Affinage

ITGB2

Integrin beta-2 · UniProt P05107

Length
769 aa
Mass
84.8 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITGB2 (CD18) is the obligate common beta subunit of the leukocyte beta2 integrin heterodimers (LFA-1/CD11a, Mac-1/CD11b, CR4/CD11c, and CD11d), and it is the molecular core that licenses integrin surface assembly and adhesive function: reconstitution of functional integrin and adhesion in patient cells requires only restoration of CD18, establishing it as the genetic and functional defect in leukocyte adhesion deficiency type I (PMID:1972597). As a heterodimer it engages ICAM-1 and additional ligands including endothelial counter-receptors, fibrinogen, fucosylated proteoglycans, and oligodeoxynucleotides, with contributions distributed across both the CD11 alpha and CD18 beta chains (PMID:1980124, PMID:2809204, PMID:9095175, PMID:12391246). Its ligand-binding affinity is switched on by inside-out activation that produces a divalent-cation-dependent, signaling-sensitive conformational change in CD18 reported by activation neoepitopes and coupled to high-affinity ICAM-1 binding (PMID:11714770, PMID:24314082); this activation is driven by stimulus-induced serine-predominant phosphorylation of CD18 and by upstream tyrosine-kinase and redox signaling (Lck, Src-family kinases, S-thiolation) (PMID:2574726, PMID:12115650, PMID:10556796). CD18 forms functional surface units with co-receptors uPAR and CD63 and is modulated by folate receptor beta and by its own sialylation state, which tunes adhesion and downstream Syk/p38 signaling (PMID:8874219, PMID:8871662, PMID:27534550, PMID:36719745), while shear-dependent cathepsin B cleavage of the CD18 ectodomain governs surface retention and extravasation velocity (PMID:14595007, PMID:28904019). In vivo, beta2 integrins are required for neutrophil firm adhesion and the spatially distinct steps of transendothelial and transbasement-membrane migration, T-regulatory cell development and suppressive function, macrophage fusion into giant cells, and LC3-associated phagocytosis and internalization of bacteria, and their loss is protective in myocardial and choroidal ischemia-reperfusion injury, autoimmune diabetes, and lung injury (PMID:8101543, PMID:9653089, PMID:16339524, PMID:27315778, PMID:29923444, PMID:32041787, PMID:30967528, PMID:9843832, PMID:12766082, PMID:19223596). CD18 also serves as the receptor exploited by multiple bacterial toxins, including H. pylori VacA, A. actinomycetemcomitans leukotoxin, and staphylococcal leukocidin LukGH, with species specificity mapping to defined extracellular CD18/CD11b domains (PMID:18191791, PMID:17635865, PMID:31852826). Loss-of-function mutations in ITGB2 cause leukocyte adhesion deficiency type I across humans, dogs, and zebrafish (PMID:1968911, PMID:10512685, PMID:34557186).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1989 High

    Established that CD18, not the CD11 alpha subunits, is the regulated signaling target within the integrin complex, framing inside-out control as acting on the shared beta chain.

    Evidence 32P metabolic labeling, immunoprecipitation, and phosphoamino acid analysis of PMA/FMLP-stimulated human leukocytes

    PMID:2574726

    Open questions at the time
    • Did not identify the responsible kinase or the specific phosphoacceptor residues
    • Did not link phosphorylation to a conformational or affinity change
  2. 1989 High

    Resolved that LFA-1 and Mac-1 contribute roughly equally to neutrophil-endothelial adhesion but through distinct ligands, establishing functional division of labor among CD18 heterodimers.

    Evidence Individual-chain mAb blocking and anti-ICAM-1 competition in PMN-endothelial adhesion assays

    PMID:2809204

    Open questions at the time
    • Did not identify the non-ICAM-1 Mac-1 endothelial ligand
  3. 1990 High

    Identified ICAM-1 as a counter-receptor for the CD11b/CD18 heterodimer, defining a molecular adhesion pair.

    Evidence Purified Mac-1 substrate binding and COS cell co-transfection of alpha and CD18 chains with reciprocal adhesion assays and mAb blocking

    PMID:1980124

    Open questions at the time
    • Did not map the ICAM-1 binding site on the heterodimer
  4. 1990 High

    Demonstrated that CD18 is both necessary and sufficient for beta2 integrin surface assembly and adhesion, and that LAD-causing point mutations act by impairing CD18 surface expression.

    Evidence Patient allele sequencing with mutant CD18 expression in COS cells, plus retroviral CD18 transfer into LAD lymphocytes with functional rescue

    PMID:1968911 PMID:1972597

    Open questions at the time
    • Did not resolve how individual residues affect folding versus alpha-chain pairing
    • Did not address in vivo correction
  5. 1992 High

    Defined transcriptional control of CD18 during myeloid differentiation, explaining how integrin availability is set developmentally.

    Evidence CD18 promoter reporter assays with AP-1 and PU.1 elements and nuclear run-on in differentiating myeloid lines

    PMID:1350225

    Open questions at the time
    • Did not connect transcriptional regulation to functional integrin output in vivo
  6. 1996 Medium

    Showed CD18 heterodimers operate within multi-protein surface units, with uPAR and CD63 co-regulating Mac-1 ligand binding and linking it to Src-family tyrosine kinase signaling.

    Evidence CHO co-transfection of Mac-1 and uPAR with fibrinogen degradation assays, and co-IP of CD63 with CD11/CD18 plus kinase activity assays

    PMID:8871662 PMID:8874219

    Open questions at the time
    • Co-IP and functional assays from single laboratories without structural definition of the interfaces
    • Stoichiometry and direct versus indirect association not established
  7. 1997 Medium

    Broadened the CD18 heterodimer ligand repertoire by showing Mac-1 binds oligodeoxynucleotides on both alpha and beta chains and mediates their internalization.

