Abstract:Sepsis is a life-threatening organ dysfunction, caused by dysregulation of the host response to infection. To understand the underlying mechanisms of sepsis, the vast spectrum of extracellular vesicles (EVs) is gaining importance in this research field. A connection between EVs and sepsis was shown in 1998 in an endotoxemia pig model. Since then, the number of studies describing EVs as markers and mediators of sepsis increased steadily. Extracellular vesicles in sepsis could be friends and foes at the same tim… Show more
“…EV secretion and NET casting are commonly observed in pathological conditions, including systemic inflammation 17 , 36 . They are seemingly well-understood structures in terms of formation and basic functions yet their mutual interactions/dependency, and thus overall impact on pathological conditions, remain mostly unknown.…”
Section: Discussionmentioning
confidence: 99%
“…A connection between EVs and sepsis was first shown over two decades ago in an endotoxemia pig model 16 , 17 . Since then, the topic was intensively explored due to EVs diversity, wide spectrum of activities and observation that they act as a double-edged sword being pro- and anti-inflammatory/pro-coagulant 18 – 20 .…”
Extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) are pivotal bioactive structures involved in various processes including inflammation. Herein we report the interactions between EVs and NETs during murine endotoxemia studied in situ directly in the vasculature (cremaster muscle, liver sinusoids) using intravital microscopy (IVM). We captured NETs and EV release in real time by both non- and polarized neutrophils in liver but not in cremaster vasculature. When comparing numbers of circulating EVs of various origin (nanoparticle tracking analysis—NTA, flow cytometry) with those interacting with endothelium and NETs (IVM) we observed that whereas platelet and monocyte/macrophage-derived EVs dominate in blood and peritoneal lavage, respectively, mostly neutrophil-derived EVs interact with the vascular lining, NETs and leukocytes. Despite the interaction, NETs do not affect EV formation as NET release inhibition did not alter EV release. However, EVs inhibit NETs formation and in particular, erythrocyte-derived EVs downregulate NET release and this effect is mediated via Siglec-E-dependent interactions with neutrophils. Overall, we report that EVs are present in NETs in vivo and they do modulate their release but the process in not bidirectional. Moreover, EVs isolated from body fluids might not reflect their importance in direct endothelial- and leukocyte-related interactions.
“…EV secretion and NET casting are commonly observed in pathological conditions, including systemic inflammation 17 , 36 . They are seemingly well-understood structures in terms of formation and basic functions yet their mutual interactions/dependency, and thus overall impact on pathological conditions, remain mostly unknown.…”
Section: Discussionmentioning
confidence: 99%
“…A connection between EVs and sepsis was first shown over two decades ago in an endotoxemia pig model 16 , 17 . Since then, the topic was intensively explored due to EVs diversity, wide spectrum of activities and observation that they act as a double-edged sword being pro- and anti-inflammatory/pro-coagulant 18 – 20 .…”
Extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) are pivotal bioactive structures involved in various processes including inflammation. Herein we report the interactions between EVs and NETs during murine endotoxemia studied in situ directly in the vasculature (cremaster muscle, liver sinusoids) using intravital microscopy (IVM). We captured NETs and EV release in real time by both non- and polarized neutrophils in liver but not in cremaster vasculature. When comparing numbers of circulating EVs of various origin (nanoparticle tracking analysis—NTA, flow cytometry) with those interacting with endothelium and NETs (IVM) we observed that whereas platelet and monocyte/macrophage-derived EVs dominate in blood and peritoneal lavage, respectively, mostly neutrophil-derived EVs interact with the vascular lining, NETs and leukocytes. Despite the interaction, NETs do not affect EV formation as NET release inhibition did not alter EV release. However, EVs inhibit NETs formation and in particular, erythrocyte-derived EVs downregulate NET release and this effect is mediated via Siglec-E-dependent interactions with neutrophils. Overall, we report that EVs are present in NETs in vivo and they do modulate their release but the process in not bidirectional. Moreover, EVs isolated from body fluids might not reflect their importance in direct endothelial- and leukocyte-related interactions.
“…In sepsis, the role of exosomes has been summarized recently 14 , exosomes of different cellular origin were suggested as potential sepsis biomarkers. They ensure the diagnosis of sepsis earlier than classical clinical in ammation markers, such as CRP, leucocyte count, or IL-6 14 . Exosome-derived miRNAs have been well investigated for the diagnosis and survival prediction of sepsis, and can serve as novel biomarkers for the development of sepsis 15 .However, there are still many unknown and unexplored factors of exosomes' diagnostic value in clinic.…”
Section: Introductionmentioning
confidence: 99%
“…A growing body of evidence indicates that exosomes play a critical biological role in cellular interactions and in uence a broad variety of cellular activities in health and disease 13 . In sepsis, the role of exosomes has been summarized recently 14 , exosomes of different cellular origin were suggested as potential sepsis biomarkers. They ensure the diagnosis of sepsis earlier than classical clinical in ammation markers, such as CRP, leucocyte count, or IL-6 14 .…”
Sepsis, a life-threatening clinical issue caused by infection, can be diagnosed early through the analysis of exosomes in plasma. Plasma exosomes were extracted and identified by group (a sepsis group, a non-sepsis group, and a healthy control group). iTRAQ was used to identify the differentially expressed proteins among the three groups. The identified proteins were measured by ELISA in plasma samples. LCN2 and MGP were differentially expressed among the three groups. The median level of LCN2 were 131.93 (96.26,183.65), 52.79 (31.39,89.05) and 33.80 (26.80,47.06) ng/ml in the sepsis, non-sepsis and healthy control group, respectively. The plasma MGP levels in these three groups were 1.16 (1.06,1.30), 0.99 (0.91,1.07) and 0.89 (0.80,1.02) ng/ml, respectively. For both biomarkers, the sepsis group had higher levels than the non-sepsis group(P < 0.05). The area under the curve values of LCN2 and MGP were 0.903 and 0.813, respectively. When combined, these two biomarkers had a sensitivity of 0.900 and a specificity of 0.900 in distinguishing sepsis from non-sepsis. Plasma exosome proteome analysis has revealed that LCN2 and MGP may serve as effective biomarkers for diagnosing sepsis, further research is necessary to validate their diagnostic efficiency.
“…EVs can inhibit viral replication and thereby decrease direct viral injury. 12 Their ability to block IL-6, IL-6 precursors (IL-1β), and inflammatory cytokines (tumor necrosis factor α [TNF-α], IL-8, and MIP-2) at multiple points within the pathway 13 , 14 while upregulating IL-10 results in downregulation of cytokine production and reduction in systemic injury. Figure 1 Mechanistic efficacy of extracellular vesicles against severe SARS-CoV-2 infection SARS-CoV-2 acts through the direct and indirect pathway to induce systemic inflammatory injury.…”
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