Introduction
Extracellular vesicles
EVs isolation and characterization methods
The role of EVs during systemic inflammation and organ injury
EVs in sepsis/SIRS
EVs in injury and trauma
EVs in traumatic brain injury
EVs in acute cardiac injury
EVs in acute respiratory distress syndrome (ARDS)
EVs in acute kidney injury
EVs in liver injury
EVs in polytrauma
EVs as diagnostic/prognostic markers in acute organ injury
Disease | EV-derived miRNA | Role |
---|---|---|
SIRS/sepsis | ||
LPS-induced sepsis (mice) In vitro | miR-155 (pro-inflammatory miRNA) | Promotes endotoxin-induced inflammation in mice [51] Increases IL-6 production; increases TNF-α production and decreases SOCS1 mRNA expression in RAW macrophages stimulated with LPS in vitro [52] |
LPS-induced sepsis (mice) CLP-induced sepsis | miR-146 (anti-inflammatory miRNA) | Reduces the pro-inflammatory response to LPS [51] miR-146a was transferred to macrophages, resulted in M2 polarization, and finally led to increased survival in septic mice [55] |
Septic cardiomyopathy (in vitro) | miR-233 (anti-inflammatory) | miR-233 leads to downregulation of Sema3A and Stat3 leading to cardio protection (reduced inflammation/cell death) [54] |
Treatment of LPS-induced sepsis | Let-7b (anti-inflammatory) | LPS‑preconditioned mesenchymal stromal cells modify macrophage polarization by exosomal Let-7b via TLR4/NF-κB/STAT3/AKT regulatory signaling pathway [56] |
TBI | ||
Blood brain barrier permeability | miR-132 | |
Systemic inflammation | miR-146, miR-155 (neuroinflammatory) | Systemic inflammation leads to increased release of EVs in cerebrospinal fluid containing neuroinflammatory miRNAs miR-146 and miR-155 [184] |
TBI (rats) | miR-129-5p, miR-212–5p, miR-9-5p | |
TBI (rats) | miR-152-5p, miR-21, miR-374b-5p | |
TBI (mice) | miR-155 (neuroinflammatory) | Microglial-derived, contribute to progressive neuroinflammatory response [185] |
TBI (mice) | miR-124-3p (anti-neuroinflammatory) | Inhibits neuronal inflammation; promote neurit outgrowth after scratch injury, improves neurologic outcome [186] |
TBI (patients, mice, in vitro) | miR-873 | Inhibits neuroinflammation by inhibition of NF-kB signaling and s transform M1 microglia into M2 phenotype [187] |
Traumatic spinal cord injury | miR-216a-5p (MSC-derived, therapeutic) | Inhibits neuroinflammation, promotes neuronal regeneration, inhibits TLR-4/NF-kB, activates PI3K/Akt signaling pathway, initiates the shift of microglia M1 to M2 phenotype [82] |
Cardiac injury | ||
Cardiac hypertrophy (in vitro) | miR-21 | Downregulates sorbin and SH3 domain containing protein 2 cardiac hypertrophy [188] |
Cardiac injury (mice) | miR-155 (inflammatory) | miR-155 inhibits fibroblast proliferation by downregulation of son of sevenless 1 expression, promotes inflammation [189] |
Doxorubicin-induced cardiomyopathies (in vitro) | miR-34a | Abolishes the doxorubicin-induced cardiomyocyte senescence via upregulation of the phosphatase 1 nucelar targeting subunits [93] |
Cardiac injury (obese mice) | miR-194 | Impairs ATP production and basal oxygen consumption, impaired cardiac function, increased NT-proBNP in humans [102] |
Hypoxic stress (in vitro) | miR-19a (anti-apoptotic) | Targets PTEN which results in the activation of the Akt and ERK cell survival signaling pathway reduces apoptosis [110] |
Ischemic heart disease (mice) | miR-122 (anti-apoptotic, MSC-derived) | Anti-apoptotic by direct targeting of methyl CpG binding protein 2 [111] |
ARDS | ||
Community-acquired pneumonia (patients) | miR-126, miR-27a, miR-146a and miR-155 | Good predictors of ARDS development, miR-126 is a predictor of 28-days mortality [122] |
Oxidative stress-induced ARDS (mice) | miR-320a, miR-221-3p, miR-145p, miR-342-3p | Up-regulated in oxidative-stress-induced ARDS [123] |
Acid-induced ARDS (mice) | miR-221-3p, miR-17-5p (inflammatory) | miR-17/221 modulates macrophage ß1 integrin recycling macrophage recruitment lung inflammation [120] |
ARDS | miR-211 and miR-320 (inflammatory) | Activate alveolar macrophages pro-inflammatory cytokines [120] |
LPS lung macrophages (in vitro/mice) | miR-221/222 | Epithelial cell proliferation [190] |
Acute kidney injury | ||
Chronic kidney injury (patients) | miR-29, miR-200 (urine) | Correlates with renal function and the degree of tubular-intestinal fibrosis [140] |
End-stage chronic kidney disease (patients) | miR-133 (plasma) | miRNA is linked to inflammation and renal endothelial dysfunction [141] |
Kidney fibrosis (rats) | Let-7cp, miR-532-3p, miR-429 and let-7a-5p (plasma) | Up-regulated [142] |
Diabetic kidney disease (diabetic patients) | miR-130a and miR-145a (urine) | Up-regulated [143] |
Acute liver injury | ||
Liver injury (mice) | miR-122 | |
Inflammatory liver disease (mice) | miR-155 and miR-146 | Up-regulated in inflammatory liver diseases [159] |
Alcoholic steaotohepatitis (patients + mice) | miR-122, Let7f, miR-34a | Up-regulated in plasma [160] |