    Evidence ODN binding assays with fibrinogen competition, anti-Mac-1 mAb inhibition, and internalization quantification

    PMID:9095175

    Open questions at the time
    • Single laboratory; binding site on CD18 not mapped
    • Physiological relevance of ODN binding not established
  8. 1998 High

    Established in vivo nonredundant roles for CD18 in neutrophil tissue migration, T cell activation, and PMN-driven myocardial reperfusion injury.

    Evidence CD18 null mice with intravital cremaster imaging, T cell proliferation assays, and myocardial ischemia-reperfusion infarct measurement

    PMID:9653089 PMID:9843832

    Open questions at the time
    • Did not separate the contributions of individual heterodimers
    • Mechanism of T cell activation defect not resolved
  9. 1999 Medium

    Linked CD18 to systemic bacterial dissemination and placed integrin activation downstream of redox/tyrosine-kinase signaling.

    Evidence CD18-deficient mice with oral Salmonella organ burden assays, and H2O2/inhibitor pharmacology with activation neoepitope readouts in neutrophils

    PMID:10548107 PMID:10556796

    Open questions at the time
    • Redox signaling work is single-laboratory pharmacology without molecular identification of S-thiolated targets
    • Phagocyte type mediating Salmonella transport not fully defined
  10. 2001 High

    Directly demonstrated that leukocyte activation drives a cation-dependent CD18 conformational change that correlates with high-affinity ICAM-1 binding, providing the structural basis of inside-out activation.

    Evidence Activation-epitope mAb panel on T cells and LAD-1 variant cells with ICAM-1 affinity correlation

    PMID:11714770

    Open questions at the time
    • Did not resolve the atomic conformational rearrangement
    • Cytoplasmic signal triggering the change not defined
  11. 2002 High

    Identified Lck-dependent tyrosine kinase signaling and proteoglycan ligands as upstream and counter-receptor determinants of CD18 maturation and adhesion.

    Evidence Lck-deficient Jurkat cells with rescue for integrin maturation, and purified CD11b/CD18 binding to fucoidin and fucosidase-treated epithelium

    PMID:12115650 PMID:12391246

    Open questions at the time
    • Lck mechanism on CD18 phosphorylation not directly demonstrated
    • Identity of the epithelial fucosylated proteoglycan ligand not defined
  12. 2003 High

    Showed CD18 surface levels are post-translationally regulated by shear-dependent cathepsin B ectodomain cleavage, and that CD18 is required for choroidal neovascularization.

    Evidence Confocal/flow analysis of sheared neutrophils with protease inhibitor panel, and CD18-/- laser CNV model

    PMID:12766082 PMID:14595007

    Open questions at the time
    • Did not identify the cleavage site on CD18
    • Did not establish consequences of shed ectodomain
  13. 2005 High

    Extended CD18 function beyond innate adhesion to adaptive tolerance by showing LFA-1 is required for T regulatory cell development and suppression.

    Evidence CD18-/- NOD mice with Treg enumeration, in vitro suppression, and adoptive transfer colitis assays

    PMID:16339524

    Open questions at the time
    • Mechanism by which LFA-1 supports Treg development not defined
  14. 2008 High

    Defined CD18 as a receptor hijacked by bacterial virulence factors, with species-specific extracellular domains mapping toxin susceptibility.

    Evidence LFA-1-deficient Jurkat complementation for VacA, and chimeric beta2-integrin domain mapping for LtxA cytotoxicity

    PMID:17635865 PMID:18191791

    Open questions at the time
    • Did not resolve the structural toxin-binding interface on CD18
    • Did not link toxin entry to integrin signaling
  15. 2013 High

    Distinguished two mechanistically distinct modes of CD11b/CD18 activation and defined alpha-chain phosphorylation as functionally required for a beta2 integrin.

    Evidence Single-molecule force spectroscopy of LA1 versus Mn2+ activation, and Ser1158Ala mutagenesis of CD11c with phagocytosis assays

    PMID:24129562 PMID:24314082

    Open questions at the time
    • Did not connect alpha-chain phosphorylation to CD18 conformational state
    • Physiological agonist driving each activation mode not defined
  16. 2016 Medium

    Identified CD18 heterodimers as drivers of macrophage fusion and revealed additional membrane partners modulating adhesion.

    Evidence Mac-1-/- and CD11d-/- mice in IL-4 fusion and peritoneal models, and MS identification of FRbeta-Mac-1 interaction with collagen adhesion assays

    PMID:27315778 PMID:27534550

    Open questions at the time
    • Fusion counter-receptor not identified
    • FRbeta interaction is single-laboratory MS discovery without structural validation
  17. 2017 Medium

    Showed cathepsin B cleavage of CD18 governs the balance between vessel retention and interstitial migration speed during extravasation.

    Evidence In vivo corneal angiogenesis imaging of CtsB-/- and CD18-/- leukocytes with CD18 surface measurement

    PMID:28904019

    Open questions at the time
    • Single laboratory; CD18 ECM ligands slowing migration not identified
  18. 2018 Medium

    Defined Mac-1 as the phagocytic receptor initiating LC3-associated phagocytosis and intracellular bacterial killing.

    Evidence In vivo Listeria infection with genetic Mac-1 identification and macrophage killing assays

    PMID:29923444

    Open questions at the time
    • Single laboratory; signaling connecting Mac-1 to LAP machinery not defined
  19. 2019 High

    Resolved the spatial and structural division of labor among CD18 heterodimers and bacterial toxins, mapping LFA-1 and Mac-1 to sequential extravasation hotspots and the LukGH interface to CD11b-I.

    Evidence LFA-1/Mac-1 FRET knock-in mice with two-photon imaging, and crystal/SAXS structure of LukGH-CD11b-I with species-specific cytolysis assays

    PMID:30967528 PMID:31852826

    Open questions at the time
    • Did not define the basement-membrane ligand for Mac-1 at hotspot II
    • Structural basis of physiological ligand binding to CD18 itself not resolved
  20. 2020 High

    Separated CD18's roles in bacterial attachment versus internalization and placed talin-1/kindlin-3 as the inside-out effectors of internalization.

