While extracellular vesicles (EVs) have been shown to play a role in CNS disorders, the intersection of EVs, drug use, and HIV is of particular interest. The interactions of HIV and drugs of abuse are a growing concern given the increasing incidence of HIV transmission via shared needles in illicit drug use. As a drug commonly taken through shared needles, METH is being investigated due to its role in exacerbating HIV-mediated inflammation through both increased vesicular shedding and extracellular release. In vivo experiments have shown that cocaine-induced EV release impacts synaptic plasticity through noncoding RNA. Nicotine studies have also highlighted how the differential packaging of antioxidant enzyme cargoes into EVs affects nicotine-mediated HIV pathogenesis. Additionally, studies of both morphine and heroin have demonstrated differences in the miRNA cargoes of EVs, potentially impacting gene expression and exacerbating HIV. Studies of alcohol use in combination with HIV have shown that EV cargoes such as cytokines are affected in HIV-infected subjects who use alcohol. Investigating EV cargo alterations in all forms of substance abuse studies may allow the EV, HIV, and addiction fields to progress towards diagnosis and remedies for substance-abuse-induced toxicity in HIV patients.
Extracellular vesicles (EVs) are a broad, heterogeneous class of membranous lipid-bilayer vesicles that facilitate intercellular communication throughout the body. Secreted from all cell types, these cargo carriers have become important targets of investigation in various fields of study for their potential role in disease pathologies, drug-delivery systems, and therapeutics [1,2]. For the purpose of this review, all three classes of EVs—exosomes (30–150 nm), microvesicles (100–500 nm), and apoptotic bodies (500–5000 nm)—are collectively referred to as EVs, as endorsed by the International Society for Extracellular Vesicles [3]. EVs carry a variety of cargo types, including proteins, lipids, DNA fragments, and a variety of small noncoding RNAs, including miRNAs, mRNAs, and siRNAs [4,5]. The contents of EVs are reflective of the intracellular environments of their host cells, and EVs are released by both healthy and diseased cells [6]. EVs can transfer these cargoes from host cells to recipient cells, inducing functional transformations within recipient cells [7,8,9]. Regulation of EV secretion remains an active area of study, although certain stimuli and cellular conditions have been implicated in triggering EV release from different cell types [10].
EVs play a role in various aspects of healthy physiology, including immune responses [11,12], embryonic stem-cell communication during embryo implantation [13], and exercise [14,15]. EVs also shuttle essential biomolecules between cells that are critical for intercellular communication [16], antigen presentation [17], and signal transduction [18]. Moreover, EVs derived from mesenchymal stem cells have garnered interest in the fields of tissue repair, inflammation, anticancer therapy [19], and stroke [20,21]. Further, compelling evidence marks EVs as a potential drug-delivery system [1,22,23,24]; indeed, engineered EVs are capable of passing through the blood–brain barrier (BBB) [25], which has traditionally been a roadblock for efficient drug delivery to the brain [26,27,28,29].
Besides their beneficial role in the maintenance of physiological homeostasis and potentially therapeutic, diagnostic, and drug-delivery capabilities, EVs have been implicated in many pathogenies, including cardiovascular disease [30], neurodegenerative disorders [31,32,33,34], traumatic brain injury [35,36], HIV [37,38], and a wide range of cancers [39,40,41,42,43]. For instance, EVs may contribute to cancerous proliferation through angiogenesis, migratory and invasive capacities, and formation of metastatic lesions [44]. Dissecting the role and effects of EVs in these disease pathologies presents an ongoing challenge and an opportunity to progress understanding of the mechanisms underlying a diverse array of pressing health issues. Specifically, EV contents may indicate pathological changes in the body, and analysis of the molecular cargoes of the EVs may contribute to the advancement of diagnostic and treatment methods for these diseases.
