Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway

Li, Xiaoli; Li, Heng; Zhang, Min; Xu, Haowen; Liu, Yue; Zhang, Xinxin; Wang, Shan; Wang, Congcong; Li, Yanbin; Dou, Ying‐Chun; Duan, Rui‐Sheng

doi:10.1186/s12974-016-0475-0

Cited by 39 publications

(30 citation statements)

References 60 publications

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“…Immature bone marrow DCs are able to secrete tolerogenic exosomes, which are involved in the suppression of immune responses in a rat model of experimental autoimmune myasthenia gravis. These EVs upregulate levels of IDO/Treg and decrease synthesis of anti‐R97‐116 IgG, IgG2a and IgG2b antibodies [170]. Moreover, DC‐derived EVs can mediate the activation of CD4 + T cells through an endocrine mechanism, leading to improved cardiac function and wound healing after myocardial infarction [171].…”

Section: ‘Theranostic’ Applications Of Immune Cell‐derived Evsmentioning

confidence: 99%

Biological roles and potential applications of immune cell‐derived extracellular vesicles

Wen

Seeger

Fabbri

et al. 2017

J of Extracellular Vesicle

144

128

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Extracellular vesicles (EVs) deliver bioactive macromolecules (i.e. proteins, lipids and nucleic acids) for intercellular communication in multicellular organisms. EVs are secreted by all cell types including immune cells. Immune cell-derived EVs modulate diverse aspects of the immune system to either enhance or suppress immune activities. The extensive effects of immune cell-derived EVs have become the focus of great interest for various nano-biomedical applications, ranging from the medical use of nanoplatform-based diagnostic agents to the development of therapeutic interventions as well as vaccine applications, and thus may be ideal for ‘immune-theranostic’. Here, we review the latest advances concerning the biological roles of immune cell-derived EVs in innate and acquired immunity. The intercellular communication amongst immune cells through their EVs is highlighted, showing that all immune cell-derived EVs have their unique function(s) in immunity through intricate interaction(s). Natural-killer (NK) cell-derived EVs, for example, contain potent cytotoxic proteins and induce apoptosis to targeted cancer cells. On the other hand, cancer cell-derived EVs bearing NK ligands may evade immune surveillance and responses. Finally, we discuss possible medical uses for the immune cell-derived EVs as a tool for immune-theranostic: as diagnostic biomarkers, for use in therapeutic interventions and for vaccination.

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Section: ‘Theranostic’ Applications Of Immune Cell‐derived Evsmentioning

confidence: 99%

Biological roles and potential applications of immune cell‐derived extracellular vesicles

Wen

Seeger

Fabbri

et al. 2017

J of Extracellular Vesicle

144

128

View full text Add to dashboard Cite

show abstract

“…Beside analyses of their protein cargo, EVs have been reported to carry DNA or distinct RNAs and they are able to transfer genetic information from cell to cell ( 20 – 26 ). Thus, EVs are increasingly recognized as mediators of intercellular communication ( 27 – 30 ), and their role in the pathogenesis of autoimmune diseases or tumor growth has been discussed ( 3 , 31 – 36 ). However, while the EV field is rapidly expanding, there is an urgent need to better define vesicle subpopulations.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle Subtypes Released From Activated or Apoptotic T-Lymphocytes Carry a Specific and Stimulus-Dependent Protein Cargo

et al. 2018

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Extracellular vesicles (EVs) are released from nearly all mammalian cells and different EV populations have been described. Microvesicles represent large EVs (LEVs) released from the cellular surface, while exosomes are small EVs (SEVs) released from an intracellular compartment. As it is likely that different stimuli promote the release of distinct EV populations, we analyzed EVs from human lymphocytes considering the respective release stimuli (activation Vs. apoptosis induction). We could clearly separate two EV populations, namely SEVs (average diameter <200 nm) and LEVs (diameter range between 200 and 1000 nm). Morphology and size were analyzed by electron microscopy and nanoparticle tracking analysis. Apoptosis induction caused a massive release of LEVs, while activated T-cells released SEVs and LEVs in considerably lower amounts. The release of SEVs from apoptotic T-cells was comparable with LEV release from activated ones. LEVs contained signaling proteins and proteins of the actin-myosin cytoskeleton. SEVs carried cytoplasmic/endosomal proteins like the 70-kDa heat shock protein 70 (HSP70) or tumor susceptibility 101 (TSG101), microtubule-associated proteins, and ubiquitinated proteins. The protein expression profile of SEVs and LEVs changed substantially after the induction of apoptosis. After apoptosis induction, HSP70 and TSG101 (often used as exosome markers) were highly expressed within LEVs. Interestingly, in contrast to HSP70 and TSG101, gelsolin and eps15 homology domain-containing protein 3 (EHD3) turned out to be specific for SEVs irrespective of the stimulus causing the EV release. Finally, we detected several subunits of the proteasome (PSMB9, PSMB10) as well as the danger signal HMGB1 exclusively within apoptotic cell-released LEVs. Thus, we were able to identify new marker proteins that can be useful to discriminate between distinct LEV subpopulations. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD009074.

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“…A recent study showed that dendritic cell-derived exosomes (DEXs) deliver antigen-specific signals and can be regarded as inert vehicles that mimic DCs and activate T cells [16]. The biological function of DEXs in tumors and inflammatory diseases has been demonstrated in a number of studies [17-19]. However, to our knowledge, there have been no studies investigating the biological function of DEXs in liver I/R or whether DEXs can modulate CD4+ T cell activation and differentiation.…”

Section: Introductionmentioning

confidence: 99%

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

Zheng¹,

Li²,

Wei³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). Methods: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co-cultured BMDCs/DEXs and naïve T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naïve T cells by WB and FCM. Results: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-β, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naïve T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naïve T cells. Conclusion: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naïve T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury.

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Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway

Cited by 39 publications

References 60 publications

Biological roles and potential applications of immune cell‐derived extracellular vesicles

Biological roles and potential applications of immune cell‐derived extracellular vesicles

Extracellular Vesicle Subtypes Released From Activated or Apoptotic T-Lymphocytes Carry a Specific and Stimulus-Dependent Protein Cargo

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

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