    Evidence CRISPR CD18-deficient human monocytes and murine neutrophils, ectopic CR3 CHO expression, and phagocytosis assays with talin/kindlin manipulation

    PMID:32041787

    Open questions at the time
    • Did not define how surface glycans cooperate with CD18 during binding
  21. 2023 Medium

    Showed CD18 glycosylation and EV-displayed integrin tune adhesion, migration, and tissue injury, extending CD18 regulation to post-translational glycan state and intercellular vesicle transfer.

    Evidence Sialidase inhibition with transepithelial migration and Syk/p38 readouts, and engineered ITGAM/ITGB2 EV competition in a severe pancreatitis lung injury model

    PMID:36719745 PMID:37022097

    Open questions at the time
    • Single-laboratory reports; molecular link between sialylation and conformational activation not resolved
    • EV integrin mechanism is indirect competition evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream phosphorylation, redox modification, and glycan state are integrated to produce the specific CD18 conformational transition that confers high-affinity ligand binding, and the atomic structure of CD18 engaging its physiological ligands, remain unresolved.
  • No structure of full beta2 heterodimer bound to a physiological ligand in the corpus
  • Causal chain from CD18 serine phosphorylation to affinity change not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0038024 cargo receptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1474244 Extracellular matrix organization 2
Partners
CD63FOLR2ICAM1ITGALITGAMITGAXLCKPLAUR
Complex memberships
CD11d/CD18CR4 (CD11c/CD18)LFA-1 (CD11a/CD18)Mac-1/CR3 (CD11b/CD18)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 ICAM-1 is a counter-receptor for Mac-1 (CD11b/CD18): purified Mac-1 adsorbed to artificial substrates binds ICAM-1-expressing cells, and COS cells co-transfected with Mac-1 alpha and beta (CD18) chains attach to purified ICAM-1 substrates. This binding is blocked by mAbs to both ICAM-1 and Mac-1, establishing ICAM-1 as a ligand for the CD11b/CD18 heterodimer. Purified protein binding assays, cDNA transfection of COS/L cells, reciprocal cell adhesion assays, mAb blocking The Journal of cell biology High 1980124
1989 CD18 undergoes stimulus-induced phosphorylation: in resting leukocytes CD18 phosphorylation is minimal, but PMA induces rapid, sustained, high-stoichiometry CD18 phosphorylation predominantly on serine residues (with minor phosphothreonine and phosphotyrosine), while FMLP induces transient CD18 phosphorylation. The CD11 alpha subunits show only minimal changes, indicating CD18 is the primary regulated phosphorylation target in the complex. Metabolic radiolabeling with 32P, immunoprecipitation, phosphoamino acid analysis, PMA/FMLP stimulation of human leukocytes The Journal of cell biology High 2574726
1989 CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) each contribute approximately equally (~50% each) to PMN adhesion to unstimulated endothelial cells, but through different ligands: CD11a/CD18 binds ICAM-1, while CD11b/CD18 binds a distinct, non-ICAM-1 ligand on endothelial cells. CD11c/CD18 does not participate in this adhesion. mAb blocking of individual CD11 chains, anti-ICAM-1 antibody competition, ICAM-1-coated surface down-modulation assays, PMN-endothelial cell adhesion assays Journal of immunology High 2809204
1990 Two point mutations in the CD18 coding sequence (Arg593→Cys and Lys196→Thr) each impair CD18 cell-surface expression when introduced into transfected COS cells, identifying conserved residues in the cysteine-rich repeats and another conserved integrin region as critical for normal CD18 surface expression. cDNA cloning and sequencing of patient alleles, transfection of mutant CD18 into COS M6 cells, surface expression analysis The Journal of clinical investigation High 1968911
1990 Retrovirus-mediated transduction of a functional CD18 gene into LAD patient lymphocytes restores surface expression of CD11a/CD18 (LFA-1) and reconstitutes LFA-1-dependent adhesive function, demonstrating that CD18 is the functional defect in LAD and is sufficient for integrin surface assembly. Retrovirus-mediated gene transfer, molecular analysis of proviral integration and CD18 mRNA, flow cytometry for surface CD11a/CD18, functional LFA-1 adhesion assays Science High 1972597
1993 CD18 gene targeting in mice produces a hypomorphic allele (2–16% of normal CD18 expression); homozygous mutant mice show mild granulocytosis and impaired inflammatory responses (reduced peritonitis and delayed cardiac allograft rejection), demonstrating that CD18 is required for normal leukocyte integrin-dependent adhesion in vivo. Gene targeting (insertional mutation), flow cytometry for CD18 expression, chemical peritonitis model, cardiac transplant rejection model Journal of immunology High 8101543
1998 CD18 null mice develop chronic dermatitis, elevated neutrophil counts, and markedly defective T cell proliferation in response to TCR stimulation, demonstrating that CD11/CD18 integrins are required for normal neutrophil tissue migration and T cell activation in vivo. CD18 null mouse (gene-targeted), intravital microscopy of cremaster muscle, T cell proliferation assays (staphylococcal enterotoxin A, MHC alloantigens) The Journal of experimental medicine High 9653089
