Leukocyte Breaching of Endothelial Barriers: The Actin Link

Alon, Ronen; Buul, Jaap D. van

doi:10.1016/j.it.2017.05.002

Cited by 47 publications

(47 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The endothelial cells were traditionally proposed to facilitate gap enlargement via myosin driven contraction, yet we and other groups have recently ruled out this alternative mechanism for endothelial gap formation. 10,11,32 Our new results further suggest that endothelial gap formation is simultaneously regulated by both the leukocyte nuclei and by the endothelial cytoskeleton. In addition to restricting gap widening by squeezing leukocytes, the endothelial cytoskeleton restricts the ability of the endothelial cell to be lifted above the slide by the squeezed leukocyte nucleus.…”

Section: Discussionsupporting

confidence: 60%

“…Our data indicate that the size of endothelial gaps generated by squeezing leukocytes is probably dictated by the dimension of the leukocyte nuclei more than by the resistance of the endothelial cytoskeleton to leukocyte squeezing. The endothelial cells were traditionally proposed to facilitate gap enlargement via myosin driven contraction, yet we and other groups have recently ruled out this alternative mechanism for endothelial gap formation . Our new results further suggest that endothelial gap formation is simultaneously regulated by both the leukocyte nuclei and by the endothelial cytoskeleton.…”

Section: Discussionmentioning

confidence: 63%

“…The endothelial resistance to nuclear squeezing is low, likely because of the high elasticity of the endothelial stress fibers and the fast turnover of the short actin filaments interlaced in between these actin bundles. 10,32 Our results also elude to the possibility that the pulling and pushing forces normally exerted by the leukocyte actomyosins are sufficiently high to propel even the stiffer nucleus of lamin A overexpressing leukocytes into the leukocyte pseudopodia and thereby override the low mechanical resistance imposed by the endothelial cytoskeleton. These actomyosin derived forces are also strong enough to squeeze the stiff lamin A enriched nuclei through thin and porous barriers, such as those imposed by matrigels.…”

Section: Discussionmentioning

confidence: 74%

See 2 more Smart Citations

Frontline Science: Elevated nuclear lamin A is permissive for granulocyte transendothelial migration but not for motility through collagen I barriers

Yadav

Feigelson

Roncato

et al. 2018

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

Transendothelial migration (TEM) of lymphocytes and neutrophils is associated with the ability of their deformable nuclei to displace endothelial cytoskeletal barriers. Lamin A is a key intermediate filament component of the nuclear lamina that is downregulated during granulopoiesis. When elevated, lamin A restricts nuclear squeezing through rigid confinements. To determine if the low lamin A expression by leukocyte nuclei is critical for their exceptional squeezing ability through endothelial barriers, we overexpressed this protein in granulocyte-like differentiated HL-60 cells. A 10-fold higher lamin A expression did not interfere with chemokinetic motility of these granulocytes on immobilized CXCL1. Furthermore, these lamin A high leukocytes exhibited normal chemotaxis toward CXCL1 determined in large pore transwell barriers, but poorly squeezed through 3 μm pores toward identical CXCL1 gradients. Strikingly, however, these leukocytes successfully completed paracellular TEM across inflamed endothelial monolayers under shear flow, albeit with a small delay in nuclear squeezing into their sub-endothelial pseudopodia. In contrast, CXCR2 mediated granulocyte motility through collagen I barriers was dramatically delayed by lamin A overexpression due to a failure of lamin A high nuclei to translocate into the pseudopodia of the granulocytes. Collectively, our data predict that leukocytes maintain a low lamin A content in their nuclear lamina in order to optimize squeezing through extracellular collagen barriers but can tolerate high lamin A content when crossing the highly adaptable barriers presented by the endothelial cytoskeleton.

show abstract

Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 74%

See 1 more Smart Citation

Frontline Science: Elevated nuclear lamin A is permissive for granulocyte transendothelial migration but not for motility through collagen I barriers

Yadav

Feigelson

Roncato

et al. 2018

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The interaction between the leukocyte integrins and their ligands, such as immunoglobulin-like intercellular adhesion molecules, mediates firm adhesion to the endothelium, enabling the leukocyte to force its way between endothelial cells (52). During this transendothelial migration, the leukocyte squeezes in between two neighboring endothelial cells without disrupting the integrity of the endothelial barrier (61). For neutrophils, this is accomplished by homotypic binding of platelet endothelial cell adhesion molecule-1 (PECAM-1) on the neutrophil with PECAM-1 within the endothelial junction (62).…”

