Corrigendum: The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy
Year: 2024
Type: erratum
Abstract: 1 IntroductionCoronavirus disease 2019 (COVID-19) is an infectious and severe respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a positive sense single-stranded RNA beta-coronavirus that infects the lower and upper respiratory tract and has recently affected millions of people worldwide (1-3). Primary symptoms of COVID-19 include fever, cough, pneumonia, and shortness of breath, and histological pictures of this disease are characterized by mononuclear inflammatory cells, severe pneumocyte hyperplasia, interstitial thickening, hyaline membrane formation, and prominent alveolar damage with eosinophilic exudates (4, 5).During COVID-19, a cascade of inflammatory pathways is activated, leading to massive cytokine release from the host immune system in response to SARS-CoV-2 infection (6, 7). In this regard, the vast increase in the secretion of circulating proinflammatory cytokines such as tumor necrosis factors (TNFs), interleukins (ILs), chemokines, and interferons (IFNs) leads to the exacerbation of the host inflammatory response to the pathogen. This exacerbation in the host’s inflammatory response increases the severity of the disease (8-10). This hyperinflammation or imbalanced inflammation during SARS-CoV-2 infection is called “cytokine storm”, which is one of the main hallmarks of the deterioration of the COVID-19 immunopathogenesis and triggers acute respiratory distress syndrome (ARDS), multi-organ failure (MOF), acute lung injury (ALI), decreased lung function, and finally, death of the host (11, 12). In this context, in recent years, various clinical and omics-based studies have investigated the molecular mechanisms behind the SARS-CoV-2 infection in different disease stages and different tissues (13-17). Surprisingly, most of these studies have observed the activation of inflammatory mechanisms and hyperinflammation in COVID-19 patients. Therefore, developing effective therapeutic strategies by targeting critical factors in regulating host inflammatory response can provide a potential and promising solution for the survival of COVID-19 patients, especially the prevention of cytokine storms (18-20). The peroxisome proliferator-activated receptors (PPARs) are a subgroup of ligand-activated transcription factors and members of the nuclear receptor superfamily that play a crucial role in regulating energy balance, carbohydrate and lipid metabolism, cell growth, and differentiation (21, 22). PPARs can regulate the transcriptional activity of target genes by two different mechanisms: (1) binding to the promoter region of target genes with DNA sequences known as peroxisome proliferator response elements (PPREs) as a ligand-dependent transcription factor, and (2) controlling gene expression through association with PPRE-independent activator proteins (21, 23). Several previous reports highlighted the core role of PPARs in many human diseases, such as different types of cancer (24, 25), atherosclerosis (26), and type 2 diabetes (27, 28).Interestingly, in addition to the central roles of PPARs in regulating energy homeostasis, such as fatty-acid metabolism and glucose utilization, growing evidence suggests that members of the nuclear receptor superfamily, such as PPARs, also have significant regulatory effects on inflammatory processes (29). Indeed, extensive research has proven that PPARs have potential anti-inflammatory effects during inflammation-related disease (30, 31). In this regard, previous literature, based on available evidence, has suggested that subtypes of PPARs exert their anti-inflammatory effects and subsequently control the host's inflammatory response through different mechanisms such as successful competition with other inflammatory transcription factors for the recruitment of essential and shared co-activator proteins, inhibition of binding of inflammatory transcription factors such as AP-1, nuclear factor-κB (NF-κB), NFAT, and STATs to their response elements through direct physical protein-protein interaction, blocking MAPK-induced signaling cascades, preventing the clearance of proinflammatory genes co-repressors, and upregulation in the expression of anti-inflammatory genes (32). For example, it has been discussed that the activation of PPARs during inflammatory bowel disease (IBD) leads to the suppression of the main pathways of inflammation, such as NF-κB signaling. Subsequently, the activation of PPARs inhibits the production of proinflammatory cytokines such as TNF-α, IL6, and IL1B. Therefore, it was concluded that anti-inflammatory responses induced by the activation of PPARs might restore the physio-pathological imbalance associated with this disorder (21). The interference of viral infections such as SARS-CoV-2 in the PPARs signaling is a completely