1996 Mac-1 (CD11b/CD18) and the urokinase receptor (uPAR/CD87) form a functional unit on monocytic cells: uPAR engagement by urokinase inhibits Mac-1-mediated fibrinogen binding and degradation (up to 91% inhibition) and Factor X binding, while vitronectin-mediated uPAR attachment enhances subsequent Mac-1 fibrinogen degradation 3–4-fold. This co-regulation was reproduced in CHO cells co-transfected with human Mac-1 and uPAR. Co-expression in CHO cells (transfection), fibrinogen binding and degradation assays, Factor X binding assays, monocytic cell lines, fresh monocytes Blood High 8874219
1997 Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein: binding of thymidine homopolymer occurs on both the CD11b alpha subunit and the CD18 beta subunit; soluble fibrinogen competes for this binding; anti-Mac-1 mAbs inhibit binding; increased surface Mac-1 expression correlates with increased ODN internalization by PMNs. Binding assays with phosphodiester and phosphorothioate ODNs, competition with fibrinogen, anti-Mac-1 mAb inhibition, upregulation by TNF-alpha, internalization quantification Nature medicine Medium 9095175
1999 CD18-expressing phagocytes transport Salmonella from the gastrointestinal tract to the bloodstream: CD18-deficient mice are resistant to extraintestinal dissemination of SPI1-deficient S. typhimurium to liver and spleen after oral administration, establishing a CD18-dependent pathway for systemic bacterial dissemination. CD18-deficient mouse model, oral Salmonella challenge, organ bacterial burden quantification Nature High 10548107
1998 CD18 deficiency significantly reduces myocardial infarct size and PMN infiltration after ischemia-reperfusion: CD18-/- mice show ~57% reduction in infarct area and 54% reduction in PMN infiltration compared to wild-type, demonstrating that CD18-mediated neutrophil-endothelial adhesion is required for PMN-driven myocardial reperfusion injury. CD18-/- and ICAM-1-/- mouse models, surgical myocardial ischemia-reperfusion, infarct size measurement, PMN infiltration histology The American journal of physiology High 9843832
1999 A missense mutation (Cys36Ser) in canine ITGB2 disrupts a conserved cysteine (likely a disulfide bond) and causes canine leukocyte adhesion deficiency (CLAD): mutant CD18 fails to support CD11/CD18 surface expression, confirmed by retroviral transduction of mutant vs. normal canine CD18 into human LAD EBV B-cells. Sequence analysis, retroviral vector transduction of LAD B-cells, flow cytometry for CD11/CD18 surface expression Genomics High 10512685
2003 CD18 deficiency (gene knockout) inhibits choroidal neovascularization (CNV): CD18-/- mice show significantly fewer CNV lesions with fluorescein leakage and significantly smaller CNV volumes after laser photocoagulation compared to wild-type, demonstrating a nonredundant role for CD18-mediated leukocyte adhesion in CNV development. CD18-/- mouse laser photocoagulation CNV model, confocal volumetric CNV measurement, fluorescein angiography Investigative ophthalmology & visual science High 12766082
2008 The CD18 (beta2 integrin) subunit is the T-lymphocyte receptor for Helicobacter pylori vacuolating cytotoxin VacA: VacA enters activated T lymphocytes by binding CD18 and exploiting LFA-1 recycling. LFA-1-deficient Jurkat cells are resistant to VacA-induced vacuolation and IL-2 modulation; genetic complementation with LFA-1 or Mac-1 (containing human CD18) restores sensitivity. VacA targets human but not murine CD18. LFA-1-deficient Jurkat T cells, genetic complementation with human CD18-containing integrins, vacuolation assays, IL-2 secretion assays, species-specificity analysis Cell host & microbe High 18191791
2007 Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin (LtxA): chimeric beta2-integrins expressed in LtxA-resistant cells confer susceptibility, and the cysteine-rich tandem repeats encompassing integrin-EGF-like domains 2, 3, and 4 of the CD18 extracellular region are critical for species-specific LtxA-induced cytotoxicity. Chimeric beta2-integrin expression in resistant cell lines, domain-deletion analysis, cytotoxicity assays Infection and immunity High 17635865
2002 CD11b/CD18-dependent PMN interactions with intestinal epithelium are mediated by fucosylated proteoglycans: fucoidin directly binds CD11b/CD18 in a divalent cation- and sulfation-dependent manner blocked by anti-CD11b mAbs; fucosidase treatment of T84 epithelial cells reduces adhesion to purified CD11b/CD18; proteoglycan synthesis inhibition blocks T84 adhesion to CD11b/CD18. Purified CD11b/CD18 adhesion assays, fucoidin direct binding, anti-CD11b mAb blocking, fucosidase and neuraminidase treatment, proteoglycan synthesis inhibition, ligand blotting Journal of immunology High 12391246
2001 CD18 undergoes conformational change upon leukocyte activation: mAbs recognizing activation-induced neoepitopes on CD18 reveal a subpopulation of LFA-1 with altered conformation that correlates with cell adhesion, requires divalent cations, is sensitive to cellular signaling, is absent in LAD-1 variant cells defective in LFA-1 activation, and co-occurs with high-affinity ICAM-1 binding. Function-blocking CD18 mAbs suppress this conformational change. Novel activation-epitope mAb panel, flow cytometry on T lymphocytes and LAD-1 variant cell lines, correlation with ICAM-1 binding affinity, recombinant LFA-1 Journal of immunology High 11714770
