Table 1.
Role of microbial EVs in pathogenesis.
| Organ | Disease | EV species of origin | Pathogenic effects | Ref. |
|---|---|---|---|---|
| Skin | Atopic dermatitis | Staphylococcus aureus (S. aureus) | The application of S. aureus EVs induced activation of dermal fibroblasts, increasing the production of pro-inflammatory mediators such as IL-6, thymic stromal lymphopoietin, macrophage inflammatory protein-1a, and eotaxin. In addition, the application of S. aureus EVs caused epidermal thickening with infiltration of the dermis by mast cells and eosinophils, which are associated with the enhanced cutaneous production of IL-4, IL-5, IFN-c, and IL-17. | Hong et al.121 |
| α-Hemolysin in S. aureus EVs was cytotoxic to HaCaT keratinocytes and induced necrosis. In addition, α-hemolysin in S. aureus EVs induced skin barrier disruption and epidermal hyperplasia and caused dermal inflammation. | Hong et al.48 | |||
| Acne vulgaris | Propionibacterium acnes (P. acnes) |
P. acnes EVs significantly increased the secretion of cytokines, such as IL-8, GM-CSF, CXCL-1, and CXCL-5, promoting the infiltration of neutrophils. In addition, P. acnes EVs induce dysregulated epidermal differentiation of human keratinocytes via TLR2-mediated signaling pathways. P. acnes EVs may play pivotal roles in the early stages of the development of acne vulgaris by initiating inflammatory cytokine cascades in keratinocytes. |
Choi et al.50 | |
| Lung | Asthma or chronic obstructive pulmonary disease (COPD) | Staphylococcus aureus (S. aureus) |
After stimulation with S. aureus EVs, alveolar macrophages induced both TNF-a and IL-6 production, and airway epithelial cells induced only IL-6 production. Repeated airway exposure to S. aureus EVs induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a TLR2-dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EVs and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of IFN-γ or IL-17. Neutrophilic inflammation led to airway hyperreactivity and fibrosis that contributed to asthma development, and the combination of increased elastase production and fibrosis caused COPD. |
Kim et al.55 |
| Pulmonary inflammation | Pseudomonas aeruginosa (P. aeruginosa) | P. aeruginosa EVs increased the concentrations of several chemokines and cytokines in the lungs and alveolar macrophages. The inflammatory responses to P. aeruginosa EVs were partly regulated by the TLR2 and TLR4 pathways. P. aeruginosa EVs cause pulmonary inflammation, which was only partly controlled by TLR2 and TLR4. Furthermore, P. aeruginosa EVs caused dose- and time-dependent pulmonary cellular inflammation. | Park et al.57 | |
| Emphysema | Escherichia coli (E. coli) | Airway exposure to E. coli EVs increased the production of pro-inflammatory cytokines, such as TNF-a and IL-6. In addition, the repeated inhalation of E. coli EVs induced neutrophilic inflammation and emphysema, and elastase activity was enhanced. Emphysema and elastase activity were reversed by the absence of the IFN-γ or IL-17A genes. In addition, during the early period, lung inflammation was dependent on IL-17A and TNF-a. Moreover, the production of IFN-γ was eliminated by the absence of IL-17A, whereas IL-17A production was not abolished by IFN-γ absence. In summary, E. coli EVs induced IL-17A-dependent neutrophilic inflammation and thereby emphysema via upregulation of elastase activity. | Kim et al.54 | |
| Lung fibrosis |
Bacteroides ovatus (B. ovatus), Bacteroides stercoris (B. stercoris), Prevotella melaninogenica (P. melaninogenica) |
The EVs of three bacterial species (B. ovatus, B. stercoris, and P. melaninogenica) induced IL-17B expression and consequently promoted Th17 cell development via TLR-Myd88 adaptor signaling. The expanded lung microbiota induced IL-17B expression and consequently Th17 cell expansion to promote lung fibrosis. | Yang et al.58 | |
| Chronic inflammatory airway diseases | Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) | E. coli EVs and S. aureus EVs induced MUC5AC expression via the ERK1/2 and p38 MAPK signaling pathways in human airway epithelial cells. E. coli EVs and S. aureus EVs significantly activated phosphorylation of ERK1/2 MAPK and p38 MAPK. An ERK1/2 MAPK inhibitor, a p38 MAPK inhibitor, an ERK1/2 MAPK siRNA, and a p38 MAPK siRNA significantly blocked the MUC5AC mRNA expression induced by E. coli EVs and S. aureus EVs. | Bae et al.56 | |
| Gastrointestinal | Gastric disease | Helicobacter pylori (H. pylori) |
H. pylori and H. pylori EVs induced the expression of IL-8 mRNA and protein. IL-8 expression was induced to different levels in response to H. pylori EVs from hosts with different gastric diseases. Exposure to H. pylori EVs increased the phosphorylation and reduced the degradation of inhibitor of NF-κB alpha. H. pylori EVs may aid the development of various gastric diseases by inducing IL-8 and NF-κB expression. |
Choi et al.69 |