new issue and interest in this area has been very motivated by the COVID-19 pandemic. Emerging studies show that SARS-CoV-2, by modulating PPAR subtypes, leads to metabolic changes (especially lipid metabolism) and exacerbation of pulmonary inflammation in lung epithelial cells of COVID-19 patients (33). Therefore, these findings have suggested that the use of agonists of PPARs with the aim of their activation may be a useful therapeutic strategy to reverse the inflammatory and metabolic changes caused by SARS-CoV-2 infection (34). AdditionallyIn this regard, it has been reported that several natural ligands of PPARs, such as turmeric, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), lead to a decrease in the production of proinflammatory cytokines through interaction with PPARs and then induction of their activity (35, 36). For example, a very recent study has identified possible mechanisms by which the PPARα agonist palmitoylethanolamide (PEA) antagonizes the NF-κB signaling pathway and subsequently reduces the production of TNF-α, IL1B, and other inflammatory mediators such as inducible nitric oxide synthase (iNOS) and COX2 through selective activation of PPARα in cultured murine alveolar macrophages during SARS-CoV-2 infection (37). Moreover, it has been suggested that synthetic agonists of PPARγPPARs, such as thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorative effects on severe viral pneumonia-like COVID-19 (38). On the other hand, by integrating different transcriptome datasets with computational network-based systems biology methods, promising therapeutic targets, including PPARα and PPARγPPAR subtypes, have been identified for the modulation of inflammatory processes caused by COVID-19 (39, 40). Therefore, PPARs and their ligands have crucial therapeutic potential with key immunomodulatory effects on inflammatory mechanisms and cytokine/chemokine production during infectious and inflammation-related diseases such as the COVID-19 pandemic. Nevertheless, considering the importance of immunopathology’s role of the inflammatory response in COVID-19 patients and the role of PPARs in controlling inflammation, in this review, we (1) provide a summary of general information about PPARs such as subtypes, structure, tissue expression, and function, (2) investigate the molecular mechanisms of the exacerbation of the host inflammatory response during COVID-19, (3) describe the anti-inflammatory mechanisms mediated by PPARs, and (4) discuss the anti-inflammatory roles of PPAR subtypes during COVID-19 pandemic on the basis of the recent clinical and omics-based literature.2 PPARs: Subtypes, structure, tissue expression, and function2.1 PPAR subtypes and structureThe PPARs are ligand-dependent/activated transcription factors, members of the nuclear-hormone-receptor superfamily (including the receptors for thyroid hormone, vitamin D, ecdysone, retinoic acids, and some orphan receptors) that transduce a wide range of signals, including environmental, nutritional, and inflammatory events, to a set of cellular responses at the transcriptional gene level; they were named due to their joint property in increasing the number and activity of peroxisomes (41-43). So far, three isoforms of PPARs, namely, PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3), have been identified in vertebrates (including human, mouse, rat, hamster, and Xenopus), which are encoded by distinct genes on different chromosomes. have a of and different tissue and regulatory and recent years, various in and in studies have reported that isoforms of PPARs regulate lipid and glucose metabolism and have regulatory roles in cell and and and the immune and inflammation In addition to the it is that the activation of PPAR subtypes reduces the expression of proinflammatory cytokines and inflammatory cell significant anti-inflammatory PPARα is the known PPAR that was from a DNA as a nuclear receptor that the effects of an and known as peroxisome This of PPARs is in tissues such as the and tissue PPARα is in the carbohydrate metabolism and of and their such that activation reduces lipid it has been highlighted that PPARα increases the expression of which is a that the nuclear and transcriptional activity of with NF-κB signaling and the inflammatory response increasing evidence has that the anti-inflammatory of PPARα are by a decrease in the secretion of several key inflammatory factors such as cytokines IL1B, and AP-1, and Moreover, it has been reported that the activation of PPARα leads to the upregulation of anti-inflammatory factors such as receptor and PPARα can with responses that are critical during inflammation by targeting controlling the inflammatory response is the most PPAR which is in and and immune cells such as the and the and it a key role in a of including tumor cell differentiation and