Non-Coding RNAs in Environmental Stress Response: Comparison
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Air pollution has increased over the years, causing a negative impact on society due to the many health-related problems it can contribute to. Although the type and extent of air pollutants are known, the molecular mechanisms underlying the induction of negative effects on the human body remain unclear. Emerging evidence suggests the crucial involvement of different molecular mediators in inflammation and oxidative stress in air pollution-induced disorders. Among these, non-coding RNAs (ncRNAs) carried by extracellular vesicles (EVs) may play an essential role in gene regulation of the cell stress response in pollutant-induced multiorgan disorders.

  • air pollution
  • stress
  • heat shock proteins
  • non-coding RNAs
  • respiratory diseases
  • Extracellular Vesicles (EVs)
  • Cardiovascular Diseases
  • Neurodegenerative Diseases

1. ncRNAs as Part of EVs Cargo

RNA is part of the EVs’ cargo and is at the center of many functions attributed to EVs since it can alter gene expression and function in recipient cells. EVs are a heterogeneous group of vesicles released from cells under physiological and pathological conditions [104,105][1][2] that contain a cargo of bioactive molecules reflecting their parental cells and can modulate recipient cells’ behavior [106,107][3][4]. EVs are now considered an additional mechanism for intercellular communication, enabling cells to exchange information through proteins, lipids, and genetic material [108][5]. EVs are released from cells into the extracellular space and can be found in all biological fluids: blood [109][6], urine [110][7], saliva [111][8], cerebrospinal fluid [112][9], breast milk [113][10], bronchoalveolar lavage fluid (BALF) [114][11] etc. Furthermore, EV’s biogenesis has been a significant evolutionary advancement because the cargo encapsulated inside the vesicular structures is protected from the degradation of ribonucleases, deoxyribonucleases, and proteases that are abundant in the extracellular space. These enzymes cannot traverse the EVs lipid bilayer [115][12]. The uptake of EVs by recipient cells can be either selective (via ligand-receptor interaction) or non-selective [116][13]. EVs are generally classified according to certain intrinsic properties, including density, size, and biogenesis processes. They are generally divided into three subtypes according to their biogenesis mechanism: exosomes, microvesicles and apoptotic bodies [117][14]. The International Society for Extracellular Vesicles (ISEV) currently encourages the use of the term “extracellular vesicles” as a generic term for all secreted vesicles, considering the lack of consensus for the identification of specific markers to distinguish between the different subtypes of EVs [118][15].
EV-associated RNAs (EV-RNA) consist of RNA fragments of different sizes and include mRNA, pre-miRNA and mature miRNA precursors, snoRNA, rRNA, tRNA, lncRNA, piRNA, and mitochondrial RNA [119][16]. Initially, the focus on EVs cargo was on proteins, but the discovery 2007 of biologically active RNA particles in small EVs amplified the potential role of EVs in biology [120][17]. Currently, the Vesiclepedia database includes more than 27,000 entries for mRNAs and more than 10,000 entries for non-coding RNAs [121][18]. The role of non-coding encapsulated RNAs in EVs is emerging, especially in liquid biopsy diagnostics, a promising non-invasive alternative to traditional methods of diagnosis and prognosis [122][19]. The liquid biopsy method is based on identifying clinically relevant biomarkers. It allows for early diagnosis and monitoring of diseases from their earliest stages, which would bring enormous benefits to human health.
It has been shown that the ncRNA content inside EVs is higher than in the cells from which they originate, in contrast to the protein and lipid content that reflect the parent cells [123,124][20][21]. This has led researchers to hypothesize the existence of highly selective RNA-loading mechanisms inside EVs. The interactions with RNA-binding proteins (RBPs), such as argonaute 2 (AGO2), ALIX and annexin A2, appear to be crucial to explain the highly controlled and specific process of selective ncRNA packaging in EVs [125,126,127,128,129][22][23][24][25][26]. It must be noted that RBPs constitute about 25% of the protein content of EVs [130][27]. Furthermore, it was shown that post-transcriptional modifications at the 3′ end of miRNAs could also influence their selective loading into EVs [129][26]. RNA-EVs are divided into three types: RNAs with known functions, such as intact mRNA and miRNA; RNAs with probable but unproven intercellular mediator functions, such as piRNA; and, thirdly, RNA fragments (e.g., tRNA and mRNA and rRNA fragments) with unknown functions, which may be non-functional degradation products [119][16]. EVs could also play a potential role in drug therapy due to their cargo-protecting characteristic, as they could be used to deliver drugs in a targeted manner to cells (e.g., cancer cells). This opens the door to potential RNA-based therapies, including siRNAs, miRNAs, antisense oligonucleotides, mRNAs, guide RNAs and self-amplifying RNAs. The advantages of the therapeutic use of EVs include their high biocompatibility and stability and their limited immunogenicity [130][27].

