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Singh A, Chaudhary R. Potentials of peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ: An in-depth and comprehensive review of their molecular mechanisms, cellular Signalling, immune responses and therapeutic implications in multiple diseases. Int Immunopharmacol 2025; 155:114616. [PMID: 40222274 DOI: 10.1016/j.intimp.2025.114616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.
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Affiliation(s)
- Alpana Singh
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India.
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Ghannam IAY, Hassan RM, Abdel-Maksoud MS. Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics. Bioorg Chem 2025; 156:108226. [PMID: 39908735 DOI: 10.1016/j.bioorg.2025.108226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/07/2025]
Abstract
Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPARα agonists (fibrates), PPARγ agonists (thiazolidindiones), and PPARβ/δ agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.
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Affiliation(s)
- Iman A Y Ghannam
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
| | - Rasha M Hassan
- Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt
| | - Mohammed S Abdel-Maksoud
- Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt
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Ortiz-Cerda T, Argüelles-Arias F, Macías-García L, Vázquez-Román V, Tapia G, Xie K, García-García MD, Merinero M, García-Montes JM, Alcudia A, Witting PK, De-Miguel M. Effects of polyphenolic maqui ( Aristotelia chilensis) extract on the inhibition of NLRP3 inflammasome and activation of mast cells in a mouse model of Crohn's disease-like colitis. Front Immunol 2024; 14:1229767. [PMID: 38283356 PMCID: PMC10811055 DOI: 10.3389/fimmu.2023.1229767] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 12/21/2023] [Indexed: 01/30/2024] Open
Abstract
Introduction Crohn's disease (CD) involves activation of mast cells (MC) and NF-кB in parallel with the PPAR-α/NLRP3 inflammasome/IL-1β pathway in the inflamed colon. Whether polyphenols from maqui (Aristotelia chilensis) represent a natural alternative treatment for CD is unclear. Therefore, we used an animal model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis to investigate protective effects of maqui extract through monitoring NLRP3 inflammasome and MC activation in colon tissue. Methods Maqui extract was administered via orogastric route to mice after (post-Treatment group) or prior (pre-Treatment group) to TNBS-induction. Colon pathology was characterized by histoarchitectural imaging, disease activity index (DAI), and assessing NF-кB, p-NF-кB, PPAR-α/NLRP3 expression and IL-1β levels. Results Compared to mice treated with TNBS alone administration of anthocyanin-rich maqui extract improved the DAI, colon histoarchitecture and reduced both colon wet-weight and transmural inflammation. Induction with TNBS significantly increased colonic NLPR3 inflammasome activation, while co-treatment with maqui extract (either post- or pre-Treatment) significantly downregulated NLRP3, ASC and caspase-1 levels, which manifested as reduced colonic IL-1β levels. Supplemented maqui extract marginally diminished NF-кB activity in epithelial cells but reached statistical significance in immune cells (as judged by decreased NF-кB phosphorylation). PPAR-α signaling was largely unaffected by Maqui whereas MC infiltration into the colon mucosa and submucosa decreased and their level of degranulation was suppressed. Conclusion These outcomes show the post- and pre- Treatment effect of a polyphenolic extract rich in anthocyanins from maqui the acute phase of TNBS- induced CD-like colitis is linked to suppression of the NLRP3 inflammasome and reduced MC responses. These data indicate that maqui extract represents a potential nutraceutical for the treatment of inflammatory bowel disease (IBD).