metabolism, energy balance, and and lipid of PPARγ increases by increasing differentiation and the transcription of genes for Moreover, this has been as a potential therapeutic target for different types of cancer due to various including inhibition of cell increasing cell differentiation in tumor cells and In of regulating inflammation, recent has reported that PPARγ the inflammatory caused by NF-κB activation and the production of proinflammatory cytokines such as TNF-α, IL1B, and through the inhibition of NF-κB On the other hand, PPARγ effects by targeting inflammatory factors such as AP-1, and and their activity to inflammatory damage In PPARγ the expression of several essential inflammatory target genes such as and a recent study that PPARγ inhibits inflammatory responses by activation as as of and The PPARβ/δ is the of PPARs, which has been as as PPARα and it of with a molecular of This is in is especially in the and of which are in lipid Indeed, the PPARβ/δ in fatty-acid in and and and glucose information on the role of PPARβ/δ in the of inflammation is and research is to the PPARβ/δ and inflammation or inflammatory In some PPARβ/δ has been to have anti-inflammatory For example, it was that activation of PPARβ/δ reduces the expression of NF-κB and genes including TNF-α, IL6, and three PPAR subtypes have distinct roles in regulating metabolic and on the tissue function, and natural and synthetic ligands of and PPARγ are in of PPAR activation of PPARs by ligands is associated with changes in the including from and association with transcriptional binding to and Moreover, of many mechanisms of PPARs that the receptor is of a with nuclear the acid receptor (21, Therefore, activation with the are to the and to DNA sequences of a direct of DNA by one or two or response the transcription of target genes This is called the peroxisome proliferator response and is in the promoter of target genes binding the ligand-activated to the target DNA through this to co-activator such as and receptor co-activator 1 which have activity and the of In this regard, previous studies have reported that the binding of co-activator to the can and transcriptional regulatory changes in the the regulatory of PPAR target genes COVID-19 and cytokine which the lower and upper respiratory host cells through 2 receptors and a wide range of clinical from such as fever, cough, and to with and inflammation symptoms to with cellular of SARS-CoV-2 viral single-stranded RNA or other RNA can be as by immune and epithelial cells through the activation of receptors such as receptors retinoic receptors and receptors of key inflammation-related transcription factors such as nuclear factor-κB (NF-κB), activator and regulatory factors are and the transcription of proinflammatory chemokines, and such as IL6, TNF-α, and Moreover, proinflammatory cytokines such as IL6, TNF-α, and in and signaling by binding to their receptors on immune cells to production of proinflammatory cytokines and subsequently positive to the cytokine of the inflammatory response and secretion of proinflammatory cytokines and by immune and respiratory epithelial cells leads to recruitment of and immune cells such as cells natural cells, and and cells to the of infection to inflammatory cytokines Indeed, growing evidence suggests that the epithelial cells and immune cells in COVID-19 of proinflammatory cytokines that an inflammatory or imbalanced inflammation as “cytokine with severe and In this regard, extensive studies have recently reported that circulating of proinflammatory cytokines IL6, TNF-α, and have been identified in patients with severe COVID-19 it has been highlighted that cytokine is one of the main of tissue and which are the of COVID-19 severity and death of patients Therefore, we that to target the critical inflammatory factors during SARS-CoV-2 infection be a in developing therapeutic strategies to control the cytokine and COVID-19 mechanisms mediated by the many studies have concluded that PPARs, in addition to critical in glucose and lipid metabolism, play an essential role in controlling various types of the inflammatory response Indeed, the inflammatory role of PPARs was highlighted a previous study that PPARα was associated with of proinflammatory cytokines In with this a recent study in addition to the of PPARγ also leads to of IL6, and during in an that PPARγ expression pulmonary inflammation and were associated with the of Moreover, several previous studies have that PPARα and PPARγ activation lead to inflammation in and infection In addition to these in recent years, the central role of PPARs to control inflammation and the of proinflammatory cytokines has been in many inflammatory including lung inflammatory diseases and inflammation that PPARs the transcription of main inflammatory transcription factors, including AP-1, nuclear of cells