2003 Fluid shear stress causes cleavage of the extracellular domain of CD18 from neutrophil surfaces via cysteine protease (cathepsin B) activity: shear (5 dyn/cm²) cleaves the extracellular but not cytoplasmic CD18 domain, is abolished by extracellular Ca²⁺ chelation and cathepsin B inhibitors (but not cathepsin L, calpain, elastase, or metalloprotease inhibitors), and results in CD18 redistribution rather than cytoplasmic internalization. Confocal microscopy of single adherent neutrophils, flow cytometry, protease inhibitor panel, Ca²⁺ chelation, domain-specific antibody epitope mapping Proceedings of the National Academy of Sciences of the United States of America High 14595007
2002 Lck tyrosine kinase is required for CD11a/CD18 surface expression and activation in T cells: Lck-deficient Jurkat cells (JCaM1.6) show dramatically reduced CD3- and phorbol ester-induced adhesion to ICAM-1 and lower CD11a/CD18 surface expression, with CD18 predominantly in an immature, unassociated form; retransfection of Lck restores adhesion. Lck-deficient Jurkat cell line (JCaM1.6), Src-kinase inhibitor PP2, flow cytometry, cell surface labeling, Lck retransfection rescue European journal of immunology High 12115650
1999 Redox signaling via oxidative S-thiolation is required for CD11b/CD18 activation: H₂O₂ induces CD11b/CD18-dependent neutrophil adhesion and activation neoepitope expression; this is inhibited by tyrosine kinase inhibitors and sulfhydryl-complexing agents. Physiological agonists (TNF-alpha)-induced integrin activation is blocked by flavoprotein oxidoreductase inhibitor (DPI), free radical scavengers, tyrosine kinase inhibitors, and PAO, but not by integrin-activating KIM185 mAb. H₂O₂ treatment of neutrophils, activation neoepitope mAb (clone 24), tyrosine kinase inhibitors, PAO, DPI, free radical scavengers, chronic granulomatous disease patient neutrophils European journal of immunology Medium 10556796
1996 CD63 associates physically with CD11/CD18 on neutrophil surfaces and crosslinking of CD63 upregulates CD11/CD18 expression and increases neutrophil adhesion to endothelium via a CD18-dependent mechanism. CD63-associated protein kinase activity is predominantly tyrosine kinase activity (Lyn, Hck), linking CD63-CD18 complexes to intracellular signaling. Co-immunoprecipitation, flow cytometry for CD11/CD18 expression, neutrophil-HUVEC adhesion assays, mAb blocking, kinase activity assay, Src family kinase identification Journal of immunology Medium 8871662
1992 CD18 expression is transcriptionally regulated during myeloid differentiation via a defined promoter: the CD18 promoter contains AP-1 elements mediating PMA transcriptional response and a PU.1 binding site; a CD18 promoter-luciferase construct increases expression after PMA in U937 cells, and nuclear run-on studies confirm transcriptional regulation during TPA-induced HL-60 monocytic differentiation. Promoter cloning, primer extension, RNase protection, DNA sequencing, luciferase reporter assay, nuclear run-on transcription Blood High 1350225
2005 CD18 (LFA-1) is required for optimal development and function of CD4+CD25+ T regulatory cells: CD18-/- mice have reduced Treg numbers, defective thymic and peripheral Treg development, and LFA-1-deficient Tregs fail to suppress conventional T cells in vitro or prevent colitis in lymphopenic hosts following adoptive transfer. CD18-/- mouse (NOD background), Treg enumeration, in vitro suppression assays, T cell adoptive transfer colitis model Journal of immunology High 16339524
2009 Genetic deficiency of Itgb2 completely prevents autoimmune diabetes and insulitis in NOD/LtJ mice, and abolishes T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions, demonstrating that CD18 (beta2 integrin) mediates diabetogenic T-cell adhesion to islet endothelium. Itgb2 gene-targeted NOD/LtJ mice, diabetes incidence monitoring, insulitis scoring, in vitro hydrodynamic flow T-cell adhesion assays, adoptive transfer studies Diabetes High 19223596
2017 Cathepsin B cleaves CD18 from the leukocyte surface to regulate extravasation from angiogenic vessels: CtsB-deficient leukocytes accumulate more in angiogenic vessels, extravasate less, and retain higher CD18 surface expression. CD18-deficient leukocytes extravasate later but migrate faster once outside vessels, revealing that CD18-ECM interactions slow interstitial transmigration velocity. In vivo corneal angiogenesis/cytokine implant model, CtsB-/- and CD18-/- leukocyte tracking, CD18 surface expression measurement FASEB journal Medium 28904019
2019 Crystal/SAXS structures of staphylococcal leukocidin GH (LukGH) in complex with the alpha-I domain of CD11b (CD11b-I domain of CD18 heterodimer) reveal two binding interfaces on LukG and LukH protomers; human CD11b-I induces LukGH oligomerization in solution (required for cytolytic pore formation), while murine CD11b-I binds weakly and does not support oligomerization, explaining species specificity. Crystal structure and SAXS of LukGH-CD11b-I complex, LukGH variant engineering, murine vs. human CD11b-I binding assays, oligomerization assays, cytolysis assays with murine neutrophils Proceedings of the National Academy of Sciences of the United States of America High 31852826