Central nervous system (CNS) cells like neurons, microglia, astrocytes, oligodendrocytes, ependymal, and brain endothelial cells communicate by releasing EVs containing signaling molecules [45,46]. EVs aid in the signal transmission between neurons and glial cells, along with communication between CNS and peripheral body systems [47,48,49]. EVs maintain cellular homeostasis and clear abnormal aggregates; however, they also contribute to pathogenesis by delivering toxic substances to healthy cells, leading to inflammation and neurodegeneration [50] and thereby perpetuating CNS-associated neurodegenerative disorders [51,52]. Such CNS disorders include lysosomal storage disorders, Parkinson’s disease (PD) [53], Alzheimer’s disease (AD) [54,55,56,57], Huntington’s disease, amyotrophic lateral sclerosis [58], epilepsy, and multiple sclerosis [59,60,61,62,63]. EVs exacerbate disease pathogenesis by providing transportation to abnormally folded proteins and disease factors like α-synuclein [64], amyloid beta (Aβ) and Tau [65,66], huntingtin, and superoxide dismutase 1 [52,58].
EVs in diseased states differ significantly in their morphology and function, making them ideal biomarker candidates [67] as they contain unique proteins depending on the healthy or diseased microenvironment conditions [68,69]. The ability of EVs to cross the BBB, combined with their prevalence in bodily fluids, makes it possible to detect certain biomarkers found in difficult-to-assess regions like the CNS and spleen [70]. EVs may also contribute to neuroprotection; in AD, EVs sequester Aβ in vitro and promote its clearance, thus reducing neurotoxicity [71,72,73]. Moreover, neuronal EVs carry extracellular RNAs [74,75], including disease miRNA signatures that could be used as biomarkers to diagnose CNS disorders [58,76,77,78].
Additionally, EVs are potential candidates as therapeutic delivery agents as they can be easily loaded with therapeutic drugs, are minimally degraded, maintain their morphology and function, and can cross the BBB [2,79,80,81,82]. Due to their ability to carry functional small miRNA, tRNAs, lipids, and proteins [83], EVs are excellent carriers of the therapeutic agents. Besides acting as protective barriers against degradation and immunoreactivity, EVs can also increase the efficiency of delivery to targets, further aiding drug delivery and therapy for CNS diseases.
Investigations into the role of EVs in drug addiction and as future therapeutics for addiction are currently represented by a small but developing body of work [84]. Recent evidence points to a role of EV cargoes, specifically noncoding regulatory miRNAs [85], in mediating the body’s response to a variety of addictive substances, including cocaine [86,87], cannabinoids [88], nicotine [89], alcohol [90], and opioids [91,92]. These studies indicate that EVs and their cargoes may play a significant role in modulating addiction to a variety of substances, but further investigation is required to understand the full impact of EVs on addictive pathways and of addictive substances on EV secretion, uptake, and cargo content. There is a significant gap in the knowledge connecting substance abuse and our understanding of EVs and their cargoes in those addiction pathologies, although many investigators are currently working to close that gap.
Cargo | Condition | EV Source | Model | Up/Down | Reference | |
---|---|---|---|---|---|---|
miRNA | 29b | Morphine + HIV | Astrocyte | Rat primary cultures | Up | [172] |
21 | Heroin + HIV | Plasma | Human | Up | [173] | |
146a | Heroin + HIV | Plasma | Human | Up | [145,173] | |
126 | Heroin + HIV | Plasma | Human | Up | [173] | |
