoracic duct. In this process, L-selectin-dependent adhesion to HEV ligands supports the entry of lymphocytes into peripheral lymph nodes, where they scan for antigens presented by dendritic cells. This cyclic trafficking is essential for maintaining a diverse pool of naive lymphocytes poised for rapid activation, with L-selectin expression on central memory T cells further sustaining surveillance in non-inflamed tissues.^[39]^[1]^[40] Upon encounter with cognate antigen in secondary lymphoid organs, L-selectin is rapidly downregulated on activated lymphocytes through proteolytic shedding, primarily mediated by ADAM17 metalloprotease, which shifts their trafficking from lymphoid recirculation to peripheral inflammatory sites. This downregulation prevents re-entry into lymph nodes and promotes the differentiation of effector T and B cells, which upregulate alternative adhesion molecules like LFA-1 and VLA-4 for tissue-specific migration. The process ensures that activated lymphocytes efficiently target infection or inflammation sites while avoiding unnecessary lymphoid retention.^[41]^[42]^[43] In gut-associated lymphoid tissue (GALT), L-selectin contributes to mucosal lymphocyte homing by binding to sulfated carbohydrate determinants on mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on HEVs in Peyer's patches. This interaction complements alpha4beta7 integrin binding to MAdCAM-1, enabling the recruitment of naive and memory B cells to initiate mucosal immune responses against enteric pathogens. The sulfation of MAdCAM-1, facilitated by enzymes like GlcNAc6ST-1, enhances its avidity for L-selectin, supporting localized surveillance in the intestinal mucosa.^[44]^[45]^[46]

Neutrophil and Monocyte Recruitment

L-selectin plays a critical role in the recruitment of neutrophils and monocytes to sites of inflammation through homotypic interactions mediated by P-selectin glycoprotein ligand-1 (PSGL-1). On neutrophils, L-selectin expressed on one cell binds to PSGL-1 on adjacent neutrophils, facilitating secondary capture and clustering that promotes swarming behavior and enhances collective migration to inflammatory foci.^[1] Similarly, in monocytes, L-selectin-PSGL-1 homotypic binding supports clustering and adhesion under shear flow, contributing to efficient monocyte accumulation during the innate immune response.^[1]^[33] During acute inflammation, L-selectin serves as a secondary tethering molecule in post-capillary venules, where it enables the capture of free-flowing neutrophils and monocytes by already adherent leukocytes expressing PSGL-1 ligands. This mechanism stabilizes rolling and promotes subsequent firm adhesion, particularly in larger venules where primary endothelial selectin interactions may be insufficient.^[1]^[47] In this context, L-selectin contributes to the initial rolling step by supporting leukocyte-leukocyte contacts that bridge to the endothelium. In bacterial infections, such as those caused by Staphylococcus aureus, L-selectin-mediated recruitment is enhanced by the upregulation of endothelial ligands like peripheral node addressin (PNAd), which increases neutrophil trafficking to infected tissues.^[1]^[48] This ligand induction, triggered by bacterial components via Toll-like receptor signaling, amplifies L-selectin-dependent adhesion and emigration, bolstering innate defenses against pathogens. Defects in L-selectin, as observed in knockout mice, lead to impaired neutrophil and monocyte recruitment into inflammatory sites, reducing emigration by 56-78% and resulting in diminished pus formation during acute responses.^[49] These deficiencies also cause delayed wound healing, with slower re-epithelialization and reduced leukocyte infiltration at injury sites.^[50]

Role in Embryogenesis

L-selectin is expressed on early embryonic hematopoietic progenitor cells, including CD34-positive cells derived from fetal liver, where it facilitates adhesive interactions essential for their migration and homing. These progenitors, which emerge during the initial waves of hematopoiesis in the yolk sac and subsequently colonize the fetal liver, utilize L-selectin to mediate rolling on endothelial surfaces under shear flow conditions. This expression pattern supports the seeding of hematopoietic stem and progenitor cells (HSPCs) into the developing bone marrow niche, enabling the transition of hematopoiesis from fetal liver to bone marrow in late gestation.^[51]^[52] In the context of embryo implantation, L-selectin plays a critical role in the initial adhesion of trophoblast cells to the endometrial epithelium. Expressed on the surface of human blastocysts, L-selectin binds to carbohydrate-based ligands, such as those recognized by MECA-79 and HECA-452 antibodies, which are upregulated on the luminal endometrial epithelium during the receptive window of the menstrual cycle. This interaction promotes a transient rolling-like adhesion, allowing the blastocyst to navigate the MUC1 glycocalyx and establish closer contact, potentially triggering downstream signals like trophinin expression for firmer attachment at pinopodes. Such mechanisms highlight L-selectin's contribution to successful maternal-fetal interface formation in early development.^[53]^[54] Studies using L-selectin knockout mice (Sell^{-/-}) demonstrate that while the protein is important for certain adhesive processes, its absence does not lead to embryonic lethality or severe disruptions in overall development. These mice are viable and fertile at birth. This contrasts with knockouts of other selectins like E- and P-selectin, which exhibit more pronounced hematopoietic abnormalities.^[55]^[56]