2. The Effects of Pollutants on the Production, Release, and Cargo of Circulating EVs

Environmental pollutants contribute to the pathogenesis of numerous human diseases, with chronic inflammation and oxidative stress as common hallmarks. Emerging evidence suggests that EVs may play a role in the relationship between environmental pollutants and the pathogenesis of chronic systemic diseases [131][28]. Physiologically, EVs from the pulmonary region exhibit protective effects against stress signals since they participate in maintaining pulmonary homeostasis. However, air pollution alters the composition of pulmonary EVs, leading to a dysregulation of the EVs cargo and increasing their production and release [132][29]. One of the functions of the respiratory epithelium is to defend the body against pathogens or environmental pollutants. In addition, it is involved in the regulation of immune responses, as well as in tissue repair and remodeling after injury [133][30]. However, repeated exposure of the respiratory epithelium to air pollution induces chronic airway inflammation that can lead to the release of inflammatory molecular signals in the circulatory system [134][31]. For instance, exposure to PM has been shown to lead to an increased release of EVs, especially in overweight subjects [135][32].
The role of alveolar macrophages and the respiratory epithelium is to rapidly eliminate inhaled harmful substances and thus maintain an anti-inflammatory state. EVs from alveolar macrophages contribute to this anti-inflammatory state by providing a suppressor of cytokine signaling (SOCS) 1 and 3 to epithelial cells. Studies have been conducted on mice exposed to cigarette smoke extract (CSE) and human smokers. Both showed reduced SOCS concentrations in BALF compared to non-smoking controls, confirming a loss in smokers of the anti-inflammatory status derived from EVs [136][33]. Exposure to CSE, PM and other air pollutants has been shown to alter transcriptomic (miRNAs) composition and increase the release of circulating EVs derived from endothelial cells and immune cells, as well as pro-inflammatory molecules [137,138,139][34][35][36]. Bronchial epithelial cells and lung fibroblasts have been shown to release CD63 + CD81 + and TF + EVs in response to respiratory toxicants [140][37]. Thus, exposure to environmental pollutants appears to shift the functionality of EVs secreted by mononuclear, epithelial, and endothelial cells from an anti-inflammatory to a pro-inflammatory phenotype. Exposure to environmental agents may ultimately trigger epigenetic changes because abnormal ncRNA expression within EVs may induce developmental changes or lead to disease progression.