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Affiliation(s)
- Tamara Ortiz-Cerda
- Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain
- Redox Biology Group, The Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Federico Argüelles-Arias
- Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
- Department of Gastroenterology, University Hospital Virgen Macarena, Seville, Spain
| | - Laura Macías-García
- Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain
| | - Victoria Vázquez-Román
- Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain
| | - Gladys Tapia
- Molecular and Clinical Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Kangzhe Xie
- Redox Biology Group, The Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | | | - Manuel Merinero
- Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain
- Departamento de Química Orgánica y Farmacéutica, Universidad de Sevilla, Seville, Spain
| | | | - Ana Alcudia
- Departamento de Química Orgánica y Farmacéutica, Universidad de Sevilla, Seville, Spain
| | - Paul K. Witting
- Redox Biology Group, The Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Manuel De-Miguel
- Departamento de Citología e Histología Normal y Patológica, Facultad de medicina, Universidad de Sevilla, Seville, Spain
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Shlykova O, Izmailova O, Kabaliei A, Palchyk V, Shynkevych V, Kaidashev I. PPARG stimulation restored lung mRNA expression of core clock, inflammation- and metabolism-related genes disrupted by reversed feeding in male mice. Physiol Rep 2023; 11:e15823. [PMID: 37704580 PMCID: PMC10499569 DOI: 10.14814/phy2.15823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/24/2023] [Accepted: 08/29/2023] [Indexed: 09/15/2023] Open
Abstract
The circadian rhythm system regulates lung function as well as local and systemic inflammations. The alteration of this rhythm might be induced by a change in the eating rhythm. Peroxisome proliferator-activated receptor gamma (PPARG) is a key molecule involved in circadian rhythm regulation, lung functions, and metabolic processes. We described the effect of the PPARG agonist pioglitazone (PZ) on the diurnal mRNA expression profile of core circadian clock genes (Arntl, Clock, Nr1d1, Cry1, Cry2, Per1, and Per2) and metabolism- and inflammation-related genes (Nfe2l2, Pparg, Rela, and Cxcl5) in the male murine lung disrupted by reversed feeding (RF). In mice, RF disrupted the diurnal expression pattern of core clock genes. It decreased Nfe2l2 and Pparg and increased Rela and Cxcl5 expression in lung tissue. There were elevated levels of IL-6, TNF-alpha, total cells, macrophages, and lymphocyte counts in bronchoalveolar lavage (BAL) with a significant increase in vascular congestion and cellular infiltrates in male mouse lung tissue. Administration of PZ regained the diurnal clock gene expression, increased Nfe2l2 and Pparg expression, and reduced Rela, Cxcl5 expression and IL-6, TNF-alpha, and cellularity in BAL. PZ administration at 7 p.m. was more efficient than at 7 a.m.
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Paw M, Wnuk D, Madeja Z, Michalik M. PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients. Int J Mol Sci 2023; 24:ijms24097721. [PMID: 37175437 PMCID: PMC10178673 DOI: 10.3390/ijms24097721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/30/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest the involvement of peroxisome proliferator-activated receptors (PPARs) in the remodeling of asthmatic bronchi. In this study, we investigated the effect of PPARδ ligands (GW501516 as an agonist, and GSK0660 as an antagonist) on the FMT potential of HBFs derived from asthmatic patients cultured in vitro. This report shows, for the first time, the inhibitory effect of a PPARδ agonist on the number of myofibroblasts and the expression of myofibroblast-related markers-α-smooth muscle actin, collagen 1, tenascin C, and connexin 43-in asthma-related TGF-β-treated HBF populations. We suggest that actin cytoskeleton reorganization and Smad2 transcriptional activity altered by GW501516 lead to the attenuation of the FMT in HBF populations derived from asthmatics. In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma.
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Affiliation(s)
- Milena Paw
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Dawid Wnuk
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Zbigniew Madeja
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Marta Michalik
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
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Gong X, Zhu L, Liu J, Li C, Xu Z, Liu J, Zhang H. Exposure to traffic-related fine particulate matter 2.5 causes respiratory damage via peroxisome proliferator-activated receptor gamma-regulated inflammation. ENVIRONMENTAL TOXICOLOGY 2022; 37:2178-2188. [PMID: 35670047 DOI: 10.1002/tox.23584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 01/25/2022] [Accepted: 02/19/2022] [Indexed: 06/15/2023]
Abstract
Exposure to particulate matter 2.5 (PM2.5) potentially triggers airway inflammation. Peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to regulate inflammatory responses in diverse cell types. Therefore, this work investigated the mechanisms of PPARγ in regulating traffic-related PM2.5-induced airway inflammation. Using the diffusion flame burner soot generation, traffic-related PM2.5 was generated and adsorbed. BALB/c male mice and human bronchial epithelial cells (16-HBE) were exposed to PM2.5 alone or co-treatment with rosiglitazone (RSG), an agonist of PPARγ. To the end of exposure, bronchoalveolar lavage fluid (BALF), venous blood and arterial blood, trachea, bronchus and lung tissues were collected. The levels of IL-1β, IL-6, and IL-17 were detected by ELISA, and the cell types in BALF were counted. Hematoxylin-eosin (H&E) assay were used to analyze the pathological conditions of lung, bronchus, and pulmonary artery. Apoptosis was detected by TUNEL, and PPARγ expression in lung and bronchus was detected by immunohistochemical (IHC) staining. Western Blot was used to detect PPARγ, NF-kB, AP-1 and STAT3 expression in lung and bronchus. The viability was detected by MTT method. PM2.5 exposure caused pathological damage to the lung, bronchus and pulmonary artery tissue, which induced apoptosis of bronchial epithelial cells. PM2.5 exposure caused local inflammation of the whole body and airway. PPARγ expression increased after PM2.5 exposure. PM2.5 exposure regulated the downstream signaling pathways to affect the inflammatory response through PPARγ. Exposure to traffic-related PM2.5 caused respiratory damage via PPARγ-regulated inflammation.