and and of transcription through an the various mechanisms PPARs use to many distinct transcription the most include main mechanisms in which ligand-activated the activity of many inflammatory is the successful competition of PPARs to the of essential and shared co-activator proteins as in a a of this successful these are available for other transcription factors Therefore, the of other transcription factors as that use the are in these of co-activator On the other hand, the direct physical association PPARs and other transcription factors the of the known as or receptor ligand-activated a new with other transcription factors, such as AP-1, NFAT, and STATs through physical preventing transcription binding to response and also their to the transcription of proinflammatory genes such as IL6, and For PPARα and PPARγ regulate the inflammatory gene response through blocking NF-κB and signaling pathways physical interaction with NF-κB Moreover, PPARs can the expression of NF-κB through the upregulation of of NF-κB The also blocking signaling by ligand-activated through inhibition of and activation preventing the clearance of is for the transcriptional activation of and NF-κB target proinflammatory genes is the of inflammation suppression by PPARs Moreover, anti-inflammatory of PPARs is their with other anti-inflammatory studies have that a significant increase in the expression of PPARs is associated with an increase in the expression of anti-inflammatory factors such as Several human and have reported that PPARs and their ligands the expression of many such as and and and such as and This inhibits recruitment to the of inflammation and reduces the immune cells and other cells for cytokine production of inflammation by PPARs during SARS-CoV-2 recent of COVID-19 in the and worldwide have to extensive clinical studies the molecular regulatory mechanisms behind this severe at this many of these extensive clinical studies reported the role of PPAR subtypes, especially PPARγ and their in controlling the host inflammatory response during SARS-CoV-2 in previous clinical a decrease in the expression of PPAR subtypes and an increase in the of proinflammatory cytokines have been observed in inflammatory of patients with severe COVID-19 in with the of clinical several recent studies and have reported of PPARs in various tissues including lung epithelial cells, and mononuclear cells in the these the of previous and studies also the interference of SARS-CoV-2 infection in PPAR signaling Surprisingly, recently that a set of including were during SARS-CoV-2 also reported that has a significant with main and the increase in expression during SARS-CoV-2 infection leads to the of a key role in the exacerbation of the inflammatory response in COVID-19 patients of the main immunopathogenesis strategies of SARS-CoV-2 infection has been suggested to with PPAR signaling to the inflammatory response In other previous studies have reported that the decrease in the expression of PPARs including and PPARβ/δ during SARS-CoV-2 infection is associated with the secretion of proinflammatory cytokines such as IL6, and TNF-α, as as cytokine it has a positive with and in COVID-19 patients Moreover, a previous study concluded that SARS-CoV-2 PPAR expression in the and one of the main anti-inflammatory for NF-κB a response in patients with severe COVID-19 Moreover, several recent studies also reported that the in PPARγ and PPARα is to acute pulmonary inflammation in COVID-19 and the of the disease from to severe finally, death it has been highlighted that the expression of PPAR subtypes, especially leads to to SARS-CoV-2 infection the decrease in PPARγ expression during SARS-CoV-2 in addition to to the of also leads to in COVID-19 patients it has recently been that of the pathway in response to SARS-CoV-2 infection leads to inhibition of PPARγ expression in an COVID-19 has clinical for people clinical that the of PPARγ are lower in Therefore, the of cytokine during SARS-CoV-2 infection is in these people study that is to inflammation in COVID-19 patients the activation of proinflammatory including IL6, IL1B, and and inflammation-related transcription factors, including and STATs induction of is evidence that the 2 inflammatory response can effects the COVID-19 immunopathogenesis due to the secretion and release of anti-inflammatory cytokines such as and and recruitment of the to the of inflammation these it has been that cytokines associated with inflammatory response such as and the secretion of several proinflammatory cytokines such as IL6, IL1B, and TNF-α, which play a central role in the of COVID-19 and hyperinflammation Moreover, the anti-inflammatory macrophages is by and which inflammatory responses by anti-inflammatory such as recent that responses which by and in the respiratory tract and are associated with clinical with