|Year : 2021 | Volume
| Issue : 4 | Page : 111-115
PM2.5 pollution and endoplasmic reticulum stress response
Eric Heng1, Areeba Maysun1, Kezhong Zhang2
1 Center for Molecular Medicine and Genetics, Detroit, MI, USA
2 Center for Molecular Medicine and Genetics; Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
|Date of Submission||02-Nov-2021|
|Date of Decision||27-Nov-2021|
|Date of Acceptance||29-Nov-2021|
|Date of Web Publication||29-Dec-2021|
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201
Source of Support: None, Conflict of Interest: None
Air pollution is a sustained problem of public health for the general population in urban areas, especially for those living in areas of intensive traffic or industrial activity. Accumulating evidence has confirmed a significant association between exposure to fine ambient particulate matter with aerodynamic diameters <2.5 μm (PM2.5) and the increase of morbidity and mortality associated with cardiovascular and metabolic diseases. It has been identified that inflammation and intracellular stress responses play important roles in PM2.5-caused pathogenesis. Unfolded protein response (UPR) is an intracellular stress signaling from the endoplasmic reticulum (ER) to help cell recovery from the stress caused by the accumulation of unfolded or misfolded proteins. Exposure to high levels of environmentally relevant PM2.5 may directly or indirectly interrupt the protein folding process in the ER, causing ER stress. A number of studies suggested that ER stress response, or UPR, interacts with mitochondrial stress and inflammatory responses, under PM2.5 exposure, to modulate functions and survival of specialized cell types that are involved in the development of cardiovascular, metabolic, and neurodegenerative diseases. In this review, we summarize the recent advance in understanding the mechanistic links between PM2.5 and ER stress response.
Keywords: Air pollution, PM2.5, endoplasmic reticulum stress, unfolded protein response
|How to cite this article:|
Heng E, Maysun A, Zhang K. PM2.5 pollution and endoplasmic reticulum stress response. Environ Dis 2021;6:111-5
| PM2.5 Pollution|| |
Substantial evidence supports PM2.5 as the fifth leading risk factor for global mortality, accounting for approximately 9 million deaths per year., Epidemiological and animal model studies have consistently linked air pollutants, primarily derived from stationary and traffic-related combustion sources, to the increase of mortality and morbidity associated with cardiovascular and metabolic diseases.,,, Ambient particulate matter in fine and ultrafine ranges (aerodynamic diameter <2.5 μm, PM2.5) is strongly associated with the pathogenesis of air pollution-associated systemic diseases.,,, Traffic-related PM2.5 is a complex mixture of particles and gases from gasoline and diesel engines, together with dust from wear of road surfaces, tires, and brakes., Airborne PM2.5 exhibits an incremental capacity to penetrate to the most distal airway units and potentially the systemic circulation., Recent studies have addressed that traffic-related PM2.5 may promote metabolic syndrome possibly through exaggerating systemic inflammation,, causing intracellular stress responses,, and disrupting energy homeostasis.,,
| Endoplasmic Reticulum Stress and Unfolded Protein Response|| |
Endoplasmic reticulum (ER) stress is a condition that occurs when the capacity of protein folding and assembly in the ER is overwhelmed or the folding process is disrupted, leading to an accumulation of unfolded or misfolded proteins in the ER lumen. This can be caused by a variety of conditions that lead to an imbalance of proteins in the ER, such as changes in the environment that force the cell to increase its protein production, defect in protein transport from the ER or ER-associated degradation (ERAD) of unfolded or misfolded proteins, and mutations that result in the overexpression of misfolded proteins [Figure 1]. The relationship between the general cellular stress response and ER stress means that many stress challenges, such as cellular calcium disruption, deoxyribonucleic acid (DNA) damage, and increased reactive oxygen species (ROS), may also contribute to ER stress.,,
|Figure 1: The pathways leading to endoplasmic reticulum stress and the associated pathogenesis. ERAD: ER-associated degradation|
Click here to view
The cell responds to ER stress with the unfolded protein response (UPR), which activates a series of pathways that reduces the misfolded or unfolded protein load. In periods of low-to-moderate ER stress, the cell may activate transmembrane sensors in the membrane of the ER, including the three most prolific UPR transducers: Inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6)., These signaling molecules alter transcriptional or translational programs to restore ER homeostasis in response to ER stress. This can be achieved by a number of different ways, including decreasing the expression of protein, increasing chaperone activity, or increasing protein transport out of the ER, either by the endomembrane system or ERAD [Figure 1]. In periods of chronic or high stress, the cell may take more drastic measures, leading to autophagy, cellular senescence, and apoptosis. Specifically, when cells encounter ER stress, the ER stress sensor PERK kinase is activated to phosphorylate translation initiation factor elF2α, leading to general protein translational attenuation. However, under prolonged or severe ER stress conditions, phosphorylated eIF2α can selectively recognize a small number of mRNAs, leading to their translation to synthesize stress proteins involved in cell death programs, Along with the PERK-mediated UPR pathway, IRE1-and ATF6-mediated UPR pathways are also activated to increase protein folding capacity and ERAD. Under ER stress, IRE1 functions as an RNase to splice the mRNA encoding X-box binding protein 1 (XBP1).,, Spliced Xbp1 mRNA encodes a transcription factor that activates the expression of a group of ER chaperones and enzymes to help protein folding, secretion, as well as ERAD of misfolded proteins. Under ER stress, ATF6 is released from the ER and transits to the Golgi where it is cleaved to produce a bZIP transcription factor that activates expression of UPR target genes encoding functions involved in protein folding, secretion, and degradation in the ER.,,
Due to its differing responses in relation to the level of stress, in many diseases, the UPR acts as a double-edged sword. While on the one hand, it may protect the cell initially from ER stress, chronic and sudden high levels of ER stress may overwhelm the cellular system, leading to programmed cell death, which could further increase cellular instability., Recently, an increasing number of studies have associated stress conditions with many common metabolic disorders such as cardiovascular disease, fatty liver disease, and type-2 diabetes. Oftentimes, many of the cell types related to these common metabolic diseases, such as hepatocytes, adipocytes, and beta cells, heavily use their ER in the secretion and processing of molecules related to lipid and glucose metabolism, rendering them susceptible to the effects of ER stress. Thus, it is important to see whether there are genetic predispositions to those conditions through the lens of ER stress.