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Affiliation(s)
- Xiaolei Gong
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Limin Zhu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinlong Liu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunxiang Li
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuoming Xu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinfen Liu
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haibo Zhang
- Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Development of mode of action networks related to the potential role of PPARγ in respiratory diseases. Pharmacol Res 2021; 172:105821. [PMID: 34403731 DOI: 10.1016/j.phrs.2021.105821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 11/30/2022]
Abstract
The peroxisome proliferator-activated receptor γ (PPARγ) is a key transcription factor, operating at the intercept of metabolic control and immunomodulation. It is ubiquitously expressed in multiple tissues and organs, including lungs. There is a growing body of information supporting the role of PPARγ signalling in respiratory diseases. The aim of the present study was to develop mode of action (MoA) networks reflecting the relationships between PPARγ signalling and the progression/alleviation of a spectrum of lung pathologies. Data mining was performed using the resources of the NIH PubMed and PubChem information systems. By linking available data on pathological/therapeutic effects of PPARγ modulation, knowledge-based MoA networking at different levels of biological organization (molecular, cellular, tissue, organ, and system) was performed. Multiple MoA networks were developed to relate PPARγ modulation to the progress or the alleviation of pulmonary disorders, triggered by diverse pathogenic, genetic, chemical, or mechanical factors. Pharmacological targeting of PPARγ signalling was discussed with regard to ligand- and cell type-specific effects in the context of distinct disease inductor- and disease stage-dependent patterns. The proposed MoA networking analysis allows for a better understanding of the potential role of PPARγ modulation in lung pathologies. It presents a mechanistically justified basis for further computational, experimental, and clinical monitoring studies on the dynamic control of PPARγ signalling in respiratory diseases.
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Salter BM, Ju X, Sehmi R. Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma. Cells 2021; 10:412. [PMID: 33669458 PMCID: PMC7920418 DOI: 10.3390/cells10020412] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/11/2021] [Accepted: 02/13/2021] [Indexed: 12/15/2022] Open
Abstract
Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5-10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.
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Affiliation(s)
| | | | - Roma Sehmi
- CardioRespiratory Research Group, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; (B.M.S.); (X.J.)
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Tiwari D, Gupta P. Nuclear Receptors in Asthma: Empowering Classical Molecules Against a Contemporary Ailment. Front Immunol 2021; 11:594433. [PMID: 33574813 PMCID: PMC7870687 DOI: 10.3389/fimmu.2020.594433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023] Open
Abstract
The escalation in living standards and adoption of 'Western lifestyle' has an allied effect on the increased allergy and asthma burden in both developed and developing countries. Current scientific reports bespeak an association between allergic diseases and metabolic dysfunction; hinting toward the critical requirement of organized lifestyle and dietary habits. The ubiquitous nuclear receptors (NRs) translate metabolic stimuli into gene regulatory signals, integrating diet inflences to overall developmental and physiological processes. As a consequence of such promising attributes, nuclear receptors have historically been at the cutting edge of pharmacy world. This review discusses the recent findings that feature the cardinal importance of nuclear receptors and how they can be instrumental in modulating current asthma pharmacology. Further, it highlights a possible future employment of therapy involving dietary supplements and synthetic ligands that would engage NRs and aid in eliminating both asthma and linked comorbidities. Therefore, uncovering new and evolving roles through analysis of genomic changes would represent a feasible approach in both prevention and alleviation of asthma.
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Affiliation(s)
| | - Pawan Gupta
- Department of Molecular Biology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh, India
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Imbalanced serum levels of resolvin E1 (RvE1) and leukotriene B4 (LTB4) in patients with allergic rhinitis. Mol Biol Rep 2020; 47:7745-7754. [PMID: 32960415 DOI: 10.1007/s11033-020-05849-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/10/2020] [Accepted: 09/17/2020] [Indexed: 10/23/2022]
Abstract
Timely and successful resolution of acute inflammation plays a crucial role in preventing the development of chronic airway inflammation in allergic rhinitis (AR). This study intends to assess the serum levels of pro-inflammatory leukotriene B4 (LTB4), anti-inflammatory mediators, including resolvin E1 (RvE1), RvD1, IL-10, and TGF-β, besides mRNA expression level of G-protein coupled receptor 120 (GPR120) and peroxisome proliferator-activated receptor-γ (PPAR-γ) receptors in peripheral blood leukocytes of AR patients. Thirty-seven AR patients and thirty age- and gender-matched healthy subjects were enrolled in this study. The serum levels of LTB4, RvE1, RvD1, IL-10, and TGF-β were measured using enzyme-linked immunosorbent assay (ELISA) technique, and the mRNA expression level of GPR120 and PPAR-γ was assessed by the real-time PCR method. The serum levels of RvE1 and LTB4 were significantly higher in patients with AR than in healthy subjects (P < 0.01 and P < 0.0001, respectively). However, a significantly lower ratio of RvE1 and RvD1 to LTB4 was found in patients with AR relative to healthy subjects (P < 0.05 and P < 0.0001, respectively). Likewise, the serum levels of both IL-10 and TGF-β cytokines were significantly reduced in patients with AR compared to healthy subjects (P < 0.01 and P < 0.0001, respectively). Furthermore, the mRNA expression of PPAR-γ was significantly lower in patients with AR than in healthy subjects (P < 0.05). Our findings indicate that imbalanced pro-resolving lipid mediator RvE1 and pro-inflammatory LTB4 might contribute to the defective airway inflammation-resolution and subsequent progression toward chronic inflammation in AR patients.
