Extracellular vesicle-mediated macrophage activation: An insight into the mechanism of thioredoxin-mediated immune activation

Abstract

Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepatocytes on macrophage activation. EVs from H9c2 rat cardiomyocytes (H9c2 EVs) and EVs from FL83b mouse hepatocytes (FL83 b EVs) have different levels of protein-bound 4-hydroxynonenal and thus different immunostimulatory effects on mouse RAW264.7 macrophages. H9c2 EVs but not FL83 b EVs induced both pro-inflammatory and anti-inflammatory macrophage activation, mediated by NFκB and Nrf-2 pathways, respectively. DOX enhanced the effects of H9c2 EVs but not FL83 b EVs. While EVs from DOX-treated H9c2 cells (H9c2 DOXEVs) suppressed mitochondrial respiration and increased glycolysis of macrophages, EVs from DOX-treated FL83b cells (FL83b DOXEVs) enhanced mitochondrial reserve capacity. Mechanistically, the different immunostimulatory functions of H9c2 EVs and FL83 b EVs are regulated, in part, by the redox status of the cytoplasmic thioredoxin 1 (Trx1) of macrophages. H9c2 DOXEVs lowered the level of reduced Trx1 in cytoplasm while FL83b DOXEVs did the opposite. Trx1 overexpression alleviated the effect of H9c2 DOXEVs on NFκB and Nrf-2 activation and prevented the upregulation of their target genes. Our findings identify EVs as a novel Trx1-mediated redox mediator of immune response, which greatly enhances our understanding of innate immune responses during cancer therapy.

Exenatide inhibits NF-κB and attenuates ER stress in diabetic cardiomyocyte models

“…These results demonstrate that Exenatide exerts protective effects on cardiomyocytes through the NF-κB signaling pathway, in agreement with previous studies [42,43]. Indeed, such studies have shown that inhibition of NF-κB prevents heart inflammation [44,45] while improving oxidative stress and countering the downregulation of anti-oxidative factors [46,47]. In addition, myocardial damage induced by a high-fat diet was also normalized by NF-κB inhibition [48].…”

Extracellular Vesicles in Innate Immune Cell Programming

“…In a model of doxorubicin toxicity cardiac EV treated with doxorubicin showed greater preponderance for macrophage activation than doxorubicin treated hepatocyte derived EV, which did not activate macrophages [81]. It remains unclear whether these differential effects of doxorubicin induced EV on macrophage activation are due to cell type difference and/or difference in EV-cargo, i.e., the presence of particular EV-proteins or EV-miRNAs.…”

Cardioprotective Role of Melatonin in Acute Myocardial Infarction

“…In rats that lack RORα receptors, the size of the myocardial infarct and degree of cardiac dysfunction after cell injury increases significantly (He et al, 2016). The related pathways by which melatonin executes its cardiac protective role via the receptor pathway includes the reperfusion injury salvage kinase (RISK) pathway, SAFE pathway and Notch pathway, with a complex association among the downstream signaling molecules (Botker et al, 2018;Coverstone et al, 2018;Shanmugam et al, 2019;Yarana et al, 2019).…”