Inhibiting extracellular vesicles formation and release: a review of EV inhibitors

Catalano, Mariadelva; O’Driscoll, Lorraine

doi:10.1080/20013078.2019.1703244

Cited by 420 publications

(431 citation statements)

References 104 publications

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“…Interestingly, the release of neutrophil-derived EVs in our model system requires N-SMase and Rab27 activity, which have previously been described to regulate the release of small EVs (Catalano and O'Driscoll, 2019;Majumdar et al, 2016;Raposo and Stoorvogel, 2013). However, whether such EVs harbor the LTB4-synthesizing machinery and to what extent they utilize Itgb2 to tether to the inflamed endothelium remains to be ascertained.…”

Section: The Autocrine/paracrine Action Of Ltb4 Requires Ev Release Fmentioning

confidence: 83%

The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

Subramanian

Melis

Chen

et al. 2019

Preprint

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The eicosanoid Leukotriene B4 (LTB4) relays chemotactic signals to direct neutrophil interstitial migration through its receptor, BLT1. However, whether the LTB4-BLT1 axis relays signals during intravascular neutrophil response has not been addressed. Here, we report that LTB4 produced by neutrophils acts as an autocrine/paracrine signal to drive neutrophil recruitment, arrest, and extravasation during infection in living mice. Using Intravital Subcellular Microscopy (ISMic), we reveal that LTB4 elicits sustained cell polarization and adhesion response during neutrophil arrest in vivo. Specifically, LTB4 signaling coordinates the dynamic redistribution of non-muscle Myosin IIA (NMIIA) and b2-integrin (Itgb2), whose retention at the cell surface facilitates neutrophil arrest. Notably, we also found that inhibition of the machinery regulating exosomes release from the cell blocks the autocrine/paracrine LTB4-dependent extravasation response. Overall, our study reveals a critical function for LTB4 in promoting neutrophil communication in the vasculature during early inflammation response. RESULTS The LTB4-BLT1 axis is required for the persistent recruitment, rolling, arrest and extravasation of neutrophils in response to infectionTo assess the role of the LTB4-BLT1 axis during neutrophil extravasation, we developed an in vivo inflammation model based on the injection of heat-killed E. coli into the hind footpad of anesthetized mice (Figs. 1A and 1B). First, we set up the optimal conditions for imaging neutrophil extravasation in a mouse strain expressing GFP in myeloid cells (LyzM-GFP) 13 . Upon infection, neutrophils accumulated in the blood vessels and extravasated ( Fig. 1A right panel, pink arrows, and Movie S1), whereas under control conditions, we observed no neutrophil retention in the vasculature (Fig. 1A left panel and Movie S1). Similar results were obtained using an adoptive transfer model, where neutrophils were purified from the bone marrow of a WT mouse, labeled with a cellpermeant fluorescent dye and injected into a recipient WT mouse (Fig. 1B, pink arrows and Movie S2). Using the latter approach, we infected the footpad of Alox5 -/mice, which are incapable of producing LTB4, and introduced neutrophils purified from either WT or Alox5 -/mice (Fig. 1C). We observed that up to 3 hours post-infection, the recruitment of Alox5 -/neutrophils to the infected footpad was significantly reduced in comparison to WT neutrophils (Figs. 1C & 1D). To gain further insights into this process, we visualized the intravascular dynamics of WT and Alox5 -/neutrophils introduced into the infected Alox5 -

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Section: The Autocrine/paracrine Action Of Ltb4 Requires Ev Release Fmentioning

confidence: 83%

The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

Subramanian

Melis

Chen

et al. 2019

Preprint

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“…Thus, lymphoma B-cell EVs derived from TP53-deficient cells specifically abrogated Fc-receptor dependent macrophage anti-tumor effects, such as ADCP. Next,, to address the functional role of EVs on the lymphoma B-cell-macrophage crosstalk, we generated lymphoma B-cells unable to release EVs by depleting RAB27A expression via the CRISPR/Cas9 approach ( Figure 5F) (Catalano and O'Driscoll, 2020). By NTA and protein concentration determination, we proved that RAB27A knockout cells (RAB27A-KO) showed deeply reduced ability to produce EVs ( Figure 5G).…”