Signaling and Interactions

Intracellular Signaling Pathways

Upon ligand engagement, L-selectin's short cytoplasmic tail undergoes serine phosphorylation, primarily at residue Ser364, mediated by protein kinase C (PKC) isozymes such as PKCα, PKCι, and PKCθ. This phosphorylation event disrupts interactions with inhibitory proteins like calmodulin, facilitating downstream signal transduction and promoting ectodomain shedding to regulate receptor availability.^[57] Concurrently, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways are activated, with rapid phosphorylation of p38 MAPK occurring within 1 minute and ERK1/2 peaking at 10 minutes following L-selectin cross-linking in neutrophils, contributing to enhanced tyrosine phosphorylation and cellular responses. L-selectin signaling also recruits Src family kinases, including Fgr, Hck, and Lyn, which phosphorylate the cytoplasmic tail and associated adapters upon clustering with ligands like PSGL-1.^[23] These kinases initiate cytoskeletal rearrangements by phosphorylating ezrin at Tyr353, recruiting phosphatidylinositol 3-kinase (PI3K) and linking L-selectin to the actin cytoskeleton via ERM (ezrin-radixin-moesin) proteins, thereby supporting microvilli formation and pseudopod protrusion during leukocyte adhesion and transmigration. Further downstream, L-selectin engagement activates the transcription factor NF-κB in leukocytes, particularly through cross-linking with sulphatides on neutrophils, leading to nuclear translocation of the p65 subunit and induction of pro-inflammatory cytokine gene expression, such as TNF-α and IL-8.^[58] This pathway amplifies inflammatory responses by promoting cytokine production essential for leukocyte activation. To terminate signaling, feedback loops involve proteolytic shedding of the L-selectin ectodomain by ADAM17 (also known as TACE), triggered by cytoplasmic tail phosphorylation and PKC activity; this process, with ADAM17 cleaving at a specific enzyme-substrate site near the transmembrane domain, rapidly downregulates surface expression and limits prolonged adhesion and signaling.

Crosstalk with Other Adhesion Molecules

L-selectin engages in inside-out signaling that activates the integrin LFA-1 (lymphocyte function-associated antigen 1), enabling its transition to a high-affinity state for binding ICAM-1 (intercellular adhesion molecule 1) on endothelial cells, thereby facilitating firm leukocyte adhesion after initial L-selectin-mediated rolling.^[59] This process involves L-selectin ligation triggering intracellular pathways, such as Src family kinases and Syk, which propagate signals leading to LFA-1 conformational changes and cytoskeletal rearrangements essential for stable arrest.^[60] Heterotypic interactions between L-selectin and P-selectin contribute to the formation of platelet-leukocyte aggregates, where P-selectin on activated platelets binds PSGL-1 (P-selectin glycoprotein ligand-1) on leukocytes, and L-selectin on one leukocyte can bind PSGL-1 on another, stabilizing these aggregates under shear flow. These interactions enhance leukocyte recruitment to sites of vascular injury or inflammation by promoting secondary tethering and amplifying adhesive forces within the aggregates.^[61] In selectin knockout models, compensatory mechanisms involving E-selectin upregulation occur during inflammation to maintain leukocyte rolling and recruitment; for instance, L-selectin-deficient mice exhibit partially preserved neutrophil trafficking due to increased E-selectin expression on endothelium, as observed in models of peritonitis and thioglycollate-induced inflammation.^[62] Double knockouts of L- and E-selectins reveal more severe impairments in leukocyte adhesion compared to single knockouts, highlighting the redundant yet interconnected roles of these molecules.^[63] L-selectin plays a key role in chemokine-triggered leukocyte arrest by cooperating with chemokine signaling to induce conformational changes in β2-integrins like LFA-1, shifting them from low- to high-affinity states for rapid firm adhesion.^[64] During rolling, L-selectin engagement shares signaling elements, such as Rap1a and PI3Kγ, with chemokines like CXCL8, ensuring synchronized integrin activation and preventing premature arrest while optimizing capture efficiency under flow.^[65]

