Mitofusin‐2 regulates leukocyte adhesion and β2 integrin activation

2021 ◽  
Author(s):  
Wei Liu ◽  
Alan Y. Hsu ◽  
Yueyang Wang ◽  
Tao Lin ◽  
Hao Sun ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Integrin Activation ◽  
Mitofusin 2 ◽  
Β2 Integrin

scholarly journals Mitofusin‐2 regulates leukocyte adhesion through the maturation of β2 integrin activation in differentiation

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Zhichao Fan ◽  
Wei Liu ◽  
Yueyang Wang ◽  
Alan Hsu ◽  
Tao Lin ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Integrin Activation ◽  
Mitofusin 2 ◽  
Β2 Integrin

scholarly journals Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice

Blood ◽  
2018 ◽  
Vol 132 (26) ◽  
pp. 2754-2762 ◽  
Author(s):  
Thomas Bromberger ◽  
Sarah Klapproth ◽  
Ina Rohwedder ◽  
Liang Zhu ◽  
Laura Mittmann ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Thrombus Formation ◽  
Alternative Mechanism ◽  
Integrin Activation ◽  
Vessel Occlusion ◽  
Crucial Step ◽  
Β2 Integrin ◽  
Biological Studies ◽  
Integrin Ligands

Abstract Targeting Talin1 to the plasma membrane is a crucial step in integrin activation, which in leukocytes is mediated by a Rap1/RIAM/Talin1 pathway, whereas in platelets, it is RIAM independent. Recent structural, biochemical, and cell biological studies have suggested direct Rap1/Talin1 interaction as an alternative mechanism to recruit Talin1 to the membrane and induce integrin activation. To test whether this pathway is of relevance in vivo, we generated Rap1 binding–deficient Talin1 knockin (Tln13mut) mice. Although Tln13mut mice showed no obvious abnormalities, their platelets exhibited reduced integrin activation, aggregation, adhesion, and spreading, resulting in prolonged tail-bleeding times and delayed thrombus formation and vessel occlusion in vivo. Surprisingly, neutrophil adhesion to different integrin ligands and β2 integrin–dependent phagocytosis were also significantly impaired, which caused profound leukocyte adhesion and extravasation defects in Tln13mut mice. In contrast, macrophages exhibited no defect in adhesion or spreading despite reduced integrin activation. Taken together, our findings suggest that direct Rap1/Talin1 interaction is of particular importance in regulating the activity of different integrin classes expressed on platelets and neutrophils, which both depend on fast and dynamic integrin-mediated responses.

scholarly journals Skap2 is required for β2 integrin–mediated neutrophil recruitment and functions

2017 ◽  
Vol 214 (3) ◽  
pp. 851-874 ◽  
Author(s):  
Mark Boras ◽  
Stephanie Volmering ◽  
Arne Bokemeyer ◽  
Jan Rossaint ◽  
Helena Block ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Leukocyte Adhesion ◽  
Direct Interaction ◽  
Neutrophil Recruitment ◽  
Integrin Activation ◽  
Leukocyte Adhesion Deficiency ◽  
Β2 Integrin ◽  
Syndrome Protein

Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase–associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott–Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice.

scholarly journals A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase

2014 ◽  
Vol 25 (19) ◽  
pp. 2948-2955 ◽  
Author(s):  
Kyoung-Jin Chung ◽  
Ioannis Mitroulis ◽  
Johannes R. Wiessner ◽  
Ying Yi Zheng ◽  
Gabriele Siegert ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Integrin Activation ◽  
Pathogen Invasion ◽  
Β2 Integrin ◽  
Tlr2 Ligand ◽  
Species Production ◽  
Rapid Activation ◽  
Slow Rolling ◽  
Inside Out

Rapid β2-integrin activation is indispensable for leukocyte adhesion and recruitment to sites of infection and is mediated by chemokine- or P-selectin glycoprotein ligand-1–induced inside-out signaling. Here we uncovered a novel pathway for rapid activation of integrin-dependent leukocyte adhesion, triggered by toll-like receptor (TLR)–mediated signaling. TLR2 or TLR5 ligation rapidly activated integrin-dependent leukocyte adhesion to immobilized ICAM-1 and fibronectin. Consistently, in vivo administration of the TLR2-ligand Pam3CSK4 increased integrin-dependent slow rolling and adhesion to endothelium within minutes, as identified by intravital microscopy in the cremaster model. TLR2 and TLR5 ligation increased β2-integrin affinity, as assessed by the detection of activation-dependent neoepitopes. TLR2- and TLR5-triggered integrin activation in leukocytes required enhanced Rap1 GTPase activity, which was mediated by Rac1 activation and NADPH oxidase-2–dependent reactive oxygen species production. This novel direct pathway linking initial pathogen recognition by TLRs to rapid β2-integrin activation may critically regulate acute leukocyte infiltration to sites of pathogen invasion.

LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 1033-1036 ◽  
Author(s):  
Tatsuo Kinashi ◽  
Memet Aker ◽  
Maya Sokolovsky-Eisenberg ◽  
Valentin Grabovsky ◽  
Chisato Tanaka ◽  
...  
Keyword(s):  
Shear Flow ◽  
Ligand Binding ◽  
Phorbol Esters ◽  
Leukocyte Adhesion ◽  
Deficiency Syndrome ◽  
Small Gtpase ◽  
High Avidity ◽  
Integrin Activation ◽  
Leukocyte Adhesion Deficiency ◽  
Rap1 Activation

AbstractRecently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.1 We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it “LAD-III.” (Blood. 2004;103:1033-1036)

scholarly journals A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets

2007 ◽  
Vol 204 (7) ◽  
pp. 1571-1582 ◽  
Author(s):  
Ronit Pasvolsky ◽  
Sara W. Feigelson ◽  
Sara Sebnem Kilic ◽  
Amos J. Simon ◽  
Guy Tal-Lapidot ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Leukocyte Adhesion ◽  
Splice Junction ◽  
Integrin Activation ◽  
Leukocyte Adhesion Deficiency ◽  
Protein Levels ◽  
Guanine Exchange Factor ◽  
Β3 Integrin ◽  
Inside Out

Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in β1, β2, and β3 integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired αIIbβ3 activation by key agonists. β2 integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFα-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil β2 integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.

scholarly journals β1 integrin activation on human neutrophils promotes β2 integrin-mediated adhesion to fibronectin

2001 ◽  
Vol 31 (1) ◽  
pp. 276-284 ◽  
Author(s):  
J. Merlijn van den Berg ◽  
Frederik P. J. Mul ◽  
Esther Schippers ◽  
Jan J. Weening ◽  
Dirk Roos ◽  
...  
Keyword(s):  
Human Neutrophils ◽  
Β1 Integrin ◽  
Integrin Activation ◽  
Β2 Integrin

P-selectin binding to P-selectin glycoprotein ligand-1 induces an intermediate state of αMβ2 activation and acts cooperatively with extracellular stimuli to support maximal adhesion of human neutrophils

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2549-2556 ◽  
Author(s):  
Yan-Qing Ma ◽  
Edward F. Plow ◽  
Jian-Guo Geng
Keyword(s):  
Intermediate State ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Surface Expression ◽  
Human Neutrophils ◽  
Integrin Activation ◽  
Extracellular Stimuli ◽  
Selectin Binding ◽  
Leukocyte Adhesion Molecules

Abstract P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and integrin αMβ2 (Mac-1, CD11bCD18) are leukocyte adhesion molecules essential for innate immunity and inflammation. The interaction of PSGL-1 with P-selectin (CD62P) mediates tethering, rolling, and weak adhesion of leukocytes, during which they become sufficiently activated in situ by locally released or displayed cytokines and chemoattractants for integrin-mediated firm adhesion. However, communication between P-selectin and the integrin, whether P-selectin can trigger β2-integrin activation, remains controversial. We found that P-selectin immunoglobulin chimera and PSGL-1 monoclonal antibodies (mAbs) increased adhesion of human neutrophils to immobilized, but not soluble, fibrinogen. This intermediate state of neutrophil adhesion was defined by moderate clustering of integrin αMβ2, no increase in CBRM1/5 (a mAb specific for the activation epitope on the αM subunit) recognition, and no increase in surface expression of αMβ2, whereas phorbol myristate acetate (PMA) induced extensive changes in these 3 parameters. Furthermore, platelet-activating factor or interleukin 8 acted in concert with P-selectin for further enhancing the activation of αMβ2. We thus propose a model in which P-selectin induces an intermediate state of integrin activation and then cooperates with other extracellular stimuli to support maximal adhesion of human neutrophils.

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