Metabolic syndrome (MetS), obesity and diabetes mellitus, are clinically classified as metabolic disorders
[61][105]. Recently, extracellular vesicles (EVs) have been emerging as a novel way of cell-to-cell communication that transfers fundamental information between the cells through the transport of proteins and nucleic acids. EVs, released in the extracellular space, circulate via the various body fluids and modulate the cellular responses following their interaction with the near and far target cells. Clinical and experimental data support their role as biomarkers and bio-effectors in several diseases including metabolic syndrome
[62][106]. New evidence shows that exosomes with flotillin immunomodulatory functions may be involved in the occurrence and development of autoimmune diabetes. For one thing, islet-derived exosomes can activate the immune system and cause an autoimmune response
[63][107]. For another, exocrine bodies originating from the immune system may lead to dysfunction and beta cell death
[64][108]. Another study showed that exosomes released by human urine-derived stem cells can prevent podocyte apoptosis and promote cell survival and angiogenesis in rats with T1DM
[65][109]. In addition to T1DM, exosomes also play a role in other autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and Sjogren’s syndrome
[66][110]. One result showed that exosomes from adipose stem cells (ADSCs) improved insulin sensitivity and hepatic steatosis, and reduced obesity, when injected into obese mice
[67][111]. Furthermore, AT macrophages (ATM) exosomes from obese mice have been shown to induce systemic insulin resistance and glucose intolerance in lean mice, and these factors are ameliorated in obese mice when ATM exosomes from lean mice are treated in obese mice
[68][112]. MiR-155 is a repressor of the adipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and has been suggested to be a key mediator of the effect of ATM exosomes on insulin resistance
[68][112]. Taken together, these studies highlight the potential importance of exosome-mediated crossover between key metabolic tissues in regulating metabolism under physiological and pathophysiological conditions
[69][113]. MiR-197, miR-23a, and miR-509-5p have now been identified as potential contributors to dyslipidemia in metabolic syndrome. In addition, a reasonable association between miR-27a and miR-320a and patients with metabolic syndrome and type 2 diabetes has also been found
[70][114]. Therefore, EVs could be new biomarkers predictive of metabolic pathologies and new exploitable structures in therapy
[71][115] (
Table 2).
Table 2. The targets of exosomes in diseases.
Disease |
Exosomal miRNAs |
Target or Pathway |
References |
Acute myeloid leukemia |
Exosomes with MICA/B (MHC I chain-related proteins A and B) |
By downregulating NKG2D receptor expression |
[72] | [116] |
Brain cancer |
Brain endothelial cells |
Rhodamine 123, PTX, DOX |
[73] | [117] |
Breast cancer |
MiR-365 in macrophage-derived exosomes |
The triphospho-nucleotide pool, the enzyme cytidine deaminase |
[74] | [118] |
Leukemia |
MiR-210 |
CD107a |
[75] | [119] |
Lung cancer |
MiR-494 |
Suppresses PTEN (PTEN (phosphatase and tensin homolog deleted on chromosome ten), it is located at 10q23.3 and the transcriptional product is 515 kb mRNA). |
[76] | [120] |
Colorectal cancer |
MiR-31-5p in (tumor-derived exosomes) TDEs |
LATS2 |
[77] | [121] |
Nasopharyngeal cancer |
MiR-24-3p |
ND |
[78] | [122] |
Esophageal cancer |
MiR-21 in TDEs |
PDCD4 |
[79] | [123] |
Head and neck cancer |
MiR-196a in cancer associate fibroblasts (CAF)- derived exosomes |
CDKN1B and ING5 |
[80] | [124] |
Pancreatic cancer |
MiR-106b in CAFs-derived exosomes |
TP53INP1 |
[81] | [125] |
2.8. Exosomes in Viral Pathogenesis
Viruses use exocrine pathways to gain entry, spread, perform viral packaging, and escape from the host immune system
[82][126]; because of the similarity of exocrine biogenetic pathways (ESCRT-dependent and independent), their fate (endocytosis, endocytosis and receptor-mediated uptake by target cells) and viral uptake, packaging and release are comparable to those of relatives
[83][127]. Viral infection stimulates host cells to secrete exocrine bodies, which act as pathogen-related molecular models, carry inflammatory mediators, and cause inflammation
[84][128]. HCV mRNA in exosomes induces secretion of interferon alpha (IFN alpha) from macrophages, and exosomes from C3/36 cells infected with Zika virus induce expression of tumor necrosis factor alpha (TNF alpha) from monocytes and cause endothelial damage to induce intravascular coagulation and inflammation. Exosomes from Kaposi sarcoma-associated herpesvirus also cause endothelial damage and induce the expression of IL6
[85][129]. Exosomes from virus-infected cells also cause apoptosis of immune cells. The 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019. It is believed that COVID-19 may be transmitted from person to person through droplets, fecal transmission and direct contact with aerosols. A relatively high basic fecundity (R 0) value estimated between 2.2 and 5.7 caused the virus to spread rapidly, resulting in a pandemic
[86][130]. COVID-19 is a highly contagious respiratory syndrome that can cause multiple organ failure and may lead to death in a small number of infections. The virus can replicate in a variety of cells expressing ACE2, including nasal epithelium, nasopharynx, upper respiratory tract, type II lung cells in the lung, gastrointestinal tract, immune cells and endothelial cells
[87][88][131,132]. Recent data have shown that lipid metabolism, including cholesterol metabolism
[89][133], is involved in the pathogenesis of COVID-19, raising the question of whether exosomes are involved in the pathogenesis of SARS-CoV-2 infection. Consistent with this idea, SARS-CoV-2 protein interaction group analysis revealed interaction with Rab protein, which is part of the ESCRT pathway involved in exocrine biogenesis. In short, exosomes from virus-infected cells can cause tissue damage by activating inflammation and cytotoxicity. For example, HIV infection induces secretion of exosomes that are enriched in viral Nef protein
[90][134]. Likewise, Epstein–Barr virus (EBV)-infected cells secrete exosomes enriched with galectin 9 that cause apoptosis of cytotoxic T cells specific to EBV-infected cells
[91][135] (
Table 3).