Clinical and Pathological Significance

Involvement in Inflammatory Diseases

L-selectin, which normally facilitates leukocyte rolling and recruitment to sites of inflammation, contributes to pathological processes in various inflammatory diseases through dysregulated expression and shedding, leading to elevated levels of soluble L-selectin (sL-selectin) in circulation. In rheumatoid arthritis (RA), sL-selectin serves as a biomarker of disease activity, with studies showing significantly lower circulating levels compared to healthy controls, correlating inversely with synovial inflammation and joint damage.^[66] Recent studies have further elucidated its mechanistic role, demonstrating that L-selectin expression on fibroblast-like synoviocytes (RA-FLS) promotes cell migration, invasion, and pro-inflammatory cytokine production via activation of the NF-κB signaling pathway, exacerbating synovitis and cartilage destruction in RA models.^[67] Similarly, in sepsis, low sL-selectin levels at admission (<470 ng/mL) predict poor outcomes and high mortality due to impaired leukocyte function and excessive systemic inflammation.^[68] In atherosclerosis, L-selectin drives monocyte recruitment to the vascular endothelium, initiating lesion formation by enabling leukocyte tethering and protrusion through the endothelial barrier under shear stress conditions. This process amplifies plaque development, as evidenced by studies showing reduced monocyte infiltration and lesion size in models treated with L-selectin inhibitors. L-selectin also contributes to thrombosis by mediating leukocyte-platelet interactions at sites of vascular injury; circulating sL-selectin levels upon hospital admission serve as a predictor of thrombotic events, reflecting heightened adhesive potential and pro-coagulant activity in inflammatory states. In inflammatory bowel disease (IBD), including ulcerative colitis, L-selectin expression is upregulated on aberrant lymphocyte subsets, promoting excessive homing to the gut mucosa and perpetuating chronic inflammation. This leads to disrupted epithelial integrity and immune cell accumulation in the lamina propria, with genetic and functional studies confirming L-selectin's role in faulty trafficking that sustains disease flares. Animal models of arthritis provide evidence for therapeutic potential, where L-selectin blockade—via knockout or siRNA knockdown—significantly reduces paw edema, arthritis scores, and synovial infiltration in collagen-induced models, highlighting its targetability in curbing inflammatory edema post-2020 experimental trials. Recent 2025 research further supports L-selectin's role in RA synoviocyte invasion, suggesting avenues for targeted NF-κB inhibitors.^[67]

Role in Cancer Progression

L-selectin, expressed on the surface of tumor-infiltrating leukocytes such as natural killer cells and monocytes, contributes to cancer progression by facilitating their recruitment into the tumor microenvironment, where these cells can induce vascular endothelial growth factor (VEGF) secretion to promote angiogenesis. This process supports tumor vascularization and growth, as recruited leukocytes interact with endothelial cells and secrete pro-angiogenic factors like VEGF in a STAT3/5-dependent manner, enhancing the formation of new blood vessels essential for nutrient supply to the tumor.^[69] Studies in various solid tumors demonstrate that this L-selectin-mediated infiltration amplifies the angiogenic switch, correlating with increased tumor burden and invasive potential.^[70] In addition to its pro-angiogenic effects, L-selectin paradoxically facilitates metastasis through enhanced adhesion between leukocytes and tumor cells, enabling circulating tumor cells to form protective clusters that evade immune detection and promote extravasation at distant sites. A comprehensive review highlights the dual role of L-selectin alongside VCAM-1 in modulating leukocyte-tumor interactions, where L-selectin binding to sialylated ligands on tumor cells strengthens heterotypic adhesions, thereby aiding metastatic dissemination while also supporting anti-tumoral immune responses under certain conditions.^[71] Experimental models, including L-selectin-deficient mice, show reduced metastatic foci formation, underscoring its contribution to tumor cell survival and colonization in organs like the lungs and liver.^[72] The soluble form of L-selectin (sL-selectin), generated by proteolytic shedding from leukocyte surfaces, serves as a potential prognostic biomarker in breast and colon cancers, with elevated plasma levels indicating advanced disease and poorer outcomes. In colorectal cancer patients, sL-selectin concentrations are elevated compared to healthy controls, particularly in those with lymph node metastasis. Similarly, in breast cancer, altered sL-selectin levels correlate with inflammatory microenvironments and tumor aggressiveness, though high L-selectin expression overall is linked to favorable survival, highlighting the need for context-specific interpretation in clinical settings.^[73] Despite these pro-tumorigenic roles, L-selectin exhibits a paradoxical anti-tumor function by enabling immune surveillance through efficient lymphocyte homing and activation against nascent tumors. L-selectin-dependent trafficking of cytotoxic T cells and natural killer cells to tumor-draining lymph nodes and the tumor site enhances anti-tumor immunity, suppressing tumor formation in preclinical models; for instance, L-selectin blockade impairs natural killer cell-mediated rejection of lymph node metastases.^[74] High L-selectin expression correlates with improved prognosis in breast and colorectal cancers by fostering an immunostimulatory microenvironment that counters metastasis.^[75] This dual nature positions L-selectin as a key modulator in the tumor microenvironment, where its effects depend on the balance between immune activation and pathological adhesion.^[71]

