scholarly journals Endothelial CD99 supports arrest of mouse neutrophils in venules and binds to neutrophil PILRs

Blood ◽  
2017 ◽  
Vol 129 (13) ◽  
pp. 1811-1822 ◽  
Author(s):  
Debashree Goswami ◽  
Sigrid März ◽  
Yu-Tung Li ◽  
Annette Artz ◽  
Kerstin Schäfer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Integrin Activation ◽  
Β2 Integrin ◽  
Neutrophil Extravasation ◽  
Key Points

Key Points Only CD99 on endothelial cells, not on neutrophils, participates in neutrophil extravasation in vivo. A new function was found for CD99: support of chemokine-induced β2-integrin activation and neutrophil arrest by binding to PILR.

scholarly journals FcγRIIB on liver sinusoidal endothelial cells is essential for antibody-induced GPVI ectodomain shedding in mice

Blood ◽  
2016 ◽  
Vol 128 (6) ◽  
pp. 862-865 ◽  
Author(s):  
David Stegner ◽  
Michael Popp ◽  
Viola Lorenz ◽  
Jacqueline K. Wax ◽  
J. Engelbert Gessner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Sinusoidal Endothelial Cell ◽  
Liver Sinusoidal Endothelial Cell ◽  
Ectodomain Shedding ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Key Points

Key Points Antibody-induced shedding of platelet GPVI in vivo and the associated transient thrombocytopenia depend on liver sinusoidal endothelial cell-expressed FcγRIIB.

scholarly journals Endothelial cells translate pathogen signals into G-CSF–driven emergency granulopoiesis

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1393-1403 ◽  
Author(s):  
Steffen Boettcher ◽  
Rahel C. Gerosa ◽  
Ramin Radpour ◽  
Judith Bauer ◽  
Franziska Ampenberger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
E Coli ◽  
Key Points

Key Points ECs express Tlr4 and Myd88 and, after in vivo LPS or E coli stimulation, are the prime sources of G-CSF. ECs are sensors of systemically spread pathogens and subsequent drivers of BM emergency granulopoiesis.

scholarly journals The LTB4–BLT1 axis regulates actomyosin and β2-integrin dynamics during neutrophil extravasation

2020 ◽  
Vol 219 (10) ◽  
Author(s):  
Bhagawat C. Subramanian ◽  
Nicolas Melis ◽  
Desu Chen ◽  
Weiye Wang ◽  
Devorah Gallardo ◽  
...  
Keyword(s):  
Neutrophil Migration ◽  
Extracellular Vesicle ◽  
Leukotriene B4 ◽  
Cell Polarization ◽  
Sterile Inflammation ◽  
Β2 Integrin ◽  
Neutrophil Extravasation ◽  
Neutrophil Response ◽  
Muscle Myosin

The eicosanoid leukotriene B4 (LTB4) relays chemotactic signals to direct neutrophil migration to inflamed sites through its receptor BLT1. However, the mechanisms by which the LTB4–BLT1 axis relays chemotactic signals during intravascular neutrophil response to inflammation remain unclear. Here, we report that LTB4 produced by neutrophils acts as an autocrine/paracrine signal to direct the vascular recruitment, arrest, and extravasation of neutrophils in a sterile inflammation model in the mouse footpad. Using intravital subcellular microscopy, we reveal that LTB4 elicits sustained cell polarization and adhesion responses during neutrophil arrest in vivo. Specifically, LTB4 signaling coordinates the dynamic redistribution of non-muscle myosin IIA and β2-integrin, which facilitate neutrophil arrest and extravasation. Notably, we also found that neutrophils shed extracellular vesicles in the vascular lumen and that inhibition of extracellular vesicle release blocks LTB4-mediated autocrine/paracrine signaling required for neutrophil arrest and extravasation. Overall, we uncover a novel complementary mechanism by which LTB4 relays extravasation signals in neutrophils during early inflammation response.

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 Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE−/− mice and activate platelets via TLR2

Blood ◽  
2016 ◽  
Vol 127 (21) ◽  
pp. 2618-2629 ◽  
Author(s):  
Sudipta Biswas ◽  
Liang Xin ◽  
Soumya Panigrahi ◽  
Alejandro Zimman ◽  
Hua Wang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Signaling Pathways ◽  
Cross Talk ◽  
Integrin Activation ◽  
Key Points ◽  
Oxidatively Modified ◽  
Activation Signaling

Key Points CAP-PEs, a novel type of oxidatively modified phospholipids, are present in vivo. CAP-PEs can activate platelets via TLRs by inducing a cross-talk between innate immunity and integrin activation signaling pathways.

scholarly journals Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation

Blood ◽  
2016 ◽  
Vol 128 (23) ◽  
pp. 2729-2733 ◽  
Author(s):  
Hisashi Kato ◽  
Yozo Nakazawa ◽  
Yumi Kurokawa ◽  
Hirokazu Kashiwagi ◽  
Yoichiro Morikawa ◽  
...  
Keyword(s):  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Integrin Activation ◽  
Activation Kinetics ◽  
Β2 Integrin ◽  
Key Points

Key Points In human CalDAG-GEFI deficiency, αIIbβ3 activation was impaired, but not agonist-induced neutrophil β2 integrin activation. Delayed αIIbβ3 activation kinetics was associated with severe bleeding tendency in CalDAG-GEFI deficiency.

scholarly journals Blocking neutrophil integrin activation prevents ischemia–reperfusion injury

2015 ◽  
Vol 212 (8) ◽  
pp. 1267-1281 ◽  
Author(s):  
Tadayuki Yago ◽  
Brian G. Petrich ◽  
Nan Zhang ◽  
Zhenghui Liu ◽  
Bojing Shao ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Integrin Activation ◽  
Β2 Integrin ◽  
Renal Ischemia Reperfusion Injury ◽  
Slow Rolling

Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia–reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin’s capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia–reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin–mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin–mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia–reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable.

scholarly journals Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow

Blood ◽  
2017 ◽  
Vol 130 (19) ◽  
pp. 2101-2110 ◽  
Author(s):  
Vasilios A. Morikis ◽  
Shannon Chase ◽  
Ted Wun ◽  
Elliot L. Chaikof ◽  
John L. Magnani ◽  
...  
Keyword(s):  
Shear Flow ◽  
Adhesion Molecule ◽  
Bond Formation ◽  
Integrin Activation ◽  
Β2 Integrin ◽  
High Affinity ◽  
Intracellular Adhesion Molecule ◽  
Key Points ◽  
Inflamed Endothelium ◽  
Catch Bonds

Key Points Neutrophils rolling on E-selectin form catch-bonds with L-selectin that mechanosignal β2-integrin bond formation with intracellular adhesion molecule 1. Rivipansel blocks E-selectin recognition of sLex on L-selectin, thereby antagonizing outside-in signaling of high-affinity β2-integrin.

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