Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction

Abstract

Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

“…Indeed, they found that systemically administration of GW4869 could reduce the total exosomes in serum and treat allergic, cardiac and Alzheimer's dysfunction 29, 30, 31. Thus, our findings provide a potential method to prevent endothelial inflammation and atherosclerosis.…”

Mifepristone Inhibits the Migration of Cervical Cancer Cells by Inhibiting Exocrine Secretion

“…The treatment of Cancer-associated fibroblasts by GW4869, an inhibitor of exosome release blocking exosome secretion [24], significantly reduced the survival of co-cultured epithelial cells, demonstrating an important role of cancer-associated fibroblast exosomes in chemotherapeutic drug resistance. These findings suggested the potential of exosome inhibitors as treatment options alongside other therapies [25].…”

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

“…Dynamic light scattering of A1-CM (Figure 2(a), Control A1-CM) revealed abundant EVs within the size range typical for mammalian exosomes and microvesicles (mean diameter: 161.5 nm; modal diameter: 128.6 nm). In mammalian cells, inhibition of the ceramide synthesis pathway using a small molecule inhibitor, GW4869, which targets neutral sphingomyelinase-2 (nSMase2), suppresses exosome secretion [32,33]. A1-EV levels were significantly reduced within the A1-CM in a GW4869 dose-dependent manner (Figure 2(a,b)): at 40 and 100 µM GW4869, two- and fivefold decreases in EV production were observed, respectively.…”