Implications in Reproductive Disorders

L-selectin, expressed on the surface of trophoblast cells, plays a crucial role in the initial adhesion of the blastocyst to the endometrial epithelium during human implantation. This interaction occurs through binding to carbohydrate ligands, such as sialyl Lewis x, present on the endometrial surface, facilitating the rolling and attachment necessary for successful embryo implantation. Defects in this L-selectin-mediated adhesion mechanism, particularly reduced expression or absence of L-selectin ligands like MECA-79 in the endometrium during the implantation window, have been associated with recurrent implantation failure (RIF), which can contribute to recurrent miscarriage by preventing proper blastocyst attachment.^[76]^[77]^[78] In the context of preeclampsia, a hypertensive disorder of pregnancy, L-selectin contributes to pathological leukocyte-endothelial interactions at the maternal-fetal interface. In preeclampsia, altered L-selectin dynamics, including increases in soluble serum levels, promote excessive leukocyte recruitment and activation, leading to vascular inflammation and endothelial dysfunction characteristic of the condition. Reviews from 2017 onward highlight how dysregulated selectin family members, including L-selectin, exacerbate uteroplacental ischemia and systemic inflammatory responses in preeclampsia, potentially through altered shedding of soluble forms that modulate adhesion. Additionally, lower maternal serum levels of soluble L-selectin (sL-selectin) have been observed in pregnancies progressing to preeclampsia, suggesting impaired regulatory mechanisms in leukocyte trafficking.^[79]^[80]^[81] L-selectin dysregulation is also implicated in infertility associated with endometriosis, where altered expression patterns in the eutopic endometrium impair endometrial receptivity. Women with endometriosis exhibit reduced expression of L-selectin ligands in the endometrial epithelium during the mid-secretory phase, correlating with decreased blastocyst attachment efficiency and higher rates of infertility. Studies have reported lower levels of sL-selectin in serum and peritoneal fluid of endometriosis patients compared to fertile controls, potentially reflecting suppressed leukocyte adhesion and chronic inflammation that hinders implantation. This molecular profile contributes to the 30-50% infertility rate observed in affected women, emphasizing L-selectin's role in endometriosis-related reproductive failure.^[82]^[83]^[84] Mouse models provide insights into L-selectin's reproductive functions, though species differences limit direct translation to humans. L-selectin knockout mice exhibit normal fertility and implantation success, indicating that alternative adhesion pathways compensate for L-selectin deficiency in rodents. However, these models demonstrate impaired leukocyte recruitment to reproductive tissues under inflammatory conditions, underscoring L-selectin's conserved role in immune modulation during gestation despite its non-essentiality for basic implantation in mice.^[85]^[86]