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11
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Shane HL, Baur R, Lukomska E, Weatherly L, Anderson SE. Immunotoxicity and allergenic potential induced by topical application of perfluorooctanoic acid (PFOA) in a murine model. Food Chem Toxicol 2020; 136:111114. [PMID: 31904477 PMCID: PMC7753950 DOI: 10.1016/j.fct.2020.111114] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/27/2019] [Accepted: 01/01/2020] [Indexed: 01/09/2023]
Abstract
Perfluorooctanoic acid (PFOA) is a per- and polyfluoroalkyl substance (PFAS) once used as a surfactant in the polymerization of chemicals. Because of its ubiquitous nature and long half-life, PFOA is commonly detected in the environment, wildlife, and humans. While skin exposure to PFOA is of concern, studies evaluating the immunotoxicity of dermal exposure are lacking. These studies evaluated the immunotoxicity of PFOA (0.5-2% w/v, or 12.5-50 mg/kg/dose) following dermal exposure using a murine model. PFOA (0.5-2%) was not identified to be an irritant or sensitizer using the local lymph node assay. The IgM antibody response to sheep red blood cell. was significantly reduced in the spleen following 4-days of dermal exposure (2%). PFOA exposure produced a significant decrease in thymus (1 and 2%) and spleen (0.5-2%) weight along with an increase in liver weight (0.5-2%). Immune cell phenotyping identified a reduction in the frequency (1 and 2%) and number (0.5-2%) of splenic B-cells. To further define the mechanism of immunotoxicity, gene expression was also evaluated in the skin. The findings support a potential involvement of the nuclear receptor PPARα. These results demonstrate that dermal exposure to PFOA is immunotoxic and raise concern about potential adverse effects from dermal exposure.
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Affiliation(s)
- Hillary L Shane
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA.
| | - Rachel Baur
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA
| | - Ewa Lukomska
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA
| | - Lisa Weatherly
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA
| | - Stacey E Anderson
- Allergy and Clinical Immunology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA
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Cigarette smoking differentially regulates inflammatory responses in a mouse model of nonalcoholic steatohepatitis depending on exposure time point. Food Chem Toxicol 2019; 135:110930. [PMID: 31678261 DOI: 10.1016/j.fct.2019.110930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 10/25/2019] [Accepted: 10/27/2019] [Indexed: 02/07/2023]
Abstract
Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 μg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.
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Stark JM, Tibbitt CA, Coquet JM. The Metabolic Requirements of Th2 Cell Differentiation. Front Immunol 2019; 10:2318. [PMID: 31611881 PMCID: PMC6776632 DOI: 10.3389/fimmu.2019.02318] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 09/13/2019] [Indexed: 12/21/2022] Open
Abstract
Upon activation, naïve CD4+ T cells differentiate into a number of specialized T helper (Th) cell subsets. Th2 cells are central players in immunity to helminths and are implicated in mediating the inflammatory pathology associated with allergies. The differentiation of Th2 cells is dependent on transcription factors such as GATA3 and STAT6, which prime Th2 cells for the secretion of interleukin- (IL-) 4, IL-5, and IL-13. Several lines of work now suggest that differentiating Th2 cells in the lymph node are potent IL-4 cytokine producers, but do not become competent IL-5- and IL-13-producing cells until after receiving cues from non-lymphoid tissue. It is evident that Th2 cells that enter tissues undergo considerable changes in chromatin architecture and gene expression, and that over this time, the metabolic requirements of these cells change considerably. Herein, we discuss the metabolic requirements of Th2 cells during their early and late differentiation, focusing on the impact of glucose and lipid metabolism, mTOR activation, the nuclear receptor PPAR-γ and several metabolites.