2016 Mac-1 (CD11b/CD18) plays a dominant role in macrophage fusion to form multinucleated giant cells: IL-4-induced fusion of Mac-1-deficient macrophages is strongly reduced in vitro, and fewer giant cells form in the inflamed peritoneum of Mac-1-/- mice compared to wild-type. Mac-1 deficiency reduces macrophage spreading but not adhesion or migration. Integrin αDβ2 (CD11d/CD18) also contributes to fusion, but less prominently. ICAM-1 deficiency does not alter fusion rate, suggesting a novel counter-receptor. Mac-1-/- and αDβ2-/- mice, IL-4-induced macrophage fusion assay, peritoneal inflammation model, spreading/adhesion/migration assays The American journal of pathology High 27315778
2018 Integrin ITGAM-ITGB2 (Mac-1/CR3) is the phagocytic receptor that initiates LC3-associated phagocytosis (LAP) of Listeria monocytogenes in tissue macrophages: LAP is required for bacterial killing and anti-listerial immunity in vivo, whereas canonical autophagy is dispensable. In vivo mouse infection model, genetic identification of Mac-1 as LAP-initiating receptor, macrophage killing assays Autophagy Medium 29923444
2013 LA1 (leukadherin-1), a small molecule CD11b/CD18 agonist, enhances CD11b/CD18:ICAM-1 binding primarily by increasing membrane tether formation rather than cytoskeleton-anchored bonds. In contrast, Mn²⁺ additionally promotes CSK-anchored bond formation, demonstrating two mechanistically distinct modes of CD11b/CD18 activation. Single-molecule force spectroscopy (AFM), K562 cells expressing CD11b/CD18, LFA-1-/- neutrophils, ICAM-1-coated AFM tips Biophysical journal High 24314082
2013 CD11c alpha-chain phosphorylation at Ser-1158 is required for CD11c/CD18 (CR4) function: alanine substitution at this site impairs adherence and phagocytosis, establishing that alpha-chain phosphorylation is functionally critical for this beta2 integrin. Phosphorylation site mapping, site-directed mutagenesis (Ser1158Ala), adherence and phagocytosis functional assays The Journal of biological chemistry High 24129562
2020 CD18 expression is dispensable for initial bacterial attachment but required for phagocytic internalization of Pseudomonas aeruginosa: CRISPR-generated CD18-deficient human monocytes and murine neutrophils fail to internalize both motile and nonmotile P. aeruginosa, while ectopic CR3 expression in CD18-negative CHO cells does not rescue initial binding. Surface N-linked glycans facilitate initial bacterial attachment; talin-1 and kindlin-3 promote CD18-dependent internalization. CRISPR/Cas9 CD18-deficient human monocytes and murine neutrophils, ectopic CR3 expression in CHO cells, phagocytosis assays with motile/nonmotile isogenic mutants, talin-1 and kindlin-3 manipulation Infection and immunity High 32041787
2016 Folate receptor beta (FRβ) physically interacts with the CD11b/CD18 (Mac-1) beta2 integrin heterodimer in the plasma membrane of FRβ+ macrophages and impedes CD11b/CD18-mediated adhesion to collagen. This was identified by affinity purification and mass spectrometry of the FRβ membrane microenvironment. Affinity purification of FRβ membrane microenvironment, mass spectrometry, adhesion assays to collagen, FRβ-transduced THP-1 monocytic cells, primary FRβ+ macrophages Journal of immunology Medium 27534550
2023 ITGAM and ITGB2 expressed on extracellular vesicles (EVs) from severe acute pancreatitis (SAP) mediate pulmonary accumulation and acute lung injury (ALI): EVs engineered to overexpress ITGAM and ITGB2 compete with SAP-EVs for pulmonary accumulation and attenuate pulmonary inflammation and endothelial barrier disruption in vivo. EV integrin overexpression engineering, integrin antagonist peptide (HYD-1) preincubation, in vivo SAP mouse model, pulmonary inflammation and endothelial barrier assays ACS nano Medium 37022097
2023 Alpha2-3-linked sialic acid on CD11b/CD18 regulates PMN transepithelial migration and integrin activation: inhibiting sialidase-mediated desialylation of CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo, reduces degranulation and superoxide release, and blocks bacterial peptide-mediated CD11b/CD18 activation and downstream Syk/p38 MAPK signaling. Sialidase inhibitors, in vitro transepithelial migration assays, in vivo intestinal inflammation model, CD11b/CD18 activation assays, Syk and p38 MAPK signaling readouts JCI insight Medium 36719745
2021 CD18 knockout in zebrafish (CRISPR/Cas9) causes key LAD-I symptoms: increased circulating neutrophils and reduced neutrophil trafficking to sterile inflammation sites. Sequence analysis shows conservation of the I-like domain and cytoplasmic NXXF motifs between zebrafish and human CD18, supporting functional orthology. CRISPR/Cas9 CD18 KO in zebrafish larvae, sequence alignment, intravital neutrophil trafficking assays Frontiers in immunology Medium 34557186
2019 LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) distinctly regulate neutrophil extravasation at two sequential hotspots: LFA-1 FRET (CD11a-YFP/CD18-CFP) mice and Mac-1 FRET (CD11b-YFP/CD18-CFP) mice show that LFA-1 and Mac-1 operate at different stages (hotspot I through endothelium, hotspot II through basement membrane/pericyte sheath), as visualized by two-photon intravital imaging. Two-photon intravital imaging, transmission electron microscopy, LFA-1 FRET and Mac-1 FRET knock-in mice Experimental & molecular medicine High 30967528

