Endothelial ICAM-1 functions in adhesion and signaling during leukocyte recruitment

Auerbach, Scott D.; Yang, Lin; Luscinskas, Francis W.

doi:10.1007/978-3-7643-7975-9_4

Cited by 9 publications

(5 citation statements)

References 53 publications

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“…The onset of the intricate process of TEM is mediated by waves of engagement of EC adhesion-molecules to their cognate ligands on T-cells, the signaling thereof mediates the adhesion-threshold necessary to pull T-cells from the bloodstream [35]. In MS, this threshold is reached by ALCAM crosslinking CD6, followed by a secondary-wave of interaction with other ubiquitous CAMs, predominantly ICAM1 [36].…”

Section: Discussionmentioning

confidence: 99%

A homing system targets therapeutic T cells to brain cancer

Samaha

Pignata

Fousek

et al. 2018

Nature

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Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.

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Section: Discussionmentioning

confidence: 99%

A homing system targets therapeutic T cells to brain cancer

Samaha

Pignata

Fousek

et al. 2018

Nature

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“…At advanced stages of disease (16 weeks of HFD), inactivation of endothelial NCK2 decreased ICAM-1 neointimal expression in both males and females (eNck2+ vs. eNck2-, p <0.05). Because endothelial cell ICAM-1 surface expression is elevated at sites of endothelial activation (20), we also determined intimal ICAM expression, which was defined as the area of the ICAM-1 signal normalized to the area of CD31 signal in a 10 μm-thick periluminal layer (intima). Intimal ICAM-1 expression did not differ by genotype or sex in animals fed HFD for 8 weeks.…”

Section: Resultsmentioning

confidence: 99%

Endothelial NCK2 Promotes Atherosclerosis Progression in Male but not Female Nck1-null Atheroprone Mice

Bywaters

Pedraza

Trache

et al. 2022

Preprint

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A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations en face during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.

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“…When ICAM-1 binds its ligand, it causes intracellular cytoskeletal rearrangement that allows leucocyte movement across the endothelial barrier. One aspect of the cytoskeletal reorganisation that occurs in the endothelial cell docking structure is a dissociation of ezrin from the intracellular tail of ICAM-1 (Auerbach et al 2007). This study proposes a similar mechanism in UECs within the implantation chamber.…”

Section: Discussionmentioning

confidence: 99%

Ezrin and EBP50 redistribute apically in rat uterine epithelial cells at the time of implantation and in response to cell contact

2010

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Uterine epithelial cells (UECs) undergo extensive morphological remodelling in preparation for an implanting blastocyst. This remodelling involves changes in the actin cytoskeleton and surface structures including microvilli. Ezrin and ezrin-radixin-moesin-binding protein-50-kDa (EBP50) link actin filaments to intra-membranous adhesion molecules and are important molecules in polarised epithelia. The current study is the first to describe the colocalisation and molecular association of ezrin and EBP50 in rat UECs by using immunofluorescence microscopy and immunoprecipitation techniques. These proteins have also been localised in relation to uterine epithelial cytoskeletal rearrangement during early pregnancy in the rat and to the effect of apical surface contact between opposing epithelial cells, blastocyst contact and contact with a silicon filament. Immunofluorescence microscopy has revealed that ezrin and EBP50 respond to contact between opposing epithelial cells and increase apically on day 6 of pregnancy. This apical distribution is also observed in UECs in contact with a silicon filament. Ezrin and EBP50 are however absent within the implantation chamber itself, seemingly mimicking the events that take place in leucocyte-endothelium binding. Thus, ezrin and EBP50 occur apically in UECs at the time of implantation in the rat and in response to a substitute blastocyst (filament) suggesting a role for these proteins in the cytoskeletal rearrangements that facilitate uterine receptivity and blastocyst-epithelial adhesion. Their loss within the implantation chamber possibly allows the subsequent invasion of the embryo.

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Endothelial ICAM-1 functions in adhesion and signaling during leukocyte recruitment

Cited by 9 publications

References 53 publications

A homing system targets therapeutic T cells to brain cancer

A homing system targets therapeutic T cells to brain cancer

Endothelial NCK2 Promotes Atherosclerosis Progression in Male but not Female Nck1-null Atheroprone Mice

Ezrin and EBP50 redistribute apically in rat uterine epithelial cells at the time of implantation and in response to cell contact

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