Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts

Dieudé, Mélanie; Turgeon, Julie; Rimbaud, Annie Karakeussian; Beillevaire, Déborah; Qi, Shijie; Patey, Nathalie; Gaboury, Louis; Boilard, Éric; Hébert, Marie‐Josée

doi:10.1111/ajt.15707

Cited by 27 publications

(35 citation statements)

References 44 publications

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“…Endothelial cells are the guardians of vascular homeostasis, they regulate leukocyte trafficking, coagulation, and vascular tone and different vascular beds display important functional differences and stress response. However, we determined previously that ApoExo are released not only by HUVECs, our model system but also by murine aortic endothelial cells as well as other cellular constituents of the vessel wall 13,20 . The present results suggest that the release of ApoExo by damaged endothelial cells can have important and broad repercussions on vascular functions due to their capacity to access the bloodstream, resist degradation and impact endothelial cells throughout the vascular tree.…”

Section: Discussionmentioning

confidence: 93%

“…ApoExo are known to foster inflammation in naïve and transplanted mice in addition to promoting the production of autoantibodies through a proteasome-dependent mechanism 13,20 . However, inhibiting the proteasome activity of ApoExo did not alleviate the endothelial phenotype induced by ApoExo suggesting that mediators other than the proteasome are responsible for this effect (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…They are characterized by the expression of an active 20S proteasome core complex regulating their immunogenic activity. Indeed, ApoExo, contrary to apoptotic bodies, induce a pro-inflammatory response in naïve and transplanted mice and fuel the production of autoantibodies 13,20 . Inhibiting the proteasome activity of ApoExo with bortezomib largely reduces their immunogenic activity.…”

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confidence: 99%

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Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway

Migneault

Dieudé

Turgeon

et al. 2020

Sci Rep

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Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture. Caspase-3 dependent death of microvascular endothelial cells leads to the release of unique apoptotic exosome-like vesicles (Apoexo). Here, we evaluate the impact of Apoexo on endothelial gene expression and function in the context of a pro-apoptotic stimulus. Endothelial cells exposed to ApoExo differentially express genes involved in cell death, inflammation, differentiation, and cell movement. Endothelial cells exposed to Apoexo showed inhibition of apoptosis, improved wound closure along with reduced angiogenic activity and reduced expression of endothelial markers consistent with the first phase of endothelial-to-mesenchymal transition (endoMT). ApoExo interaction with endothelial cells also led to NF-κB activation. NF-κB is known to participate in endothelial dysfunction in numerous diseases. Silencing NF-κB reversed the anti-apoptotic effect and the pro-migratory state and prevented angiostatic properties and CD31 downregulation in endothelial cells exposed to ApoExo. This study identifies vascular injury-derived extracellular vesicles (ApoExo) as novel drivers of NF-κB activation in endothelial cells and demonstrates the pivotal role of this signaling pathway in coordinating ApoExoinduced functional changes in endothelial cells. Hence, targeting ApoExo-mediated NF-κB activation in endothelial cells opens new avenues to prevent endothelial dysfunction.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway

Migneault

Dieudé

Turgeon

et al. 2020

Sci Rep

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“…Overtime, the chronic antibody‐medicated rejection can develop and cause gradual deterioration, leading to renal failure, and proteinuria. The rejection process could be mediated by various EVs (Cardinal et al, 2018; Dieude et al, 2020; Jung et al, 2020), which are released from the dead cells of the donor tissue. The EVs from donor tissue may carry autoantigens that trigger the production of autoantibodies, called donor specific antibody, by B cells of the recipients, thus contributing to the antibody‐mediated rejection.…”

Section: Evs In Transplantation Rejectionmentioning

confidence: 99%

Extracellular vesicles mediate cellular interactions in renal diseases—Novel views of intercellular communications in the kidney

Zhang

Liu

2021

Journal Cellular Physiology

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The kidney is a complicated and important internal organ receiving approximately 20% of the cardiac output and mediates numerous pathophysiologic actions. These include selectively filtering macromolecules of the blood, exquisite reclaimation of electrolyctes, urine concentration via an elegant osmotic mechanism, and excretion of an acid load. In addition, the renal tubules carry out secretory functions and produce hormones and cytokines. The kidney receives innervation and hormonal regulation. Therefore, dysfunction of the kidney leads to retention of metabolic waste products, and/or significant proteinuria and hematuria. In the past several decades, the role of extracellular vesicles (EVs) in intercellular communications, and the uptake of EVs by recipient cells through phagocytosis and endocytosis have been elucidated. The new knowledge on EVs expands over the classical mechanisms of cellular interaction, and may change our way of thinking of renal pathophysiology in the subcellular scale. Based on some ultrastructural discoveries in the kidney, this review will focus on the role of EVs in intercellular communications, their internalization by recipient cells, and their relationship to renal pathology.

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“…Production of autoantibodies may relate to viral infections, molecular mimicry, cryptic antigen exposure, [27][28][29][30][31][32] or as yet unrecognized mechanisms. Autoantibodies produced post-transplant could result from immunotherapy-induced loss of regulatory T-cell proliferation and loss of tolerance to self-antigens.…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B are Increased in Patients with Kidney Allograft Antibody-Mediated Rejection

Clotet-Freixas

Kotlyar

McEvoy

et al. 2020

Preprint

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Antibody-mediated rejection (AMR) causes >50% of late kidney graft losses. Although donor-specific antibodies (DSA) against HLA cause AMR, antibodies against non-HLA antigens are also linked to rejection. Identifying key non-HLA antibodies will improve our understanding of antibody-mediated injury. We analyzed non-HLA antibodies using protein microarrays in sera from 91 kidney transplant patients with AMR, mixed rejection, acute cellular rejection (ACR), or acute tubular necrosis (ATN). IgM and IgG antibodies against 134 non-HLA antigens were measured pre-transplant, at the time of biopsy-proven diagnosis, and post-diagnosis. Findings were validated in 60 kidney transplant patients from an independent cohort. Seventeen non-HLA antibodies were significantly increased (p<0.05) in AMR and mixed rejection compared to ACR or ATN pre-transplant, nine at diagnosis and six post-diagnosis. AMR and mixed cases showed significantly increased pre-transplant levels of IgG anti-Ro/SS-A and anti-CENP-B, compared to ACR. Together with IgM anti-CENP-B and anti-La/SS-B, these antibodies were also significantly increased in AMR/mixed rejection at diagnosis. Increased IgG anti-Ro/SS-A and anti-CENP-B pre-transplant and at diagnosis, and IgM anti-La/SS-B at diagnosis, were associated with the presence of microvascular lesions, but not with tubulitis or interstitial/total inflammation. All three antibodies were associated with the presence of class-II DSA (p<0.05). Significantly increased IgG anti-Ro/SS-A in AMR/mixed compared to ACR (p=0.01), and numerically increased IgM anti-CENP-B (p=0.05) and anti-La/SS-B (p=0.06), were validated in the independent cohort. This is the first study that implicates autoantibodies against Ro/SS-A and CENP-B in AMR. These non-HLA antibodies may participate in the crosstalk between autoimmunity and alloimmunity in kidney AMR.

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Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts

Cited by 27 publications

References 44 publications

Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway

Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway

Extracellular vesicles mediate cellular interactions in renal diseases—Novel views of intercellular communications in the kidney

Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B are Increased in Patients with Kidney Allograft Antibody-Mediated Rejection

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