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18). The Journal of cell biology 898 1980124
1999 Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 507 10548107
1998 Spontaneous skin ulceration and defective T cell function in CD18 null mice. The Journal of experimental medicine 264 9653089
1993 CR3 (CD11b, CD18): a phagocyte and NK cell membrane receptor with multiple ligand specificities and functions. Clinical and experimental immunology 242 8485905
1989 Constitutive and stimulus-induced phosphorylation of CD11/CD18 leukocyte adhesion molecules. The Journal of cell biology 227 2574726
1989 Two leukocyte receptors (CD11a/CD18 and CD11b/CD18) mediate transient adhesion to endothelium by binding to different ligands. Journal of immunology (Baltimore, Md. : 1950) 222 2809204
1991 CD40 signaling activates CD11a/CD18 (LFA-1)-mediated adhesion in B cells. Journal of immunology (Baltimore, Md. : 1950) 218 1706378
1997 Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nature medicine 196 9095175
1993 Gene targeting yields a CD18-mutant mouse for study of inflammation. Journal of immunology (Baltimore, Md. : 1950) 191 8101543
1995 Leukocyte CD11/CD18 integrins: biological and clinical relevance. Haematologica 180 7628754
1996 Mac-1 (CD11b/CD18) and the urokinase receptor (CD87) form a functional unit on monocytic cells. Blood 165 8874219
2012 The leucocyte β2 (CD18) integrins: the structure, functional regulation and signalling properties. Bioscience reports 146 22458844
2002 CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are involved in complement-independent antibody-mediated phagocytosis of Cryptococcus neoformans. Immunity 136 12121661
1997 Glucocorticoid receptor regulates expression of L-selectin and CD11/CD18 on human neutrophils. Circulation 132 9236448
2020 ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system. Theranostics 122 33204328
1989 Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation. Blood 122 2562920
2003 Targeted disruption of the CD18 or ICAM-1 gene inhibits choroidal neovascularization. Investigative ophthalmology & visual science 106 12766082
2017 The role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in complement-mediated phagocytosis and podosome formation by human phagocytes. Immunology letters 104 28554712
1991 Expression of cytoadhesion molecules (CD56, CD54, CD18 and CD29) by myeloma plasma cells. British journal of haematology 99 1721526
1996 CD63 associates with tyrosine kinase activity and CD11/CD18, and transmits an activation signal in neutrophils. Journal of immunology (Baltimore, Md. : 1950) 94 8871662
1990 Point mutations impairing cell surface expression of the common beta subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM) deficiency. The Journal of clinical investigation 90 1968911
2007 CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity. Journal of leukocyte biology 89 17389580
2008 Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell host & microbe 87 18191791
1998 Myocardial ischemia-reperfusion injury in CD18- and ICAM-1-deficient mice. The American journal of physiology 84 9843832
1995 Altered expression of CD11b/CD18 and CD62L on human monocytes after cell preparation procedures. Journal of immunological methods 84 7534806
2005 CD18 is required for optimal development and function of CD4+CD25+ T regulatory cells. Journal of immunology (Baltimore, Md. : 1950) 77 16339524
2002 CD11b/CD18-dependent interactions of neutrophils with intestinal epithelium are mediated by fucosylated proteoglycans. Journal of immunology (Baltimore, Md. : 1950) 77 12391246
1998 CD11/CD18 and CD14 share a common lipid A signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 75 9820516
1996 Adaptation to eccentric exercise: effect on CD64 and CD11b/CD18 expression. Journal of applied physiology (Bethesda, Md. : 1985) 75 8847330
1989 Regulation of expression of the CD11b and CD18 subunits of the neutrophil adherence receptor during human myeloid differentiation. The Journal of biological chemistry 75 2600090
1999 L- and P-selectin and CD11/CD18 in intracapillary neutrophil sequestration in rabbit lungs. American journal of respiratory and critical care medicine 74 9872849
2019 LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) distinctly regulate neutrophil extravasation through hotspots I and II. Experimental & molecular medicine 73 30967528
1990 Subcellular distribution and mobilization of MAC-1 (CD11b/CD18) in neonatal neutrophils. Blood 72 2153038
2016 CD11c/CD18 Dominates Adhesion of Human Monocytes, Macrophages and Dendritic Cells over CD11b/CD18. PloS one 71 27658051
2018 LncRNA ITGB2-AS1 Could Promote the Migration and Invasion of Breast Cancer Cells through Up-Regulating ITGB2. International journal of molecular sciences 69 29941860
1998 Alterations of neutrophil L-selectin and CD18 expression by tobacco smoke: implications for periodontal diseases. Journal of periodontal research 69 9777587
1999 A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. Genomics 68 10512685
2001 CD18 activation epitopes induced by leukocyte activation. Journal of immunology (Baltimore, Md. : 1950) 65 11714770
2003 Regulation of CD18 expression on neutrophils in response to fluid shear stress. Proceedings of the National Academy of Sciences of the United States of America 64 14595007
2023 LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis. Cancer biology & therapy 62 37370246
1992 Cloning and analysis of the CD18 promoter. Blood 62 1350225
1990 Correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer. Science (New York, N.Y.) 62 1972597
2016 The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion. The American journal of pathology 56 27315778
2007 Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin. Infection and immunity 54 17635865
2005 Influence of CR3 (CD11b/CD18) expression on phagocytosis of Bordetella pertussis by human neutrophils. Infection and immunity 52 16239529
1999 Redox regulation of beta2-integrin CD11b/CD18 activation. European journal of immunology 50 10556796
1994 Quantitation of L-selectin and CD18 expression on rabbit neutrophils during CD18-independent and CD18-dependent emigration in the lung. Journal of immunology (Baltimore, Md. : 1950) 49 7522252
2001 Dietary restriction impairs neutrophil exudation by reducing CD11b/CD18 expression and chemokine production. Archives of surgery (Chicago, Ill. : 1960) 48 11231849
1997 Increased expression of CD11b/CD18 on phagocytes in ischaemic disease: a bridge between inflammation and coagulation. European journal of clinical investigation 48 9279527
2000 Upregulation of CD14 and CD18 on monocytes In vitro by antineutrophil cytoplasmic autoantibodies. Journal of the American Society of Nephrology : JASN 44 10966488
2009 Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis. The Journal of investigative dermatology 43 19242511
1994 Neutrophil CD18 expression and blockade after traumatic shock and endotoxin challenge. Annals of surgery 42 7944665