3. ncRNAs and Links to Respiratory Diseases

Pollution is known to cause and aggravate several chronic respiratory diseases. The World Health Organization has ranked air pollution as the most common environmental cause of premature death [141][38]. Several studies have suggested that ncRNAs inside EVs are involved in respiratory diseases caused by air pollution. For example, one study found that exposure to PM increased the expression of miR-222-3p in EVs isolated from bronchial epithelial cells [142][39]. This miRNA was shown to target genes involved in oxidative stress and inflammation, suggesting that it may contribute to the development of airway inflammation and damage caused by PM exposure. In another study, miR-146a and miR-146b were significantly elevated in bronchoalveolar lavage fluid (BALF) and lung tissue homogenate from mice exposed to PM 2.5 [143][40]. Furthermore, it was seen that in bronchial epithelial cells treated with PM 2.5, there was the secretion of EVs that increased bronchial smooth muscle cell contractility and contributed to airway hyperresponsiveness [144][41].
Other studies have also reported that EVs, carrying ncRNAs in their cargo, are functionally involved in cancer initiation, progression and the development of metastases [145][42]. Exposure to PM 2.5 induced differential expression of vesicular miRNAs, leading to tumour development [146][43]. ncRNAs as cargo of EVs can be used as biomarkers of lung cancer (LC) because it was discovered that certain miRNAs are dysregulated in LC patients, including miR-21, miR-23b-3p, miR-10b-5p, miR-139-5p, miR-200b-5p, miR-378a, miR-379 and miR-4257 [147,148][44][45].
lncRNAs regulate certain biochemical and cellular processes, such as gene expression, RNA splicing and ligand-receptor engagement, which in turn mediate the pathogenesis of respiratory disorders [149][46]. They have also emerged as novel master regulators of initiation, progression, and response to therapy in various cancers. lncRNA HOX transcribed antisense RNA (HOTAIR) represses gene expression, and its high expression in LC correlates with metastasis and poor prognosis [150][47]. MALAT1 is one of the most highly valued lncRNAs in lung cancer. It modulates miR-124/STAT3 to promote carcinogenesis [151][48] and the miR-204/SLUG axis to enhance epithelial-mesenchymal transition (EMT) and lymph node metastasis [152][49]. Another widely evaluated oncogenic lncRNA in lung cancer is XIST because its downregulation has been shown to inhibit tumor growth via the upregulation of E-cadherin and downregulation of Bcl-2 [153][50].
In COPD, there is severe airway inflammation with consequent damage to the lung parenchyma. This leads to the destruction of the alveolar wall and rarefaction of the alveolar sacs, resulting in breathing difficulties and reduced lung function (irreversible airway obstruction) [154][51]. Air pollution is a significant risk factor for COPD, and exposure to particulate matter (PM) has been shown to induce inflammation and oxidative stress in the lungs, which can contribute to the development and progression of COPD. Prevention is the key to minimizing risk factors, such as air pollution and cigarette smoke. It has been shown that miR-210 and miR-218 expression is significantly higher in EVs released from primary human bronchial epithelial cells (HBEC) after exposure to cigarette smoke. This promotes airway fibrosis in the pathogenesis of COPD [155][52]. It was subsequently observed that following exposure to cigarette smoke, EVs showed a reduced expression of specific miRNAs, including let-7d, miR-191, miR-126 and miR125a, promoting apoptotic cell clearance [156][53]. Most studies report a global downregulation of miRNAs in response to cigarette smoke, especially from human alveolar macrophages, probably by modification of DICER, an RNA endonuclease involved in miRNA maturation [157,158][54][55]. The expression of some miRNAs, such as miR-638 and miR-101, appear to correlate with the severity of regional emphysema [159,160][56][57]. Among lncRNAs, increased expression of SCAL1 was seen in airway epithelial cells as part of the oxidative stress response to cigarette smoke exposure [161][58].
Asthma is a chronic inflammatory disease characterized by airway remodeling and bronchial hyperresponsiveness caused by both genetic factors and environmental stress factors. Air pollution is a major environmental factor that can exacerbate asthma symptoms. Exposure to air pollutants, such as particulate matter, ozone, nitrogen dioxide, and sulfur dioxide, can trigger inflammation in the airways, leading to asthma attacks. EVs derived from bronchoalveolar lavage fluid of asthmatic patients contained higher levels of certain miRNAs than healthy controls, suggesting that these EVs may play a role in the development of asthma [162,163][59][60]. ncRNAs play a key role in the onset and progression of asthma by regulating gene transcription [164][61]. miRNAs influence asthma pathogenesis by regulating immune cells, bronchial epithelial cells and airway smooth muscle cells (ASMCs). It has been shown that miR-1, miR-18a, miR-21, miR-146a, miR-155, miR-210 and miR-1248 can regulate T-cell function and the production of Th2 cytokines involved in the pathogenesis of asthma [165,166,167][62][63][64]. A significantly reduced expression of let-7a, miR-21, miR-133a, miR-155, miR-328 and miR-1248 was found in exhaled breath condensates from asthmatic subjects compared to healthy subjects [163][60]. Among lncRNAs, it was shown that lncRNA-MEG3 could competitively adsorb miR-17 in CD4+ T cells of asthmatic patients [168][65]. lncRNA MALAT1, on the other hand, adsorbs miR-155 by negatively regulating it and altering the Th1/Th2 balance among CD4+ T cells [169][66]. Another lncRNA under investigation is lncRNA PVT1, which, if over-regulated, could inhibit miR-149 expression in bronchial epithelial cells, promoting airway inflammation and cell barrier destruction, thus accelerating the development of asthma [170][67].

