Cleaved CD31 as a target for in vivo molecular imaging of inflammation

Vigne, Jean-Louis; Bay, Sylvie; Aid‐Launais, Rachida; Pariscoat, Guillaume; Rucher, Guillaume; Sénémaud, Jean; Truffier, Ariane; Anizan, Nadège; Even, Guillaume; Ganneau, Christelle; Andreata, Francesco; Borgne, Marie Le; Nicoletti, Antonino; Guludec, Dominique Le; Caligiuri, Giuseppina; Rouzet, François

doi:10.1038/s41598-019-56163-x

Cited by 9 publications

(6 citation statements)

References 31 publications

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“…In our previous studies, we demonstrated that P8RI, a CD31 agonist peptide, effectively rescued and sustained the functionality of CD31 ITIM in T lymphocytes ( Clement et al, 2015 ; Fornasa et al, 2012 ; Fornasa et al, 2010 ) and macrophages ( Andreata et al, 2018 ), thereby providing promising potential for theranostic applications ( Hoang et al, 2018 ; Vigne et al, 2019 ). In the context of neutrophils, we found that the CD31 agonist consistently sustained CD31 phosphorylation ( Figure 4—figure supplement 1A ) and clustering ( Figure 4—figure supplement 1B ) during fMLP activation ( Figure 4—figure supplement 1C ), specifically targeting the CD31 molecule ( Figure 4—figure supplement 1D ), and fine-tuning cytoskeleton dynamics ( Figure 4—figure supplement 1E ).…”

Section: Resultsmentioning

confidence: 99%

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation

Andreata

Clément

Benson

et al. 2023

eLife

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Effective neutrophil migration to sites of inflammation is crucial for host immunity. A coordinated cascade of steps allows intravascular leukocytes to counteract the shear stress, transmigrate through the endothelial layer and move towards the extravascular, static environment. Those events are tightly orchestrated by integrins but, while the molecular mechanisms leading to their activation have been characterized, the regulatory pathways promoting their detachment remain elusive. In light of this, it has long been known that Platelet-Endothelial Cell Adhesion Molecule (Pecam1, also known as CD31) deficiency blocks leukocyte transmigration at the level of the outer vessel wall, yet the associated cellular defects are controversial. In this study, we combined an unbiased proteomic study with in vitro and in vivo single-cell tracking in mice to study the dynamics and role of CD31 during neutrophil migration. We found that CD31 localizes to the uropod of migrating neutrophils along with closed β2-integrin and is required for essential neutrophil actin/integrin polarization. Accordingly, the uropod of Pecam1-/- neutrophils is unable to detach from the extracellular matrix, while antagonizing integrin binding to extracellular matrix components rescues this in vivo migratory defect. Conversely, we showed that sustaining CD31 co-signaling actively favors uropod detachment and effective migration of extravasated neutrophils to sites of inflammation in vivo. Altogether, our results suggest that CD31 acts as a molecular rheostat controlling integrin-mediated adhesion at the uropod of egressed neutrophils thereby triggering their detachment from the outer vessel wall to reach the inflammatory sites.

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Section: Resultsmentioning

confidence: 99%

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation

Andreata

Clément

Benson

et al. 2023

eLife

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“…Decreases in barrier resistivity should be accompanied by reorganization of membrane-localized tight junction proteins that line the gaps between adjacent endothelial cells. Thus, membrane-localization of CLDN-5 was assessed by fluorescent readout of spatial colocalization with platelet endothelial cell adhesion molecule 1 (PECAM-1), which is constitutively expressed along the membrane of vascular cells. , Loss of BBB integrity can manifest as a redistribution of membrane-localized CLDN-5 to increased intracellular clusters that no longer co-localize with PECAM-1 (Figure a,c). We also observed marked increases in the fluorescent readout of vascular cell adhesion molecule 1 (VCAM-1) in the bEnd.3 monolayers (Figure a,d), which typically exhibits low basal expression of VCAM-1.…”

Section: Results and Discussionmentioning

confidence: 99%

Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Blood–Brain Barrier Damage Relevant to NeuroCOVID Brain Inflammation

Chiang,

Stout,

Yanchik-Slade

et al. 2023

ACS Appl. Nano Mater.