2023 Extracellular Vesicle ITGAM and ITGB2 Mediate Severe Acute Pancreatitis-Related Acute Lung Injury. ACS nano 40 37022097
1990 Contribution of CR3, CD11b/CD18 to cytolysis by human NK cells. Molecular immunology 40 1980339
2014 Integrin αDβ2 (CD11d/CD18) is expressed by human circulating and tissue myeloid leukocytes and mediates inflammatory signaling. PloS one 36 25415295
2002 Expression of CD16, CD18 and CD56 in tributyltin-exposed human natural killer cells. Chemico-biological interactions 35 11823004
2002 Neutrophil migration into indomethacin induced rat small intestinal injury is CD11a/CD18 and CD11b/CD18 co-dependent. Gut 35 11950807
2013 Agonist leukadherin-1 increases CD11b/CD18-dependent adhesion via membrane tethers. Biophysical journal 34 24314082
2011 Primary porcine Kupffer cell phagocytosis of human platelets involves the CD18 receptor. Transplantation 33 21836538
2008 The ITGB2 immunomodulatory gene (CD18), enterocolitis, and Hirschsprung's disease. Journal of pediatric surgery 32 18675632
1995 Deformability and CD11/CD18 expression of sequestered neutrophils in normal and inflamed lungs. American journal of respiratory cell and molecular biology 32 7576688
1990 Protein kinase C-mediated regulation of the expression of CD14 and CD11/CD18 in U937 cells. International journal of cancer 32 1689274
2002 Lck tyrosine kinase is important for activation of the CD11a/CD18-integrins in human T lymphocytes. European journal of immunology 31 12115650
2013 Integrin CD11c/CD18 α-chain phosphorylation is functionally important. The Journal of biological chemistry 30 24129562
1996 Passage of CD18- and CD18+ bovine neutrophils into pulmonary alveoli during acute Pasteurella haemolytica pneumonia. Veterinary pathology 30 8952022
1999 Influence of age and plasma treatment on neutrophil phagocytosis and CD18 expression in foals. Veterinary microbiology 29 10189199
1995 Investigation of the complement receptor 3 (CD11b/CD18) in human rectal epithelium. Clinical and experimental immunology 29 7586695
2023 Single-cell analyses reveal the dynamic functions of Itgb2+ microglia subclusters at different stages of cerebral ischemia-reperfusion injury in transient middle cerebral occlusion mice model. Frontiers in immunology 28 37063847
2021 β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration. Frontiers in immunology 28 34858434
2020 The differential role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in the adherence, migration and podosome formation of human macrophages and dendritic cells under inflammatory conditions. PloS one 27 32365067
1999 The role of alpha4 (CD49d) and beta2 (CD18) integrins in eosinophil and neutrophil migration to allergic lung inflammation in the Brown Norway rat. American journal of respiratory cell and molecular biology 27 10030843
2022 The Profile and Clinical Significance of ITGB2 Expression in Non-Small-Cell Lung Cancer. Journal of clinical medicine 25 36362654
2018 LC3-associated phagocytosis initiated by integrin ITGAM-ITGB2/Mac-1 enhances immunity to Listeria monocytogenes. Autophagy 25 29923444
2019 Molecular mechanism of leukocidin GH-integrin CD11b/CD18 recognition and species specificity. Proceedings of the National Academy of Sciences of the United States of America 24 31852826
2006 Expression of CD18 on the neutrophils of patients with diabetic retinopathy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 24 16847684
2018 Intracellular β2 integrin (CD11/CD18) interacting partners in neutrophil trafficking. European journal of clinical investigation 23 29896791
1995 The kinetics of surface expression of CD11/CD18 integrins and CD54 on monocytes and macrophages. Clinical and experimental immunology 23 7743678
1994 Polymorphonuclear granulocyte expression of CD11a/CD18, CD11b/CD18 and L-selectin in normal individuals. FEMS immunology and medical microbiology 23 7516231
2021 Molecular Insights Into Neutrophil Biology From the Zebrafish Perspective: Lessons From CD18 Deficiency. Frontiers in immunology 21 34557186
2016 Folate Receptor β Regulates Integrin CD11b/CD18 Adhesion of a Macrophage Subset to Collagen. Journal of immunology (Baltimore, Md. : 1950) 21 27534550
2013 Polymorphism of ITGB2 gene 3'-UTR+145C/A is associated with biliary atresia. Digestion 21 23921155
2021 Stanniocalcin-2 promotes cell EMT and glycolysis via activating ITGB2/FAK/SOX6 signaling pathway in nasopharyngeal carcinoma. Cell biology and toxicology 20 33797657
2021 LINC01272/miR-876/ITGB2 axis facilitates the metastasis of colorectal cancer via epithelial-mesenchymal transition. Journal of Cancer 20 34093798
2014 Expression of CD11b and CD18 on polymorphonuclear neutrophils stimulated with interleukin-2. Central-European journal of immunology 20 26155126
2009 Genetic deficiency of Itgb2 or ItgaL prevents autoimmune diabetes through distinctly different mechanisms in NOD/LtJ mice. Diabetes 20 19223596
2002 A prospective evaluation of the CD14 and CD18 gene polymorphisms and risk of stroke. Stroke 20 11935032
1996 Granulocyte dysplasia and dysfunction, and CD11/CD18 defects in myelodysplastic syndromes. Leukemia & lymphoma 20 9031107
2015 Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1. Human immunology 19 26639818
1993 Role of protein synthesis and CD11/CD18 adhesion complex in neutrophil emigration into the lung. Experimental lung research 19 8467763
2025 Extracellular vesicle surface engineering with integrins (ITGAL & ITGB2) to specifically target ICAM-1-expressing endothelial cells. Journal of nanobiotechnology 18 39885580
2018 Evaluation of ITGB2 (CD18) and SELL (CD62L) genes expression and methylation of ITGB2 promoter region in patients with systemic sclerosis. Rheumatology international 18 29356883
1995 Down regulation of CD11b and CD18 expression in atherosclerotic lesion-derived macrophages. The American surgeon 18 7618805
2023 Sialylation regulates neutrophil transepithelial migration, CD11b/CD18 activation, and intestinal mucosal inflammatory function. JCI insight 17 36719745
2023 ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures. Cellular oncology (Dordrecht, Netherlands) 17 38150154
2021 LncRNA ITGB2-AS1 promotes the progression of clear cell renal cell carcinoma by modulating miR-328-5p/HMGA1 axis. Human cell 17 34170494
2017 Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 28904019
2016 The complement receptor 3 (CD11b/CD18) agonist Leukadherin-1 suppresses human innate inflammatory signalling. Clinical and experimental immunology 17 27118513
1995 Expression and role of adhesion molecule CD18 on bovine neutrophils. Canadian journal of veterinary research = Revue canadienne de recherche veterinaire 17 7704836
2023 Characterization of tumor microenvironment in glioblastoma multiforme identifies ITGB2 as a key immune and stromal related regulator in glial cell types. Computers in biology and medicine 16 37660569
2020 Distinct Contributions of CD18 Integrins for Binding and Phagocytic Internalization of Pseudomonas aeruginosa. Infection and immunity 16 32041787

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