| PM2.5 Exposure Selectively Activates the Pathways of Endoplasmic Reticulum Stress Response|| |
A number of studies with both animal models and in vitro culture cells showed that exposure to high concentrations of PM2.5 induces ER stress and differentially activates the UPR pathways. Inhalation exposure of the mice to environmentally relevant PM2.5 induces ER stress and activation of UPR in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. PM2.5-induced ER stress relies on the production of ROS. Interestingly, PM2.5 exposure activates PERK/eIF2α-mediated UPR pathway, but not IRE1/XBP1-mediated UPR pathway, leading to ER stress-associated apoptosis in mouse lung or liver tissues. Indeed, PM2.5 exposure decreases the activity of IRE1 in splicing Xbp1 Mrna.
Interestingly, another study with animal models showed that chronic inhalation exposure to PM2.5 for 10 months induces macrophage infiltration and IRE1-mediated UPR pathway in mouse white adipose tissue in vivo. Specifically, PM2.5 exposure induces two distinct UPR signaling pathways mediated through IRE1: (1) IRE1/XBP1-mediated ERAD of unfolded or misfolded proteins, and (2) Regulated IRE1-dependent Decay (RIDD) of mRNAs. In line with UPR activation and macrophage infiltration, the pathways of lipogenesis, adipocyte differentiation, and lipid droplet formation were also elevated, as indicated by the gene expression profiles, in the adipose tissue of the mice exposed to PM2.5. These studies suggest that PM2.5 exposure induces different UPR programs in a context-dependent manner. While PM2.5 exposure induces PERK/eIF2α-mediated UPR pathway in the lung and liver, it induces IRE1/XBP1and IRE1/RIDD UPR pathways in adipose tissues.
The effect of PM2.5-induced ER stress is expanded to autophagy. Associated with the cardiovascular system, PM2.5 challenge induced ER stress response and subsequent autophagy and apoptosis in vascular endothelial cells. PM2.5-induced autophagy and apoptosis rely on ER stress, as demonstrated by the treatment of the ER stress inhibitor 4-PBA. Further, In vitro PM2.5 exposure promotes the regulatory axis of angiotensin II (ANGII) production, ACE/ANGII/AT1R axis, in human umbilical vein endothelial cells and rat aortic endothelial cells (RAECs). IRE1/XBP1-mediated UPR is responsible for augmented ACE/ANGII/AT1R axis in vascular endothelial cells under PM2.5 exposure. Interestingly, PM2.5-triggered IRE1/XBP1-UPR pathway links HIF1α to augment ACE/ANGII/AT1R axis in vascular endothelial cells. Ablation of IRE1/XBP1/HIFα-dependent ACE/ANGII/AT1R axis inhibited oxidative stress and proinflammatory responses in the vascular endothelial cells under PM2.5 exposure.
It was reported that PM2.5 can penetrate the skin via aryl hydrocarbon receptors, leading to skin senescence, inflammatory skin diseases, DNA damage, and carcinogenesis.,, A recent study showed that fisetin, a bioactive flavonoid, protects from PM2.5-induced oxidative stress and apoptosis by inhibiting ER stress response in human Keratinocytes cells. This work confirmed that exposure to PM2.5 induces ER stress response and ER stress-associated apoptosis, mediated through PERK-eIF2α-ATF4-CHOP axis., Fisetin can inhibit PM2.5-indued expression of the ER chaperone BiP/GRP78, phosphorylated eIF2α, ATF4, and CHOP, and reduce the cytosolic Ca2+ levels and production of ROS triggered by PM2.5. More evidence for the link between ER stress response and oxidative stress in PM2.5-caused damage is emerging. It was recently demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant and anti-inflammatory genes and is critical for protection against PM2.5-induced oxidative stress in the lung of mice. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure, while Nrf2 facilitates lung injury during PM2.5 exposure and the CYP450 pathway is involved in this process.
| Conclusive remarks|| |
Exposure to PM2.5, a complex mixture of environmental-relevant nanoparticles, can lead to the activation of multiple signaling pathways at the cellular level. As the major intracellular stress signaling, ER stress response or UPR is critical for cells to make survival or death decision under ER stress conditions. Exposure to PM2.5 can induce ER stress, but induction of UPR pathways by PM2.5 is context-dependent. With animal models, PM2.5 exposure induces PERK/eIF2α-mediated UPR pathway, but IRE1/XBP1-mediated UPR pathway, in the liver and lung. However, exposure to PM2.5 can induce IRE1/XBP1-mediated UPR pathway in mouse adipose tissues or vascular endothelial cells. These findings provide important insights into PM2.5-triggered cell stress responses and increase our understanding of pathophysiological effects of particulate air pollution on the development of metabolic and cardiovascular diseases.
EH and AM were summer students who engaged in research works at Wayne State University School of Medicine.
Financial support and sponsorship
Portions of this work were supported by National Institutes of Health grants DK090313 and DK126908 (to KZ).
Conflict of interest
Dr. Kezhong Zhang is an Editor-in-Chief of Environmental Disease. The article was subject to the journal's standard procedures, with peer review handled independently of this Editor-in-Chief and their research groups.
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