4. ncRNAs as Mediators of the Crosstalk between Air Pollution and Cardiovascular Diseases

Cardiovascular diseases (CVDs) are a group of disorders affecting the heart and the blood vessels, such as heart failure, coronary heart disease and acute myocardial infarction (AMI) and represent one of the leading causes of morbidity and mortality in the world [171][68].
Besides genetic causes, increasing compelling evidence has demonstrated that exposure to environmental air pollution, especially particulate matter (PM), significantly contributes to the development of CVDs and acute cardiac events like stroke, likely by triggering pulmonary inflammation, systemic inflammation, autonomic nervous system imbalance, oxidative stress, endothelial dysfunction and prothrombotic changes [172,173,174,175,176][69][70][71][72][73]. Accordingly, it has been shown that short-term exposures to PM and nitrogen oxides are consistently associated with increased risks of hypertension and triggering of myocardial infarction (MI) and stroke. In contrast, long-term exposures are largely associated with increased risk of atherosclerosis, incident MI, hypertension, and incident stroke and stroke mortality [177][74].
In recent years, researchers have started to investigate the underlying epigenetic component of CVDs. NcRNA-mediated gene regulation has been proposed to play a key role in the possible correlation between air pollutant exposure and the risk of CVDs [178,179,180][75][76][77]. It has been well established that short and long ncRNAs are involved in cardiac development and physiological functions. Moreover, they significantly contribute to the development and progression of various CVDs [181,182,183][78][79][80].
A cohort study by Bollati et al. analyzed male workers’ miRNA profile in peripheral blood leukocytes after a three-day exposure to ambient PM rich in metals. The examined subjects were not affected by CVDs, or other conditions in which systemic inflammation occurs, such as cancer and respiratory diseases. A qRT-PCR analysis revealed a significant increase in miR-21 and miR-222. Moreover, a positive correlation was found between the levels of miR-21 and 8-hydroxy-guanine (8-OH-dG), suggesting a relationship with oxidative stress [184][81]. Similarly, mir-222 has been found in higher concentrations in the extracellular fraction of saliva in schoolchildren following recent exposure to ultrafine particles (UFP) [185][82]. Both miR-21 and miR-222 are highly expressed in the cardiovascular system, regulating critical biological pathways. For instance, miR-21 has been reported to exert a cardioprotective role [186][83].
On the contrary, they are dysregulated in numerous CVDs, suggesting they could be used as promising cardiovascular biomarkers and novel therapeutic targets/agents in CVDs, including air pollution-correlated ones [187,188][84][85]. However, in a cohort of 153 elderly males, an inverse relationship was found between eight leukocyte miRNAs, including miR-21 and miR-222, and PM 2.5 exposure. According to the authors, considering the activity of the predicted target mRNAs, this negative association should result in increased inflammation, endothelial dysfunction, and atherosclerosis [189][86]. The contradictory results could be due to differences in the methodologies used by the two research teams, the particle composition, the time of exposure and/or the characteristics of the participants.
Chen and colleagues observed that in healthy young subjects, short-term exposure to PM was positively associated with the expression (mRNAs, proteins, or both) of cytokines involved in inflammation, coagulation, and endothelial dysfunction, including IL1, IL6, TNF, toll-like receptor 2, coagulation factor 3, and endothelin 1. On the contrary, it was negatively associated with the expression of miRNAs predicted to target these cytokines’ mRNAs, such as miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p. Thus, the authors suggested that a possible correlation between PM exposure and CVD development might be mediated by miRNAs controlling specific cytokine expression [190][87].