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Despite limited evidence for infection of SARS-CoV-2 in the central nervous system, cognitive impairment is a common complication reported in "recovered" COVID-19 patients. Identification of the origins of these neurological impairments is essential to inform therapeutic designs against them. However, such studies are limited, in part, by the current status of high-fidelity probes to visually investigate the effects of SARS-CoV-2 on the system of blood vessels and nerve cells in the brain, called the neurovascular unit. Here, we report that nanocrystal quantum dot micelles decorated with spike protein (COVID-QDs) are able to interrogate neurological damage due to SARS-CoV-2. In a transwell co-culture model of the neurovascular unit, exposure of brain endothelial cells to COVID-QDs elicited an inflammatory response in neurons and astrocytes without direct interaction with the COVID-QDs. These results provide compelling evidence of an inflammatory response without direct exposure to SARS-CoV-2-like nanoparticles. Additionally, we found that pretreatment with a neuro-protective molecule prevented endothelial cell damage resulting in substantial neurological protection. These results will accelerate studies into the mechanisms by which SARS-CoV-2 mediates neurologic dysfunction.

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“…This observed change in TJ localization leading to decreased TEER is also consistent with the data from our positive control treatment with a tight junction-disrupting peptide (TJDP) derived from the first extracellular loop of Claudin-1 (37). Membrane-associated CLDN-5 was defined as CLDN-5 fluorescence colocalizing with expression of platelet endothelial cell adhesion molecule 1 (PECAM-1), which is constitutively expressed in cells of the vascular compartment and regulates vascular integrity and immune cell trafficking (38, 39). Additionally, previous reports observed induction of a pro-inflammatory state in endothelial cultures exposed to soluble S (6).…”

Section: Resultsmentioning

confidence: 99%

A Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Dysregulation of the Neurovascular Unit Relevant to Brain Inflammation

Chiang

Stout

Yanchik-Slade

et al. 2022

Preprint

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Despite limited evidence for competent infection and viral replication of SARS-CoV-2 in the central nervous system (CNS), neurologic dysfunction is a common post-acute medical condition reported in “recovered” COVID-19 patients. To identify a potential noninfectious route for SARS-CoV-2-mediated neurological damage, we constructed colloidal nanocrystal quantum dots linked to micelles decorated with spike protein (COVID-QDs) as a biomimetic to interrogate how blood-brain barrier (BBB) dysregulation may subsequently induce neuroinflammation in the absence of infection. In transwell co-culture of endothelial bEnd.3 monolayers and primary neuroglia, we exposed only the bEnd.3 monolayers to COVID-QDs and examined by fluorescence microscopy whether such treatment led to (i) increased inflammation and leakage across the bEnd.3 monolayers, (ii) permeability of the COVID-QDs across the monolayers, and (iii) induction of neuroinflammation in neuroglial cultures. The results of our study provide evidence of neuroinflammatory hallmarks in cultured neurons and astrocytes without direct exposure to SARS-CoV-2-like nanoparticles. Additionally, we found that pre-treatment of our co-cultures with a small-molecule, broad-spectrum inhibitor of mixed lineage and leucine rich repeat kinases led to reversal of the observed dysregulation in endothelial monolayers and resulted in neuroglial protection. The results reported here may serve to guide future studies into the potential mechanisms by which SARS-CoV-2 mediates neurologic dysfunction.

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Cleaved CD31 as a target for in vivo molecular imaging of inflammation

Cited by 9 publications

References 31 publications

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation

Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Blood–Brain Barrier Damage Relevant to NeuroCOVID Brain Inflammation

A Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Dysregulation of the Neurovascular Unit Relevant to Brain Inflammation

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