Table 3. Exosomes in the pathogenesis of viral infections.
Virus |
Source |
Function |
References |
Avian influenza (H5N1) |
miR-483-3P |
Increased production of proinflammatory cytokines in vascular endothelial cells |
[92] | [136] |
HIV |
Nef |
Susceptibility to infection and apoptosis of CD4 cells |
[90][93] | [134,137] |
KSHV |
miRNA and others |
IL6 production and cellular metabolism |
[85] | [129] |
Coronavirus |
CD9 |
Proviral |
[94] | [138] |
EV-A71 |
Viral protein and nucleic acid |
Virus spread |
[95] | [139] |
2.9. Exosomes in Transplantation
Transplantation is the treatment of choice for many terminal organ failures. However, it comes with an important risk of chronic rejection. Exosomes are key mediators of donor recognition by the host immune system through protein transfer of the preformed donor MHC-peptide complex in host APC that subsequently activates donor-specific T cells
[96][140]. Moreover, studies focusing on blocking this phenomenon are increasing and show promise. However, exosomes derived from host immune cells have shown interesting capacities to modulate rejection, as in other pathological conditions. Exosome-based therapies are currently being studied to specifically silence the immune system toward the graft. Several cell types are candidates for sources of exosomes: mesenchymal stem cells, regulatory T cells, M2 macrophages and immature dendritic cells, which are well-known immunoregulatory cells
[97][98][99][100][141,142,143,144].
2.10. Anti-Inflammatory and Antimicrobial Vesicles
Mesenchymal stem cells (MSCs) can interact with the immune system to prevent infection through both direct and indirect mechanisms
[101][145]. MSCs, exosomes secreted by these cells can be used as complementary antimicrobial agents, as a substitute for or in combination with antibiotics under specific physiological conditions or specific priming conditions
[102][146]. In particular, antimicrobial properties are associated with the paracrine of several antimicrobial peptides (AMP), which have a wide range of antimicrobial properties, as well as specific extracellular vesicle (EV) secretion, including the release of immunomodulatory factors MSCs that retain antimicrobial properties
[103][147] and are considered safer than parental cell administration
[104][148]. EVS as a cell-free agent and/or drug carrier may have therapeutic effects for sepsis
[104][148] and may be developed as a superior drug delivery vehicle
[105][149].
EV number, size and their biologically active material is altered in numerous inflammatory conditions and 数量、大小及其生物活性物质在许多炎症条件下都会发生改变,EV can alter the cellular functions of neutrophils, monocytes, macrophages and their precursor hematopoietic stem and progenitor cells (HSCs可以改变中性粒细胞、单核细胞、巨噬细胞及其前体造血干细胞和祖细胞 (HSC) [106].[ Neutrophils150 can]的细胞功能。中性粒细胞可以释放至少两个 release at least two sub-classes of EV, termed: neutrophil derived trails 亚类,称为:中性粒细胞衍生轨迹 (NDTRS), which are generated by integrin mediated interactions by migrating neutrophils in response to vascular wall forces and neutrophil derived microvesicles ,它们是由整合素介导的相互作用产生的,通过迁移响应血管壁力的中性粒细胞和中性粒细胞衍生微泡 (NDMV), which are dependent on the PI3K pathway and,依赖于中性粒细胞活化后通过膜起泡释放 PI3K 通路 [ released151 by, membrane152]]。间充质干细胞 blebbing following neutrophil activation [107][108]. Mesenchymal stem cell (MSC) EV modulate通过抑制中性粒细胞募集来调节缺血性损伤期间的神经保护作用,并介导与中性粒细胞耗竭观察到的类似保护作用 neuroprotection[ during153 ischemic]。单核细胞衍生的 injury by inhibiting neutrophil recruitment and mediate similar protective effects to those observed with neutrophil depletion [109]. Monocyte-derived EV may可用作诊断生物标志物,用于评估病理学,其中单核细胞表型导致炎症性疾病,如感染、血脂异常、糖尿病、肥胖症和心血管疾病 provide[ utility154 as diagnostic biomarkers for the assessment of pathologies where monocyte phenotypes contribute to the inflammatory disease such as infection, dyslipidemia, diabetes, obesity and cardiovascular diseases [110]. In conclusion, ]。总之,EV, especially exosomes, can be used as the carrier of ,尤其是外泌体,可以作为K,的载体,有望提高治疗效果,减少不良反应[ which155 is expected to improve the therapeutic effect and reduce adverse reactions [111].]。