Section: Extracellular Vesicle Secretion From Tp53-deficient Lymphomamentioning

confidence: 96%

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

Izquierdo

Vorholt

Sackey

et al. 2020

Preprint

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Highlights• Loss of TP53 in B-cell lymphoma induces resistance towards chemoimmunotherapy (CIT) by inhibition of macrophage effector function through PDL1 upregulation • Loss of TP53 increases formation of extracellular vesicles (EVs) carrying PDL1 • EVs inhibit antibody-mediated cellular phagocytosis (ADCP), a key macrophage effector function in CIT • Targeting PDL1 on EVs with immune checkpoint inhibitors overcomes TP53-mediated resistance to CIT Summary Chemoimmunotherapy (CIT) is the standard of care in B-cell malignancies. It is relying on synergistic effects of alkylating chemotherapy and monoclonal antibodies via secretory crosstalk with effector macrophages. Here, we observed that loss of p53 function mediates resistance to CIT by suppressing macrophage phagocytic function. Loss of p53 leads to an upregulation of PDL1 and an increased formation of extracellular vesicles (EVs). EVs directly inhibit macrophage phagocytosis by PDL1 surface expression. Suppression of phagocytic function by lymphoma cell-derived EVs could be abrogated by pre-incubation of EVs with anti-PDL1 antibodies, CRISPR-KO of PDL1 and abrogation of EV formation by RAB27A-KO in lymphoma cells. Immune checkpoint inhibition represents a viable 3 strategy to overcome EV-mediated resistance to chemoimmunotherapy in lymphoma. SignificanceLoss of TP53 mediates cell autonomous resistance to genotoxic chemotherapy, moreover non-cell autonomous effects may cause therapy resistance mediated by the tumor microenvironment. We identify a TP53dependent mechanism that mediates resistance to synergistic chemoimmunotherapy by increasing formation of EVs and expression of the PDL1 immune checkpoint. PDL1 on EVs is directly responsible for macrophage suppression, preventing the exertion of the essential effector function of antibody-dependent cellular phagocytosis. This novel mechanism of resistance is in turn targetable by PDL1 checkpoint inhibition. Enhanced EV-release and immune checkpoint expression in lymphoma are novel mechanisms of macrophage modulation in the lymphoma microenvironment.We provide a novel principle of resistance to chemoimmunotherapy (CIT) representing of immediate relevance to treatment of refractory B-cell lymphoma.

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“…A third, and still nascent, approach related to EV-based therapy is based on the concept that interfering with EV secretion or uptake may attenuate harmful effects on target cells [11,64]. In this regard, several pharmacological agents are being explored that have been shown to inhibit EV trafficking, modify lipid metabolism, or decrease EV secretion.…”

Section: Therapeutic Potential Of Evsmentioning

confidence: 99%

“…In this regard, several pharmacological agents are being explored that have been shown to inhibit EV trafficking, modify lipid metabolism, or decrease EV secretion. However, the complexity of EV biogenesis poses significant challenges to the development of specific agents able to selectively block EV production (see Reference [64] for an in-depth review of this topic).…”

Section: Therapeutic Potential Of Evsmentioning

confidence: 99%

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

Hernández

Arab

Reyes

et al. 2020

Cells

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In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.

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Inhibiting extracellular vesicles formation and release: a review of EV inhibitors

Cited by 420 publications

References 104 publications

The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

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Inhibiting extracellular vesicles formation and release: a review of EV inhibitors

Cited by 420 publications

References 104 publications

The LTB4-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

The LTB4-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

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Product

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The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation

The LTB₄-BLT1 axis regulates actomyosin and β2 integrin dynamics during neutrophil extravasation