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Affiliation(s)
- Julian M Stark
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Christopher A Tibbitt
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Jonathan M Coquet
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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14
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Ahsen ME, Chun Y, Grishin A, Grishina G, Stolovitzky G, Pandey G, Bunyavanich S. NeTFactor, a framework for identifying transcriptional regulators of gene expression-based biomarkers. Sci Rep 2019; 9:12970. [PMID: 31506535 PMCID: PMC6737052 DOI: 10.1038/s41598-019-49498-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 08/27/2019] [Indexed: 12/21/2022] Open
Abstract
Biological and regulatory mechanisms underlying many multi-gene expression-based disease biomarkers are often not readily evident. We describe an innovative framework, NeTFactor, that combines network analyses with gene expression data to identify transcription factors (TFs) that significantly and maximally regulate such a biomarker. NeTFactor uses a computationally-inferred context-specific gene regulatory network and applies topological, statistical, and optimization methods to identify regulator TFs. Application of NeTFactor to a multi-gene expression-based asthma biomarker identified ETS translocation variant 4 (ETV4) and peroxisome proliferator-activated receptor gamma (PPARG) as the biomarker's most significant TF regulators. siRNA-based knock down of these TFs in an airway epithelial cell line model demonstrated significant reduction of cytokine expression relevant to asthma, validating NeTFactor's top-scoring findings. While PPARG has been associated with airway inflammation, ETV4 has not yet been implicated in asthma, thus indicating the possibility of novel, disease-relevant discovery by NeTFactor. We also show that NeTFactor's results are robust when the gene regulatory network and biomarker are derived from independent data. Additionally, our application of NeTFactor to a different disease biomarker identified TF regulators of interest. These results illustrate that the application of NeTFactor to multi-gene expression-based biomarkers could yield valuable insights into regulatory mechanisms and biological processes underlying disease.
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Affiliation(s)
- Mehmet Eren Ahsen
- Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yoojin Chun
- Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexander Grishin
- Division of Allergy & Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Galina Grishina
- Division of Allergy & Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gustavo Stolovitzky
- Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- IBM T.J. Watson Research Center, Yorktown Heights, New York, NY, USA
| | - Gaurav Pandey
- Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Supinda Bunyavanich
- Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Division of Allergy & Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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15
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Lee J, Kim S, Lee M, Kim B, Song W, Park H, Cho S, Hong S, Chang Y, Kim B. Different upper airway microbiome and their functional genes associated with asthma in young adults and elderly individuals. Allergy 2019; 74:709-719. [PMID: 30242844 DOI: 10.1111/all.13608] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 07/19/2018] [Accepted: 08/02/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Microbes in the airway have been shown to be associated with the pathogenesis of asthma. The upper airway microbiome influences the dysbiosis of the lower airway microbiome. However, to date, the influence of upper airway microbiome for adult and elderly asthma has not been fully elucidated. Here, the metagenome of upper airway microbiome of young adults and elderly was analyzed to identify their association with adult asthma. METHODS Nasopharyngeal swabs were collected from young adult and elderly asthma patients and non-asthmatic subjects. The compositions and functional genes of airway microbiome were analyzed by high-throughput sequencing. RESULTS The composition of microbiota differed between young adult and elderly, and it was different between asthmatics and non-asthmatics in each age group. Different bacteria were related to FEV1% predicted in each age group. Genes related to lysine degradation, N-glycan biosynthesis, caprolactam degradation, and PPAR signaling pathway, which could be related to the reduction in inflammation and degradation of air pollutants, were higher in non-asthmatics. Genes related to pentose phosphate pathway, lipopolysaccharide biosynthesis, flagella assembly, and bacterial chemotaxis-which may all be related to increased inflammation and colonization of pathogenic bacteria-were higher in young adult asthmatic patients. However, the functional genes of airway microbiome in elderly patients were not significantly different according to asthma morbidity. CONCLUSIONS These results suggest that the composition and function of upper airway microbiome could influence asthma pathogenesis, and the microbiome could play various roles depending on the age group.
