{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nL‐selectin (SELL) is a key adhesion receptor expressed on many leukocyte subsets—including natural killer cells, T lymphocytes, and even immature progenitors—that mediates the initial tethering, rolling, and subsequent homing of cells to secondary lymphoid organs, inflamed tissues, and even the uterine surface during implantation. SELL expression on NK cells is dynamically regulated upon activation (e.g. shedding following CD16 cross‐linking [1]), while on trophoblasts its expression facilitates interactions with the uterine wall critical for establishing pregnancy (2). In T lymphocytes, SELL is transcriptionally controlled by FOXO1, thereby promoting a quiescent, immune‐surveillance phenotype in naive and memory cells (4, 7). Early lymphoid progenitors and innate lymphoid cell precursors that express high levels of SELL display a robust homing capacity to lymphoid tissues (8, 28), and SELL contributes to the efficient surface mobilization of chemokine receptors such as CXCR4 (9).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SELL governs the formation of transient, low‐affinity bonds that initiate leukocyte rolling. Under shear flow, these bonds become stabilized, resulting in a uniquely dynamic “tethering” process characterized by very short lifetimes that increase markedly with the application of force (27). In concert with its principal ligand, PSGL‐1, and in cooperation with other adhesion molecules including integrins (10, 11, 30), SELL’s adhesive interactions finely tune leukocyte deceleration and facilitate the transition to firm adhesion. Its extracellular domain, whose ligand‐binding properties are modulated by specific N‐glycosylation patterns and even by point mutations that alter on‐ and off‐rates (13, 22, 26), is positioned on cell microvilli through associations with cytoskeletal adaptors such as the ERM proteins and the Ca²⁺‐sensing molecule calmodulin; such interactions not only ensure proper spatial organization but also regulate ectodomain shedding (12, 21, 31). Moreover, accessory extracellular matrix components—including oversulfated glycosaminoglycan chains on proteoglycans like versican—can influence SELL binding avidity (3).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSELL expression and shedding are tightly regulated during inflammation and can be altered in pathological situations. For example, activated leukocytes and pathogenic infections such as Anaplasma phagocytophilum or HIV-1 trigger rapid SELL shedding, which can compromise their adhesive interactions (19, 33) and is also observed in conditions like diabetic microangiopathy where reduced SELL levels correlate with altered neutrophil activation (23). Pharmacologically, certain nonsteroidal anti-inflammatory drugs promote SELL shedding via a TACE-dependent mechanism linked to mitochondrial uncoupling (24), and genetic polymorphisms within the SELL locus have been associated with susceptibility to IgA nephropathy and severe acne (15, 25). In addition, circulating SELL has even been proposed as a potential biomarker to stratify the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients (20).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, SELL orchestrates a spectrum of adhesion‐ and signaling‐related events that are essential for proper leukocyte trafficking and immune surveillance, yet its modulation also underlies critical aspects of pathological inflammation, tumor cell dissemination (via auxiliary ligands such as carcinoembryonic antigen [5] and basement membrane alterations [14, 16]), and tissue-specific immune responses (e.g. in the kidney [29]). Moreover, SELL expression on endothelial progenitor cells further supports its role in vascular homing and neovascularization (18), while its regulated interplay with integrins and other adhesion receptors optimizes leukocyte rolling and adhesion (17, 30, 32). These multifaceted functions of SELL are not only fundamental to the normal immune response but also represent promising targets for therapeutic intervention in diverse human diseases.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\n(1:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", 2:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", 3:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", 4:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", 5:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", 6:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", 7:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", 8:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", 9:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\n(10:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", 11:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", 12:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", 13:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", 14:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", 15:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", 16:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", 17:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", 18:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\n(19:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", 20:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", 21:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", 22:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", 23:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", 24:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", 25:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", 26:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ", 27:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\n(28:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", 29:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", 30:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": ", 31:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": ", 32:"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": ", 33:."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rizwan Romee, Bree Foley, Todd Lenvik, et al. 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