COVID-19 Therefore, it has been that the inflammatory response may exert potential effects COVID-19 Surprisingly, previous studies in several human inflammatory diseases that PPARα and PPARγ and their ligands increase the expression of anti-inflammatory associated with the inflammation such as and the of inflammation Therefore, based on these it can be concluded that PPARs can different anti-inflammatory mechanisms during SARS-CoV-2 infection through a with inflammatory reports that PPARs play an role in controlling the inflammatory response during COVID-19 by the of the key inflammatory transcription factors, especially NF-κB In this regard, it has been suggested that activation of PPARγ during COVID-19 can the circulating of TNF-α, and in the immune cells such as macrophages and through interaction with NF-κB Moreover, PPARγ as a of activation and the production of cytokines by these immune cells these the recent has also reported that activation of and PPARγ is to pulmonary caused by inflammation in COVID-19 patients has been also that may of SARS-CoV-2 infection including inflammation and metabolic such as by a positive on PPARα (33). The anti-inflammatory role of PPARβ/δ during COVID-19 has been the other two types of a reports have that PPARβ/δ transcription factors in the inflammatory including NF-κB and the expression of of the inflammatory of COVID-19 in a PPARβ/δ and PPARγ have been to play a central role in the an anti-inflammatory during COVID-19 On the other hand, the previous has that PPARα and PPARγ the of inflammatory cells by factors of the preventing the of cytokines and in the the decrease in the expression of PPARs in the stages of SARS-CoV-2 infection and the increase in their expression during the the of these receptors with the severity of the disease PPARα and PPARγ have been as effective for the of COVID-19 these receptors through an increase in the of regulatory upregulation in expression transcriptional for the and differentiation of regulatory (1) (2) the type of and (3) and the response and can the regulatory and inflammation has been by previous research and the anti-inflammatory of these cells are Therefore, it can be that the increase in the of regulatory due to the activation of PPARs can play a potential by and and significant anti-inflammatory during SARS-CoV-2 in and the of these with computational network-based of systems biology have an to gene regulatory potential targets, and the molecular mechanisms infectious disease at the In previous we and the from of and COVID-19 patients with computational network-based of systems biology in to potential therapeutic and gene COVID-19 and promising therapeutic strategies for COVID-19 a we identified gene and genes with the to SARS-CoV-2 Indeed, the genes with the have the of in their with critical which are known as genes and can be potential and for COVID-19 observed that PPARα is the genes in one of the key with anti-inflammatory function, the crucial anti-inflammatory role of this PPAR during SARS-CoV-2 infection In various with computational systems biology and and identified targets, including for COVID-19 studies have identified PPARα and PPARγ as promising to control inflammation caused by On the other hand, a study acid as an essential cytokine in COVID-19 patients this interaction and molecular it was that acid or core genes to the cytokine during COVID-19 strategies an of this one of these acid strategies to with the cytokine was to target and PPARβ/δ for activation that the of the identified by these studies that critical therapeutic targets, including and PPARγ for COVID-19 the use of PPARs agonists to to the inflammatory processes during COVID-19 has recently In this regard, it has been that PPAR activation through synthetic and can be an to the cytokine and the inflammatory effects coronavirus infection Moreover, a recent study suggested synthetic and natural ligands of PPARs in to target NF-κB transcriptional activity and inflammatory response as an strategy for the of COVID-19 patients these the recent also reported that several natural and synthetic PPARγ agonists NF-κB activity through PPARγ leading to of proinflammatory cytokines such as IL6, TNF-α, and (38). has been that PPARα activation in addition to NF-κB signaling cascade and proinflammatory cytokines such as IL6, TNF-α, and inducible nitric oxide synthase is also associated with of anti-inflammatory factors such as it has recently been that is a PPARα agonist with and that anti-inflammatory effects such as inhibition of of COX2 and activation of and release of through the of PPARα during SARS-CoV-2 infection previous studies reported that inhibits viral in lung epithelial cells by the metabolic changes caused by SARS-CoV-2 On the other hand, natural an PPARγ has a proven with and immunomodulatory evidence from clinical studies suggests