Another interesting line of research regarding the correlation between exposure to environmental contaminants and increased CVD risk focused on investigating EVs’ miRNA content. Numerous studies have shown that exposure to ambient air pollutants, including fine particulate matter (PM 2.5), coarse particulate matter (PM 10), ozone (O3), and nitrogen oxides (NOx), was significantly associated with changes in the expression of some circulating miRNAs, including miR-26a-5p, miR-146a-5p, miR-150–5p and miR-21-5p, some of which may mediate their effects on the downstream inflammation, coagulation, and blood lipid biomarkers [134,139,190,191,192,193,194,195,196][31][36][87][88][89][90][91][92][93].
In this context, Bollati and coworkers investigated whether PM and metal-rich PM may alter microvesicles (MVs) content, finding that miR-128 and miR-302 were significantly overexpressed after three days of PM exposure, compared with the beginning of the working week [134][31]. Both miRNAs regulate gene expression linked with CVDs, including coronary artery disease, cardiac hypertrophy, and heart failure pathways, suggesting MV-associated miRNAs as mediators of air pollution toxicity [134][31]. Furthermore, the effects of metal-rich PM have been evaluated in a subset of the same study population, identifying four PM-sensitive miRNAs (miR-29a-3p, miR-146a-5p, miR-421, and let-7 g-5p) that were differentially expressed compared to control samples and seem to favor a pro-inflammatory response, potentially contributing to several diseases, including CVDs and respiratory system disorders [139,191][36][88]. Similarly, Rodosthenous and colleagues investigated the relationship between short-, intermediate-, and long-term exposures to PM and the EVs-miRNome in a cohort of healthy adults. They observed long-term exposure to PM 2.5 increased some EVs’ miRNAs in serum. The predicted target genes, including interleukin 6 (IL-6), C-X-C motif chemokine ligand 12 (CXCL12), vascular cell adhesion molecule 1 (VCAM-1), a cluster of differentiation 40 (CD40), and platelet-derived growth factor subunit beta (PDGFB), are linked to CVD-related signaling pathways, such as oxidative stress, inflammation, atherosclerosis, and cardiac hypertrophy [193][90]. These results were confirmed by a subsequent study by the same authors, where it was demonstrated that an increase of multiple EVs’ mRNAs in serum from elderly males could modify the association between PM 2.5 and systolic blood pressure by targeting proteins involved in essential cardiovascular functions [194][91]. These results aligned with previous data from Motta et al., which demonstrated that miRNAs are responsible for the association between exposure to particulate air pollution and increased blood pressure, a well-established risk factor for cardiovascular disease [197][94].
Pergoli and colleagues observed that short-term exposure to PM 10 was associated with an increased release of EVs, especially from monocytes/macrophages (CD14+) and platelets (CD61+), as well as high fibrinogen levels in overweight/obese people [192][89]. The analysis of these EVs’ content revealed that nine miRNAs were downregulated in response to PM exposure. As highlighted by integrated network analysis, five of them, i.e., let-7c, miR-106a, miR-185, miR-331, and miR-652, modulate cardiovascular-linked processes, including fibrinogen levels, suggesting an association between extracellular miRNA released after short-term exposure to PM and increased coagulation [192][89]. Therefore, air pollutant exposure may affect the EVs’ content and downstream effects on target cells. Most recently, a change of small EV (sEVs) subpopulations released from the respiratory system has also been observed in response to PM 2.5 exposure, increasing CD63/CD81/CD9-positive particles [196][93]. In particular, the authors observed that these sEVs contained miR-421, which contributed to cardiac dysfunction by targeting the cardiac angiotensin-converting enzyme 2 (ACE2), suggesting the sEVs’ miRNome as responsible for the crosstalk between lung and heart upon PM 2.5 exposure [196][93].