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Affiliation(s)
- Jin‐Jae Lee
- Department of Life Science Multidisciplinary Genome Institute Hallym University Chuncheon Korea
| | - Sae‐Hoon Kim
- Department of Internal Medicine Seoul National University Bundang Hospital Seongnam Korea
- Department of Internal Medicine College of Medicine Seoul National University Seoul Korea
| | - Min‐Jung Lee
- Department of Life Science Multidisciplinary Genome Institute Hallym University Chuncheon Korea
| | - Byung‐Keun Kim
- Department of Internal Medicine Seoul National University Bundang Hospital Seongnam Korea
| | - Woo‐Jung Song
- Department of Internal Medicine College of Medicine Seoul National University Seoul Korea
| | - Heung‐Woo Park
- Department of Internal Medicine College of Medicine Seoul National University Seoul Korea
| | - Sang‐Heon Cho
- Department of Internal Medicine College of Medicine Seoul National University Seoul Korea
| | - Soo‐Jong Hong
- Department of Pediatrics Childhood Asthma Atopy Center Environmental Health Center Asan Medical Center University of Ulsan College of Medicine Seoul Korea
| | - Yoon‐Seok Chang
- Department of Internal Medicine Seoul National University Bundang Hospital Seongnam Korea
- Department of Internal Medicine College of Medicine Seoul National University Seoul Korea
| | - Bong‐Soo Kim
- Department of Life Science Multidisciplinary Genome Institute Hallym University Chuncheon Korea
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16
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Lotfi R, Rezaiemanesh A, Mortazavi SH, Karaji AG, Salari F. Immunoresolvents in asthma and allergic diseases: Review and update. J Cell Physiol 2018; 234:8579-8596. [PMID: 30488527 DOI: 10.1002/jcp.27836] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/07/2018] [Indexed: 01/22/2023]
Abstract
Asthma and allergic diseases are inflammatory conditions developed by excessive reaction of the immune system against normally harmless environmental substances. Although acute inflammation is necessary to eradicate the damaging agents, shifting to chronic inflammation can be potentially detrimental. Essential fatty-acids-derived immunoresolvents, namely, lipoxins, resolvins, protectins, and maresins, are anti-inflammatory compounds that are believed to have protective and beneficial effects in inflammatory disorders, including asthma and allergies. Accordingly, impaired biosynthesis and defective production of immunoresolvents could be involved in the development of chronic inflammation. In this review, recent evidence on the anti-inflam]matory effects of immunoresolvents, their enzymatic biosynthesis routes, as well as their receptors are discussed.
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Affiliation(s)
- Ramin Lotfi
- Student Research Committee, Department of immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Hamidreza Mortazavi
- Department of Pediatrics, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Gorgin Karaji
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farhad Salari
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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17
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Nobs SP, Kopf M. PPAR-γ in innate and adaptive lung immunity. J Leukoc Biol 2018; 104:737-741. [PMID: 29768688 DOI: 10.1002/jlb.3mr0118-034r] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 03/26/2018] [Accepted: 04/17/2018] [Indexed: 12/21/2022] Open
Abstract
The transcription factor PPAR-γ (peroxisome proliferator-activated receptor-γ) is a key regulator of lung immunity exhibiting multiple cell type specific roles in controlling development and function of the lung immune system. It is strictly required for the generation of alveolar macrophages by controlling differentiation of fetal lung monocyte precursors. Furthermore, it plays an important role in lung allergic inflammation by licensing lung dendritic cell t helper 2 (Th2) priming capacity as well as acting as a master transcription factor for pathogenic Th2 cells. Due to this plethora of functions and its involvement in multiple pulmonary diseases including asthma and pulmonary alveolar proteinosis, understanding the role of PPAR-γ in lung immunity is an important subject of ongoing research.
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Affiliation(s)
- Samuel Philip Nobs
- Department of Biology, Institute of Molecular Health Sciences, Zurich, Switzerland.,Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Manfred Kopf
- Department of Biology, Institute of Molecular Health Sciences, Zurich, Switzerland
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18
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Lee SH, Tang CH, Lin WY, Chen KH, Liang HJ, Cheng TJ, Lin CY. LC-MS-based lipidomics to examine acute rat pulmonary responses after nano- and fine-sized ZnO particle inhalation exposure. Nanotoxicology 2018; 12:439-452. [DOI: 10.1080/17435390.2018.1458918] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Sheng-Han Lee
- Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chuan-Ho Tang
- National Museum of Marine Biology and Aquarium, Pingtung, Taiwan
- Institute of Marine Biodiversity and Evolutionary Biology, National Dong Hwa University, Pingtung, Taiwan
| | - Wan-Yu Lin
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ke-Han Chen
- Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Hao-Jan Liang
- Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tsun-Jen Cheng
- Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ching-Yu Lin
- Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan
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19
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Banno A, Reddy AT, Lakshmi SP, Reddy RC. PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma. NUCLEAR RECEPTOR RESEARCH 2017; 5. [PMID: 29450204 DOI: 10.11131/2018/101306] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.