| Inflammatory bowel disease | Vibrio cholera (V. cholerae) | V. cholerae EVs activated NOD1 and NOD2, resulting in NF-κB signaling and a pro-inflammatory immune response. NOD1 and NOD2 activation by EVs is of particular interest for inflammatory diseases such as Crohn’s disease, in which targeting NOD signaling may be an effective therapeutic strategy. | Bielig et al.66 | |
| Escherichia coli (E. coli) | E. coli EVs activated NOD1 signaling pathways in intestinal epithelial cells. NOD1 silencing and RIP2 inhibition significantly abolished EV-mediated activation of NF-κB and subsequent IL-6 and IL-8 expression. In addition, endocytosed EVs colocalized with NOD1, triggered the formation of NOD1 aggregates, and promoted NOD1 association with early endosomes. | Canas et al.67 | ||
| Metabolic | Type 2 diabetes (T2D) | Pseudomonas panacis (P. panacis) |
P. panacis EVs blocked the insulin signaling pathway in both skeletal muscle and adipose tissue, thereby promoting glucose intolerance in skeletal muscle. Moreover, P. panacis EVs induced typical diabetic phenotype characteristics, such as glucose intolerance after glucose administration or systemic insulin injection. P. panacis EVs induced T2D via the induction of insulin resistance in insulin-responsive organs. |
Choi et al.71 |
| Diabetes mellitus | Porphyromonas gingivalis (P. gingivalis) | P. gingivalis EVs equipped with gingipain proteases were translocated to the liver. In addition, the hepatic glycogen synthesis in response to insulin was decreased, and thus, high blood glucose levels were maintained. P. gingivalis EVs also attenuated insulin-induced Akt/GSK-3β signaling in a gingipain-dependent fashion in hepatic HepG2 cells. The delivery of gingipains mediated by P. gingivalis EV elicited changes in glucose metabolism in the liver and contributed to the progression of diabetes mellitus. | Seyama et al.72 | |
| Cancer | Stomach cancer | Helicobacter pylori (H. pylori) | H. pylori EVs contained CagA and VacA. They induced the production of TNF-α, IL-6 and IL-1β by macrophages and IL-8 by gastric epithelial cells. Additionally, H. pylori EVs induced the expression of IFN-γ, IL-17, and H. pylori EV-specific IgG1. H. pylori EVs infiltrated and remained in the stomach for an extended time. H. pylori EVs, which are abundant in the gastric juices of gastric cancer patients, can induce inflammation and possibly cancer in the stomach, mainly via the production of inflammatory mediators from gastric epithelial cells after selective uptake by the cells. | Choi et al.77 |
| Lung cancer | Staphylococcus aureus (S. aureus) Escherichia coli (E. coli) | S. aureus and E. coli EVs triggered the Th17 response. Generally, S. aureus and E. coli EVs induced IL-17 production through polarized Th17 cells and thus caused neutrophilic inflammation. The neutrophilic inflammatory response induces epithelial cell dysplasia and MMP expression, which can lead to lung cancer. | Yang et al.53 | |
| Central nervous system | Alzheimer’s disease | Paenalcaligenes hominis (P. hominis) |
Oral administration of P. hominis EVs caused cognitive impairment in mice. P. hominis EV treatment increased NF-κB+/Iba1+, LPS+/Iba1+, and IL-1R+ cell counts in the hippocampus. P. hominis EV treatment reduced BDNF expression in the hippocampus while increasing IL-1β expression in the blood. Vagotomy significantly reduced the occurrence of cognitive impairment caused by P. hominis EV gavage. Vagotomy inhibited EV-induced changes in NF-κB+/Iba1+, LPS+/Iba1+, and IL-1R+ cell populations in the hippocampus. The occurrence of cognitive impairment induced by P. hominis EVs was significant. Fluorescein isothiocyanate (FITC)-conjugated EVs were detected in the pyramidal region of the hippocampus. However, vagotomy significantly reduced the FITC-conjugated EV-containing CD11c+ cell population. Furthermore, oral gavage of P. hominis EVs increased bacterial 16S rDNA levels in the hippocampus. The translocation of P. hominis EVs through the vagus nerve resulted in cognitive impairment induced by brain inflammation. |
Lee et al.81 |
| Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) | A. actinomycetemcomitans EVs administered via intracardiac injection into mice were successfully delivered to the brain after crossing the blood–brain barrier, and the extracellular RNA cargos increased the expression of TNF-α through the TLR-8 and NF-κB signaling pathways in the mice. Thus, host gene regulation by microRNAs originating from A. actinomycetemcomitans EVs is a novel mechanism for host gene regulation, and transfer of A. actinomycetemcomitans EV extracellular RNAs to the brain may cause neuroinflammatory diseases like Alzheimer’s disease. | Han et al.79 |
GM-CSF granulocyte−macrophage colony-stimulating factor, ERK extracellular signal-regulated kinase, MAPK mitogen-activated protein kinase, NOD nucleotide oligomerization domain, NLR NOD-like receptor, MMP matrix metalloproteinase.