5. ncRNAs and Neurodegenerative Diseases

Neurodegenerative diseases (NDDs), including Parkinson’s disease (PD), Alzheimer’s disease (AD), and other dementia disorders, affect millions of people worldwide and are caused by the progressive degeneration and death of select populations of neurons. This process leads to debilitating conditions such as cognitive, motor, and behavioral impairments [198][95]. Recent studies indicate that air pollution may also adversely affect the brain, contributing to the etiopathogenesis of neurodegenerative diseases. There is growing evidence that traffic-related air pollution (TRAP) exposure might lead to the development and progression of neurodegenerative disorders [199][96]. A study conducted in the U.S. reported that the risk of developing dementia for residents in areas with high PM 2.5 was increased by 92% compared to those who lived in areas with lower levels of particulate matter [200][97]. In addition, another study conducted on mice demonstrated the induced glutaminase-containing EVs release from microglial cells. The increment of glutamate is associated with neurodegeneration [201][98]. Several studies suggest that exposure to air pollution might be associated with PD, a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Different expression levels of several miRNAs can be used as potential diagnostic biomarkers for PD. Particularly, EV-derived miRNAs are increasingly used to diagnose the disease [202][99]. A study on blood-derived EVs in PD reported higher miR-34a-5p levels in PD patients compared to controls, whereas other similar studies on serum EV-derived miRNAs found upregulated miRNAs, such as miR-22, miR-23a, miR-24, andmiR-222, and a downregulated miRNA, miR-505, in PD patients [203,204][100][101]. Also, EVs isolated from the cerebrospinal fluid (CSF) are a promising source for PD diagnostic markers. The qRT-PCR analysis showed differences in the miR-181a-5p, miR-181b-5p, miR-9-5p and let-7b in PD patients versus control comparisons [203][100].
Various studies have demonstrated a strong association between air pollution and AD. In this neurodegenerative disease, the amyloid-beta protein (Aβ) dysregulation leads to aggregates of amyloid fibrils and neurotoxicity. A German study showed that exposure to PM 2.5 and NOx was associated with an increased risk for AD [205][102]. Moreover, a study conducted in London concluded that residents with the most exposure to nitrogen dioxide and PM 2.5 were the most likely to be diagnosed with dementia, with associations more consistent for AD [206][103]. Compared to healthy controls, a study on plasma-derived EVs of AD patients reported downregulation of miR-342-3p, miR-451 and miR-21-5p. On the contrary, other studies revealed several EV-derived miRNAs, such as miR-29a, -451a, -125b, -582-5p, -106a-5p, and -106b-5p, were upregulated in AD patients, compared to healthy controls [207,208,209][104][105][106].
Furthermore, exposure to air pollution is also associated with other types of dementia disorders, including vascular dementia (VD) and frontotemporal dementia (FTD) [210,211][107][108]. VD is dementia caused by reduced blood flow in various brain regions. In contrast, FTD is a rare type of dementia characterized by progressive nerve cell loss in the frontal and temporal lobes of the brain. Recent studies have shown that EV-derived miRNAs are involved in the pathogenesis of dementia disorders, making them valuable biomarkers for diagnosing dementia. Serum levels of EV-derived miR-135a increased, whereas levels of EV-derived miR-193b, -23a, -29a, -130b decreased in VD patients versus healthy controls. EVs isolated from FTD patients’ cerebrospinal fluid (CSF) showed downregulated expression of miR-204-5p and mirR-632 compared to healthy controls [207][104].

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