Associations with Infectious Diseases

L-selectin plays a critical role in the immune response to human immunodeficiency virus (HIV) infection by facilitating viral adhesion and entry into CD4+ T cells. The HIV-1 envelope glycoproteins bind directly to L-selectin on the surface of these cells, promoting tethering and enhancing viral infectivity, which contributes to the preferential depletion of CD4+ T lymphocytes during acute and chronic phases of infection.^[87] Additionally, HIV-1 proteins such as Nef and Vpu induce rapid downregulation and shedding of L-selectin from infected CD4+ T cells, impairing their homing to lymphoid tissues and exacerbating immune dysfunction.^[88] This progressive loss of L-selectin expression correlates with viral load and T-cell depletion, enabling immune evasion and disease progression.^[89] In tuberculosis (TB), L-selectin mediates the trafficking of naïve lymphocytes to lymph nodes and infection sites, supporting effective granuloma formation to contain Mycobacterium tuberculosis. However, in HIV-TB coinfection, HIV-induced downregulation of L-selectin on CD4+ T cells disrupts this process, leading to impaired immune cell recruitment and defective granuloma integrity.^[90] A 2024 review highlights that this dysregulation in coinfected patients results in poor granuloma formation, increased bacterial dissemination, and heightened risk of extrapulmonary TB, as L-selectin-mediated homing is essential for mounting a coordinated T-cell response.^[91] Consequently, coinfection exacerbates immunopathology, with reduced L-selectin function linking to chronic inflammation and worse clinical outcomes.^[92] During sepsis, excessive shedding of L-selectin from leukocytes, driven by ADAM17 protease activation, generates elevated soluble L-selectin (sL-selectin) levels in plasma, which correlates with disease severity and organ dysfunction.^[93] This hyper-shedding impairs neutrophil recruitment to infection sites, potentially worsening bacterial clearance and contributing to multiple organ failure, as failure to balance shedding leads to unchecked systemic inflammation.^[94] Furthermore, certain bacteria exploit mimicry of L-selectin ligands, such as sialyl Lewis X (sLeX)-like structures, to interact with host endothelium and leukocytes, promoting pathogen adhesion and modulating immune responses during septic episodes.^[1] Emerging data from 2020–2025 indicate a potential role for L-selectin in the cytokine storm of severe COVID-19, where elevated sL-selectin levels at admission positively correlate with pro-inflammatory markers like IL-6, reflecting endothelial activation and hyperinflammation.^[95] In hospitalized patients, higher sL-selectin concentrations are associated with increased risk of thrombosis and complications linked to the cytokine storm, underscoring its involvement in vascular dysfunction and multi-organ injury during acute SARS-CoV-2 infection.^[95]

Therapeutic Targeting and Inhibitors

Monoclonal antibodies targeting L-selectin have been explored for modulating acute inflammatory responses by blocking leukocyte recruitment. Aselizumab, a humanized anti-L-selectin antibody, was investigated in a phase II clinical trial for severely traumatized patients, where doses of 0.5, 1, or 2 mg/kg administered within 6 hours of injury showed no significant improvements in multiple organ failure, ventilation duration, ICU stay, or hospitalization compared to placebo, despite achieving 89% saturation of neutrophil L-selectin.^[96] The trial also noted dose-dependent increases in infections and leukopenia, though not statistically significant versus placebo.^[96] In a separate phase II trial for psoriasis during the 2000s, aselizumab demonstrated limited efficacy, contributing to its discontinuation for this indication.^[97]^[98] Small molecule inhibitors directed at the lectin domain of L-selectin aim to disrupt its carbohydrate-binding activity and prevent leukocyte tethering. These compounds, often designed as nonoligosaccharide antagonists, have shown promise in preclinical models by inhibiting selectin-mediated cell adhesion in inflammatory contexts.^[99] For instance, dimeric and trimeric synthetic inhibitors mimicking selectin ligand components effectively block sialyl Lewis X-dependent binding, reducing leukocyte rolling on endothelium.^[99] Such inhibitors have been proposed for treating inflammatory skin diseases through interference with L-selectin functions.^[100] Multivalent glycomimetics represent an advanced class of L-selectin inhibitors, leveraging clustered carbohydrate mimics to enhance binding avidity and therapeutic potency in thrombosis and cancer. A 2021 review highlights their role in modulating selectin-mediated pathologies, including neutrophil recruitment in thrombosis and tumor metastasis.^[101] For example, sialic acid-coated silver nanoparticles targeting L-selectin on neutrophils improved bacterial-mediated antitumor efficacy by depleting immunosuppressive cells, though concerns about bacterial pathogenicity persist.^[101]^[102] Similarly, sialic acid-modified doxorubicin liposomes reduced neutrophil accumulation, enhancing tumor targeting in cancer models.^[101]^[103] Soluble L-selectin (sL-selectin) levels serve as a biomarker for monitoring therapeutic responses in rheumatoid arthritis (RA) and cancer. In RA, serum sL-selectin concentrations are significantly lower than in healthy controls and correlate with disease activity, providing a marker for assessing treatment efficacy.^[66]^[104] Recent 2025 analyses confirm its utility in RA models, where L-selectin modulation influences inflammatory responses and joint pathology.^[105] In cancer, elevated soluble selectin levels, including sL-selectin, are prognostic indicators, with reductions post-therapy linked to improved outcomes in tumor control.^[106]

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