that this PPAR agonist the in COVID-19 patients by NF-κB and signaling and then TNF-α, and Moreover, caused a in the inflammatory response of cells to leading to a from proinflammatory cytokine secretion to anti-inflammatory cytokine secretion also an and damage through (1) inhibition of and and (2) suppression of and activation of PPARγ has been as an effective therapeutic strategy to control host inflammatory and immune the cytokine and inflammatory effects COVID-19 Moreover, an that is for type 2 diabetes is a synthetic PPARγ agonist that with NF-κB activity and anti-inflammatory effects through the activation of PPARγ (38). this has been as one of the most for anti-inflammatory effects for hyperinflammation (38). In addition to synthetic agonist of is of the that has significant anti-inflammatory effects and has been suggested by as a for the in many inflammatory in COVID-19 patients can SARS-CoV-2 RNA and through potential inhibition of Moreover, it has recently been suggested that activation of PPARγ by agonists such as reduces cytokine pulmonary inflammation, and in the lung of the patients during SARS-CoV-2 infection has also been reported to have potential for inflammation in COVID-19 by the expression of many cytokines and through increasing the expression of PPARα natural such as main from and have been as a possible to the cytokine in COVID-19 patients, as this increases the expression of PPARγ in tissue and as a reduces the of inflammatory cytokines including TNF-α, IL6, and the of information is available on the role of PPARβ/δ agonists during SARS-CoV-2 Therefore, research investigate the anti-inflammatory effects of natural and synthetic agonists of PPARβ/δ during the COVID-19 pandemic. at the previous on inflammatory lung diseases in it can be concluded that PPARβ/δ agonists have significant anti-inflammatory effects during lung infection natural and synthetic ligands of PPARs may have or For recent show that natural and synthetic ligands of PPARs is and can with due to the of the Moreover, it has been reported that some ligands of PPARs can exert selective or regulatory effects on the cell it has been highlighted that synthetic agonists of PPARs can lead to clinical including and and findings the potential role of PPAR subtypes and their ligands with anti-inflammatory effects during the COVID-19 which can be promising for key inflammatory factors (especially NF-κB and regulating inflammation during SARS-CoV-2 Therefore, at of PPAR subtypes be a promising therapeutic strategy to the response in COVID-19 patients and the cytokine and is an caused by SARS-CoV-2 infection with severe inflammatory of patients is an developing various for disease is solution for COVID-19 patients. The massive cytokine secretion caused by the exacerbation of the host inflammatory system in response to SARS-CoV-2 infection is known as a “cytokine storm”, which is to the of the disease from to In recent years, previous it has been suggested that one of the most effective strategies for the survival of COVID-19 patients and the severity of the disease is to control the response and with cytokine has been one of the main of disease decreased lung function, and and the death of COVID-19 patients. Therefore, to anti-inflammatory factors and their response during SARS-CoV-2 infection can provide the solution to with cytokine are ligand-dependent transcription factors to the nuclear receptor superfamily, which are the main of lipid and glucose This transcription of three and In the it has been that these subtypes, in addition to their central role in metabolism and energy balance, play roles in cell the immune cell and inflammation and inflammation-related PPARs play an anti-inflammatory role as critical of the host inflammatory response through regulatory effects on inflammatory transcription factors such as AP-1, NFAT, and extensive clinical and studies in the expression of PPARs in response to SARS-CoV-2 which has been as one of the main of SARS-CoV-2 immunopathogenesis to the host inflammatory the other hand, it has been highlighted that the activation of PPARs through natural and synthetic ligands is associated with the of prevention of cytokine and in disease severity in COVID-19 patients. Therefore, this and for developing therapeutic strategies COVID-19 and cytokine the previous has that natural and synthetic ligands of PPARs may lead to severe clinical considering the anti-inflammatory importance of PPARs to control the response during COVID-19, research investigate the or effects of PPAR subtypes to cytokine storms during SARS-CoV-2 Moreover, considering the and of natural and synthetic ligands to PPARs, of the mechanisms is to new pathways of PPARs activation severe clinical
Source: Frontiers in Immunology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,295
OpenAlex ID: W4396744754