let-7a | Heroin + HIV | Plasma | Human | Up | [173] | |
let-7b | Alcohol | Microglia | BV2 cell line | Up | [146] | |
276 | Methamphetamine (METH) | Plasma | Rat | Up | [103] | |
218b | METH | Plasma | Rat | Up | [103] | |
194-5p | METH | Plasma | Rat | Up | [103] | |
152-3p | METH | Plasma | Rat | Up | [103] | |
25 | METH | Plasma | Rat | Down | [103] | |
276 | Ketamine | Plasma | Rat | Down | [103] | |
22-3p | METH/Bipolar | Plasma | Rat | Up | [103,110] | |
107 | Nicotine | Bronchoalveolar lavage fluid (BLF) | Human | Up | [129] | |
126 | Nicotine | BLF | Human | Up | [129] | |
19a-3p | Nicotine | BLF | Human | Up | [129] | |
200a-3p | Nicotine | BLF | Human | Up | [129] | |
21-3p | Nicotine | Macrophage | RAW264.7 cell line | Up | [132] | |
21 | SIV | Brain | Monkey | Up | [160] | |
182 | Alcohol | Astrocyte | Mouse primary culture | Up | [145] | |
200b | Alcohol | Astrocyte | Mouse primary culture | Down | [145] | |
155 | Alcohol | Microglia | BV2 cell line | Up | [146] | |
140-3p | Alcohol | Fetal neural stem cells (fNSC) | Mouse | Up | [149] | |
15b-3p | Alcohol | fNSC | Mouse | Up | [149] | |
340-5p | Alcohol | fNSC | Mouse | Up | [149] | |
674-5p | Alcohol | fNSC | Mouse | Up | [149] | |
130a | HIV/Cocaine | Monocytes | Monomac-1 cell line | Up | [166] | |
lncRNA | MALAT1 | Nicotine | BLF | Human | Up | [129] |
HOTAIR | Nicotine | BLF | Human | Up | [129] | |
HOTTIP | Nicotine | BLF | Human | Up | [129] | |
AGAP-AS1 | Nicotine | BLF | Human | Up | [129] | |
ATB | Nicotine | BLF | Human | Up | [129] | |
TCF7 | Nicotine | BLF | Human | Up | [129] | |
FOXD2-AS1 | Nicotine | BLF | Human | Up | [129] | |
HOXA11-AS | Nicotine | BLF | Human | Up | [129] | |
PCAF1 | Nicotine | BLF | Human | Up | [129] | |
BCAR4 | Nicotine | BLF | Human | Up | [129] | |
mRNA | EGFR | Nicotine | BLF | Human | Up | [129] |
KRAS | Nicotine | BLF | Human | Up | [129] | |
ALK | Nicotine | BLF | Human | Up | [129] | |
MET | Nicotine | BLF | Human | Up | [129] | |
LKB1 | Nicotine | BLF | Human | Up | [129] | |
BRAF | Nicotine | BLF | Human | Up | [129] | |
PIK3CA | Nicotine | BLF | Human | Up | [129] | |
RET | Nicotine | BLF | Human | Up | [129] | |
ROS1 | Nicotine | BLF | Human | Up | [129] | |
Cytokines | 130a | HIV/Cocaine | Monocytes; Plasma | Monomac-1 cell line; Human | Up | [166,175] |
IL6/IL-8 | Smoking + HIV | Plasma | Human | Up | [175] | |
IL-6 | Smoking + HIV | Plasma | Human | Up | [175] | |
IL-1ra | Alcohol/ Nicotine + HIV | Plasma | Human | Up | [175] | |
IL-10 | Alcohol/Nicotine HIV |
Plasma | Human | Up | [175] | |
Proteins | Amyloid beta (Aβ) | HIV | Brain | Human | Up | [161] |
GFAP | HIV + Alcohol | Plasma | Human | Up | [177] | |
L1CAM | Nicotine | Plasma | Human | Up | [177] | |
α-synuclein | METH | Neuroblastoma cells | SH-SY5Y cell line | Up | [178] | |
TLR4 | Alcohol | Astrocyte | Mouse primary culture | Up | [145] | |
NFκB-p65 | Alcohol | Astrocyte | Mouse primary culture | Up | [145] | |
IL-1R | Alcohol | Astrocyte | Mouse primary culture | Up | [145] | |
Caspase-1 | Alcohol | Astrocyte | Mouse primary culture | Up | [145] | |
CPM | HIV | Plasma | Human | Up | [179] | |
CDH3 | HIV | Plasma | Human | Up | [179] | |
HPX | HIV + alcohol | Plasma | Human | Down | [176] | |
BAGE | Nicotine | Lung | Human | Up | [129] | |
PD-L1 | Nicotine | Lung | Human | Up | [129] | |
PRDX6 | HIV + Nicotine | Macrophage | U937 cells | Down | [168] | |
Catalase | HIV + Nicotine | Macrophage | U937 cells | Down | [168] | |
CSF2RA | HIV | Plasma | Human | Up | [179] | |
MANF | HIV | Plasma | Human | Up | [179] |
This entry is adapted from the peer-reviewed paper 10.3390/ijms21186765