Neutrophil adhesion to E‐selectin under shear promotes the redistribution and co‐clustering of ADAM17 and its proteolytic substrate L‐selectin

  title={Neutrophil adhesion to E‐selectin under shear promotes the redistribution and co‐clustering of ADAM17 and its proteolytic substrate L‐selectin},
  author={Ulrich Y Schaff and Polly E. Mattila and Scott I. Simon and Bruce Walcheck},
  journal={Journal of Leukocyte Biology},
E‐selectin is expressed by the vascular endothelium and binds flowing neutrophils in the blood to facilitate their recruitment into the underlying tissue at sites of inflammation. L‐selectin on neutrophils is engaged by E‐selectin and undergoes rapid clustering and then coalescence in the trailing edge of polarizing cells. These processes are believed to increase the valency and capacity of L‐selectin to signal CD18 integrin activity. Neutrophils, upon exiting the microvasculature, down… 

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

Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended β2-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium.

E-Selectin Ligands as Mechanosensitive Receptors on Neutrophils in Health and Disease

The molecular recognition and mechanical requirements of this process are highlighted to reveal how E-selectin confers selectivity and efficiency of signaling for extravasation at sites of inflammation and the mechanism of action of a new glycomimetic antagonist targeted to the lectin domain that has shown efficacy in blocking neutrophil activation and adhesion on inflamed endothelium.

L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling

How ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.

A head-to-tail view of L-selectin and its impact on neutrophil behaviour

This review will introduce the “triad of L-selectin regulation”, highlighting the inextricable links between adhesion, signalling and ectodomain shedding and also highlighting the cytosolic proteins that interconnect them.

Adam17-dependent shedding limits early neutrophil influx but does not alter early monocyte recruitment to inflammatory sites.

Substrate and myeloid cell-type specificity of Adam17-mediated cleavage of its substrates are demonstrated, and it is shown that neutrophils and monocytes use distinct mechanisms for infiltration of tissues.

Ectodomain Shedding by ADAM17: Its Role in Neutrophil Recruitment and the Impairment of This Process during Sepsis

Excessive ADAM17 sheddase activity during sepsis thus appears to undermine in a direct and indirect manner the necessary balance between intravascular adhesion and de-adhesion events that regulate neutrophil migration into sites of infection.

ADAM10-Mediated Cleavage of ICAM-1 Is Involved in Neutrophil Transendothelial Migration

It is concluded that endothelial ADAM10 contributes in part to neutrophil transendothelial migration by cleaving ICAM-1, thereby supporting the release of neutrophils from the endothelium during the final diapedesis step.

Neutrophil Adhesion and Activation under Flow

Signaling through G‐protein‐coupled receptors, selectin ligands, Fc receptors and outside‐in signaling through integrins are all involved in neutrophil activation, but their interplay in the multistep process of recruitment is only beginning to emerge.

Neutrophils exposed to A. phagocytophilum under shear stress fail to fully activate, polarize, and transmigrate across inflamed endothelium.

This model suggests that A. phagocytophilum binding to PMN under shear flow during recruitment to inflamed endothelium interferes with normal tethering via E-selectin and navigational signaling of transendothelial migration.



Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils1

The data suggest that E-selectin is unique among selectins in its capacity for clustering sialylated ligands and transducing signals leading to neutrophil arrest in shear flow.

Cooperativity Between Selectins and β2-Integrins Define Neutrophil Capture and Stable Adhesion in Shear Flow

These data are the first to quantify adhesion efficiency mediated by selectin tethering and conformational activation of β 2-integrin in neutrophils in shear flow.

Neutrophil Tethering on E-Selectin Activates β2 Integrin Binding to ICAM-1 Through a Mitogen-Activated Protein Kinase Signal Transduction Pathway1

It is concluded that neutrophils rolling on E-selectin undergo signal transduction leading to activation of cell arrest through β2 integrins binding to ICAM-1.

Neutrophil CD18-dependent arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow can be activated through L-selectin.

Data support the conclusion that L-selectin, but not E- Selectin, can signal the transition from neutrophil rolling to cell arrest under shear flow.

Neutrophil rolling altered by inhibition of L-selectin shedding in vitro

Hydroxamic acid-based metalloprotease inhibitors block L-selectin downregulation from the cell surface of stimu-lated neutrophils, without affecting Mac-1 mobilization or gen-eral neutrophil activation, and inhibit cleavage of L- selectin in a cell-free system.

Synergy between L-selectin signaling and chemotactic activation during neutrophil adhesion and transmigration.

It is proposed that cross-linking of L-selectin and binding of agonist receptors may act synergistically to amplify neutrophil activation and emigration in the inflamed vasculature.

Signaling functions of L-selectin in neutrophils: alterations in the cytoskeleton and colocalization with CD18.

It is concluded that intracellular signals from L-selectin may enhance the microvascular sequestration of neutrophils at sites of inflammation through a combination of cytoskeletal alterations leading to cell stiffening and an increase in adhesiveness mediated through alterations in beta2 integrins.

Cytoskeletal interactions regulate inducible L-selectin clustering.

The data indicate that L-selectin's lateral mobility is regulated by interactions with the actin cytoskeleton that in turn fortifies leukocyte tethering.

ADAM‐17‐independent shedding of L‐selectin

It is speculated that separate proteolytic mechanisms of L‐selectin shedding may regulate distinct antiadhesive mechanisms, such as inducible shedding for the rapid dissociation of cell–cell interactions and constitutive shed for the homeostatic maintenance of high serum levels of soluble L‐ selectin, a potential adhesion buffer.

L-Selectin Shedding Is Independent of Its Subsurface Structures and Topographic Distribution1

Results show that the recognition site(s) for PKC-induced L-selectin shedding is exclusively contained within the ectodomain; the nature of subsurface structures and surface topography are irrelevant.