Section: The Importance Of Chemokine-glycosaminoglycan Interactions Lmentioning

confidence: 99%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

View full text Add to dashboard Cite

Leukocyte migration into tissues depends on the activity of chemokines that form concentration gradients to guide leukocytes to a specific site. Interaction of chemokines with their specific G protein-coupled receptors (GPCRs) on leukocytes induces leukocyte adhesion to the endothelial cells, followed by extravasation of the leukocytes and subsequent directed migration along the chemotactic gradient. Interaction of chemokines with glycosaminoglycans (GAGs) is crucial for extravasation in vivo. Chemokines need to interact with GAGs on endothelial cells and in the extracellular matrix in tissues in order to be presented on the endothelium of blood vessels and to create a concentration gradient. Local chemokine retention establishes a chemokine gradient and prevents diffusion and degradation. During the last two decades, research aiming at reducing chemokine activity mainly focused on the identification of inhibitors of the interaction between chemokines and their cognate GPCRs. This approach only resulted in limited success. However, an alternative strategy, targeting chemokine-GAG interactions, may be a promising approach to inhibit chemokine activity and inflammation. On this line, proteins derived from viruses and parasites that bind chemokines or GAGs may have the potential to interfere with chemokine-GAG interactions. Alternatively, chemokine mimetics, including truncated chemokines and mutant chemokines, can compete with chemokines for binding to GAGs. Such truncated or mutated chemokines are characterized by a strong binding affinity for GAGs and abrogated binding to their chemokine receptors. Finally, Spiegelmers that mask the GAG-binding site on chemokines, thereby preventing chemokine-GAG interactions, were developed. In this review, the importance of GAGs for chemokine activity in vivo and strategies that could be employed to target chemokine-GAG interactions will be discussed in the context of inflammation.

show abstract

“…In the endothelium, actin filaments exist within different structures: filament bundles, such as stress fibers and junction-associated actin filaments (JAAFs), filopodia, lamellipodia-like protrusions and the membrane cytoskeleton (for reviews, see Drenckhahn, 1982;Lampugnani, 2010;Marcos-Ramiro et al, 2014;Schnittler et al, 2014;Alon and van Buul, 2017;Schnoor et al, 2017a). Actin-driven membrane protrusions at EC junctions have been suggested to act as important regulators in cell junction dynamics (Hoelzle and Svitkina, 2012;Martinelli et al, 2013;Breslin et al, 2015;Belvitch et al, 2017;Paatero et al, 2018).…”

Section: Jail Formation At Endothelial Junctionsmentioning

confidence: 99%

Putting VE-cadherin into JAIL for junction remodeling

Cao

Schnittler

2019

Journal of Cell Science

View full text Add to dashboard Cite

Junction dynamics of endothelial cells are based on the integration of signal transduction, cytoskeletal remodeling and contraction, which are necessary for the formation and maintenance of monolayer integrity, but also enable repair and regeneration. The VE-cadherincatenin complex forms the molecular basis of the adherence junctions and cooperates closely with actin filaments. Several groups have recently described small actin-driven protrusions at the cell junctions that are controlled by the Arp2/3 complex, contributing to cell junction regulation. We identified these protrusions as the driving force for VE-cadherin dynamics, as they directly induce new VE-cadherin-mediated adhesion sites, and have accordingly referred to these structures as junction-associated intermittent lamellipodia (JAIL). JAIL extend over only a few microns and thus provide the basis for a subcellular regulation of adhesion. The local (subcellular) VE-cadherin concentration and JAIL formation are directly interdependent, which enables autoregulation. Therefore, this mechanism can contribute a subcellularly regulated adaptation of cell contact dynamics, and is therefore of great importance for monolayer integrity and relative cell migration during wound healing and angiogenesis, as well as for inflammatory responses. In this Review, we discuss the mechanisms and functions underlying these actin-driven protrusions and consider their contribution to the dynamic regulation of endothelial cell junctions.

show abstract

Leukocyte Breaching of Endothelial Barriers: The Actin Link

Cited by 47 publications

References 89 publications

Frontline Science: Elevated nuclear lamin A is permissive for granulocyte transendothelial migration but not for motility through collagen I barriers

Frontline Science: Elevated nuclear lamin A is permissive for granulocyte transendothelial migration but not for motility through collagen I barriers

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

Putting VE-cadherin into JAIL for junction remodeling

Contact Info

Product

Resources

About