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Affiliation(s)
- Asoka Banno
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Aravind T Reddy
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
| | - Sowmya P Lakshmi
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
| | - Raju C Reddy
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.,Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240
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20
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Nobs SP, Natali S, Pohlmeier L, Okreglicka K, Schneider C, Kurrer M, Sallusto F, Kopf M. PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation. J Exp Med 2017; 214:3015-3035. [PMID: 28798029 PMCID: PMC5626395 DOI: 10.1084/jem.20162069] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 05/05/2017] [Accepted: 07/10/2017] [Indexed: 01/17/2023] Open
Abstract
Type-2 immune responses are well-established drivers of chronic inflammatory diseases, such as asthma, and represent a large burden on public health systems. The transcription factor PPARγ is known to promote M2-macrophage and alveolar macrophage development. Here, we report that PPARγ plays a key role in both T cells and dendritic cells (DCs) for development of type-2 immune responses. It is predominantly expressed in mouse Th2 cells in vitro and in vivo as well as human Th2 cells from allergic patients. Using conditional knockouts, we show that PPARγ signaling in T cells, although largely dispensable for IL-4 induction, is critical for IL-33-driven Th2 effector function in type-2 allergic airway responses. Furthermore, we demonstrate that IL-4 and IL-33 promote up-regulation of PPARγ in lung-resident CD11b+ DCs, which enhances migration to draining lymph nodes and Th2 priming capacity. Thus, we uncover a surprising proinflammatory role for PPARγ and establish it as a novel, important mediator of DC-T cell interactions in type-2 immunity.
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Affiliation(s)
- Samuel Philip Nobs
- Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Sara Natali
- Center of Medical Immunology, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Lea Pohlmeier
- Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Katarzyna Okreglicka
- Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Christoph Schneider
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | | | - Federica Sallusto
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
- Center of Medical Immunology, Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
| | - Manfred Kopf
- Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
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21
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Abstract
There is increasing evidence that an active lifestyle benefits both body and brain. However, not everyone may be able to exercise due to disease, injury or aging-related frailty. Identification of cellular targets activated by physical activity may lead to the development of new compounds that can, to some extent, mimic systemic and central effects of exercise. This review will focus on factors relevant to energy metabolism in muscle, such as the 5’ adenosine monophosphate-activated protein kinase (AMPK) - sirtuin (SIRT1) - Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, and the molecules affecting it. In particular, putative exercise-mimetics such as AICAR, metformin, and GW501516 will be discussed. Moreover, plant-derived polyphenols such as resveratrol and (-)epicatechin, with exercise-like effects on the body and brain will be evaluated.
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Affiliation(s)
- Davide Guerrieri
- Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA
| | - Hyo Youl Moon
- Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Henriette van Praag
- Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA
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22
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Anderson JR, Mortimer K, Pang L, Smith KM, Bailey H, Hodgson DB, Shaw DE, Knox AJ, Harrison TW. Evaluation of the PPAR-γ Agonist Pioglitazone in Mild Asthma: A Double-Blind Randomized Controlled Trial. PLoS One 2016; 11:e0160257. [PMID: 27560168 PMCID: PMC4999189 DOI: 10.1371/journal.pone.0160257] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 07/15/2016] [Indexed: 11/18/2022] Open
Abstract
Background Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a nuclear receptor that modulates inflammation in models of asthma. To determine whether pioglitazone improves measures of asthma control and airway inflammation, we performed a single-center randomized, double-blind, placebo-controlled, parallel-group trial. Methods Sixty-eight participants with mild asthma were randomized to 12 weeks pioglitazone (30 mg for 4 weeks, then 45 mg for 8 weeks) or placebo. The primary outcome was the adjusted mean forced expiratory volume in one second (FEV1) at 12 weeks. The secondary outcomes were mean peak expiratory flow (PEF), scores on the Juniper Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ), fractional exhaled nitric oxide (FeNO), bronchial hyperresponsiveness (PD20), induced sputum counts, and sputum supernatant interferon gamma-inducible protein-10 (IP-10), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and eosinophil cationic protein (ECP) levels. Study recruitment was closed early after considering the European Medicines Agency’s reports of a potential increased risk of bladder cancer with pioglitazone treatment. Fifty-five cases were included in the full analysis (FA) and 52 in the per-protocol (PP) analysis. Results There was no difference in the adjusted FEV1 at 12 weeks (-0.014 L, 95% confidence interval [CI] -0.15 to 0.12, p = 0.84) or in any of the secondary outcomes in the FA. The PP analysis replicated the FA, with the exception of a lower evening PEF in the pioglitazone group (-21 L/min, 95% CI -39 to -4, p = 0.02). Conclusions We found no evidence that treatment with 12 weeks of pioglitazone improved asthma control or airway inflammation in mild asthma. Trial Registration ClinicalTrials.gov NCT01134835
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Affiliation(s)
- J. R. Anderson
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - K. Mortimer
- Liverpool School of Tropical Medicine, Liverpool, UK and Aintree University Hospital NHS Foundation Trust, Fazakerley, United Kingdom
- * E-mail:
| | - L. Pang
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - K. M Smith
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - H. Bailey
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - D. B. Hodgson
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - D. E. Shaw
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - A. J. Knox
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