Chronic liver disease (mice) | miR-122 and miR-192 | Up-regulation accompanied with decrease in the liver, promotes liver fibrosis in mice [161] |
Liver injury (patients + mice) | miR-214 | CCN-2-dependant fibrogenesis [165] |
Drug-induced liver injury (rats) | miR-122 | Early immune response, also in absence of overt hepatocellular toxicity [162] |
Alcohol intoxication, liver injury (patients) | miR-122/let7f | Up-regulated together with the inflammatory cytokines IL-6 and IL-33 [163] |
EVs -cell origin | Found in | Function | References |
---|---|---|---|
SEPSIS/SIRS | |||
Platelets | Endotoxemia pig model | Increase correlates with pure outcome | [42] |
Monocytes (TP+/CD13+) | Patients with trauma or septic shock | Increase in trauma and sepsis correlates with ISS, APACHE II, and DIC criteria | [44] |
Neutrophils (A2MG) | Patients with sepsis | Increased | [45] |
Neutrophils (A2MG) | CLP in mice | Protect against hypothermia, reduce bacterial titers, elevate immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation | [45] |
TBI | |||
Microglia | TBI (24 h after injury) | Neuroinflammation (Il-1β) | [63] |
Microglia | Repetitive TBI in mice | Containing miR-124-3p which improve neurologic outcome and inhibit neuroinflammation | [186] |
Astrocytes | TBI in mice | Neuroinflammation | [63] |
Astrocytes | Patients with TBI and mouse model | Contain miR-873, transform M1 microglia into M2 phenotype | [187] |
Astrocytes | Acute mild traumatic brain injury in patients | Astrocyte-derived EVs contain 12–35 fold higher levels of neurotoxic complement proteins compared to neuron-derived Exos | [192] |
Choroid plexus epithelial cells | In vitro LPS treatment of cells | Pro-inflammatory reaction | [184] |
Cardiac injury | |||
Cardiomyocytes | In vitro hypoxia | Contain HSP-60 leading to cardiomyocytes apoptosis and a pro-inflammatory reaction | |
Cardiomyocytes | In vitro hypoxia | Contain TGF-signaling pathway proteins, which mediate cellular hypertrophy and proliferation | [92] |
Cardiomyocytes | Doxorubicin-induced cardiomyocyte | Reduce cardiomyocyte senescence | [94] |
Cardiomyocytes | In vitro ischemia/myocardial ischemia in rats/myocardial fibrosis in rats | Anti-apoptotic, anti-fibrotic and anti-oxidative effects | |
ARDS | |||
Endothelial cells | ALI in mice and ARDS in humans | Increase lung epitelium permeability | [114] |
Red blood cells | Injected in healthy mice | Neutrophil activation (increased superoxide production and enhanced phagocytotic ability) | [117] |
Monocytes/macrophages | In vitro: human lung epithelial cells | Synthesis of pro-inflammatory mediators | [118] |
AKI | |||
Platelets (CD41+/CD13+) | Sepsis-induced AKI | Increased | [132] |
Endothelial cells and leukocytes | DIC in patients | Disseminated intravascular coagulation | [133] |
Platelets, granulocytes, erythrocytes | Patients with multiple organ failure | Decrease Increase Increase in multiple organ failure/SEPSIS | [135] |
Liver | |||
Hepatocytes (ASGR receptor, apolipoproteins, paraoxonases and others specific proteins) | Basic proteomic studies | Contain ASGR receptor, apolipoproteins, paraoxonases and others specific proteins | [157] |
Liver epithelia (i.e., hepatocytes and cholangiocytes), natural killer T (NKT) cells, hepatic stellate cells, Kupffer cells, adult liver stem cells, and hepatic sinusoidal endothelial cells | In vitro, liver toxicity, in hepatic fibrosis, cirrhosis, hepatocellular carcinoma | Are exosome-releasing and/or exosome-targeting cells | |
Hepatocytes | Drug-induced liver injury | Contain miR-122, mediate an early immune response also in absence of overt hepatocellular toxicity | [162] |
Hepatocytes | Ischemia/reperfusion injury and partial hepatectomy-mice models | Mediate liver repair and regeneration | [164] |
Hepatic stellate cells | fibrotic or steatotic livers, or in culture-activated or ethanol-treated primary mouse cells | Fibrogenesis | [165] |
Polytrauma | |||
Platelets (CD62P+) | Serum of severe injured patients (mean ISS 33) | Increased in severe injured patients compared to healthy controls | [176] |
PNML (CD11b+) | Trauma patients (mean ISS 30) | Systemically increased | [177] |
Red blood (CD235a+), leukocytes (CD45+), endothelial cells (CD51+/CD144+) | Trauma patients (Mean ISS 26) | Increased significantly after trauma Tissue factor-bearing MPs (TFMP) was found to be a predictor of substantial bleeding early after acute trauma | [178] |
Red cells (CD235a+/annv+) Platelets (CD41+/annv+) | Traumatic injury compared to controls after 72 h | Increased; fewer CD41+/AnnV+ MVs correlate with hypocoagulability and mortality | [48] |
Platelets (CD41+) Leukocytes (CD45+) Endothelial cells (CD144+) | Trauma patients, SIRS | Correlation between EVs number and clinical outcome of trauma patients | [44] |
Monocytes (TF+/CD13+) | Trauma patients, SIRS | Correlate with ISS; APACHEII, development of SIRS | [44] |