Microvesicles with mitochondrial content are increased in patients with sepsis and associated with inflammatory responses

BACKGROUND Endothelial activation plays an important role in sepsis-mediated inflammation,but the triggering factors have not been fully elucidated.Microvesicles carrying mitochondrial content(mitoMVs)have been implicated in several diseases and shown to induce endothelial activation.AIM To explore whether mitoMVs constitute a subset of MVs isolated from plasma of patients with sepsis and contribute to endothelial activation.METHODS MVs were isolated from human plasma and characterized by confocal microscopy and flow cytometry.Proinflammatory cytokines,including interleukin(IL)-6,IL-8 and tumour necrosis factor(TNF)-α,and soluble vascular cell adhesion molecule(sVCAM)-1 were detected by ELISA.Human umbilical vein endothelial cells(HUVECs)were stimulated with the circulating MVs to evaluate their effect on endothelial activation.RESULTS MitoMVs were observed in plasma from patients with sepsis.Compared with those in healthy controls,expression of MVs,mitoMVs,proinflammatory cytokines and sVCAM-1 was increased.The number of mitoMVs was positively associated with TNF-αand sVCAM-1.In vitro,compared with MVs isolated from the plasma of healthy controls,MVs isolated from the plasma of patients with sepsis induced expression of OAS2,RSAD2,and CXCL10 in HUVECs.MitoMVs were taken up by HUVECs,and sonication of MVs significantly reduced the uptake of mitoMVs by HUVECs and expression of the above three type I IFNdependent genes.CONCLUSION MitoMVs are increased in the plasma of patients with sepsis,which induces elevated expression of type I IFN-dependent genes.This suggests that circulating mitoMVs activate the type I IFN signalling pathway in endothelial cells and lead to endothelial activation.

Molecular insights into the transgenerational inheritance of stress memory

There is accumulating evidence to show that environmental stressors can regulate a variety of phenotypes in descendants through germline-mediated epigenetic inheritance. Studies of model organisms exposed to environmental cues(e.g., diet, heat stress, toxins) indicate that altered DNA methylations, histone modifications, or non-coding RNAs in the germ cells are responsible for the transgenerational effects. In addition,it has also become evident that maternal provision could provide a mechanism for the transgenerational inheritance of stress adaptations that result from ancestral environmental cues. However, how the signal of environmentally-induced stress response transmits from the soma to the germline, which may influence offspring fitness, remains largely elusive. Small RNAs could serve as signaling molecules that transmit between tissues and even across generations. Furthermore, a recent study revealed that neuronal mitochondrial perturbations induce a transgenerational induction of the mitochondrial unfolded protein response mediated by a Wnt-dependent increase in mitochondrial DNA levels. Here, we review recent work on the molecular mechanism by which parental experience can affect future generations and the importance of soma-to-germline signaling for transgenerational inheritance.