| | - T. W. Harrison
- Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, United Kingdom
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Lei C, Jiao Y, He B, Wang G, Wang Q, Wang J. RIP140 down-regulation alleviates acute lung injury via the inhibition of LPS-induced PPARγ promoter methylation. Pulm Pharmacol Ther 2016; 37:57-64. [PMID: 26921464 DOI: 10.1016/j.pupt.2016.02.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 01/18/2016] [Accepted: 02/02/2016] [Indexed: 11/16/2022]
Abstract
Seriously inflammatory response of the lungs can induce acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) which are serious public health threats due to their high patient morbidity and mortality. While RIP140 is known to modulate proinflammatory cytokine production during an inflammatory response, its role in ALI/ARDS is unclear. In this study, we examined RIP140 and PPARγ protein expression in RAW 264.7 cells and lung tissue following LPS-induced ALI. RIP140 shRNA adenoviral knockdown significantly elevated PPARγ expression, inhibited TNF-α, IL-1β, and IL-6 production in vivo and in vitro. Conversely, treatment with a PPARγ antagonist (GW9662) reversed these outcomes. Furthermore, co-IP showed that endogenous and exogenous RIP140 interacted with DNMT3b in RAW 264.7 cells. Bisulfite conversion, pyrosequencing and activity assays demonstrated that PPARγ promoter methylation levels were increased and that PPARγ transcriptional activity was inhibited following LPS treatment in macrophages. Nevertheless, RIP140 knockdown reduced PPARγ promoter methylation levels and restored its transcriptional activity. These results indicate that RIP140 knockdown can inhibit the production of inflammation mediators and remit ALI via the repression of DNMT3b mediated PPARγ promoter methylation.
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Affiliation(s)
- Chuanjiang Lei
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China
| | - Yan Jiao
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China
| | - Bingfeng He
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China
| | - Guansong Wang
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China
| | - Qin Wang
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China
| | - Jianchun Wang
- Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, 40037, China.
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24
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Lee HY, Rhee CK, Kang JY, Park CK, Lee SY, Kwon SS, Kim YK, Yoon HK. Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma. Korean J Intern Med 2016; 31:89-97. [PMID: 26767862 PMCID: PMC4712439 DOI: 10.3904/kjim.2016.31.1.89] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 10/20/2014] [Accepted: 10/24/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND/AIMS Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. METHODS We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. RESULTS Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-κB. CONCLUSIONS These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-κB pathways.
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Affiliation(s)
- Hwa Young Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chin Kook Rhee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Young Kang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chan Kwon Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Young Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soon Suk Kwon
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Kyoon Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyoung Kyu Yoon
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Correspondence to Hyoung Kyu Yoon, M.D. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Yeouido St. Mary’s Hospital, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea Tel: +82-2-3779-2213 Fax: +82-2-780-3132 E-mail:
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De Rosa V, Galgani M, Santopaolo M, Colamatteo A, Laccetti R, Matarese G. Nutritional control of immunity: Balancing the metabolic requirements with an appropriate immune function. Semin Immunol 2015; 27:300-9. [PMID: 26527507 DOI: 10.1016/j.smim.2015.10.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/07/2015] [Accepted: 10/12/2015] [Indexed: 12/15/2022]
Abstract
The immune system is a highly integrated network of cells sensitive to a number of environmental factors. Interestingly, recent years have seen a dramatic increase in our understanding of how diet makes a crucial contribution to human health, affecting the immune system, secretion of adipocytokines and metabolic pathways. Recent experimental evidence indicates that diet and its components are able to profoundly influence immune responses, thus affecting the development of inflammatory and autoimmune diseases. This review aims to discuss some of the main topics concerning the impact of nutrients and their relative composition on immune cell development and function that may be particularly important for regulating the balance between inflammatory and tolerogenic processes. We also highlight the effects of diet on commensal bacteria and how changes in the composition of the microbiota alter intestinal and systemic immune homeostasis. Finally, we summarize the effects of dietary compounds on epigenetic mechanisms involved in the regulation of several immune related genes.
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Affiliation(s)
- Veronica De Rosa
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy; Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma 00143, Italy
| | - Mario Galgani
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy
| | - Marianna Santopaolo
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", Napoli 80131, Italy
| | - Alessandra Colamatteo
- Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma 00143, Italy; Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi 84081, Salerno, Italy
| | - Roberta Laccetti
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy; Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi 84081, Salerno, Italy
| | - Giuseppe Matarese
- Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi 84081, Salerno, Italy; IRCCS MultiMedica, Milano 20138, Italy.
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Donovan C, Bailey SR, Tran J, Haitsma G, Ibrahim ZA, Foster SR, Tang MLK, Royce SG, Bourke JE. Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease. Am J Physiol Lung Cell Mol Physiol 2015; 309:L1219-28. [PMID: 26386117 DOI: 10.1152/ajplung.00156.2015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 09/04/2015] [Indexed: 12/14/2022] Open
Abstract
Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and β-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPARγ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-(Δ12,14)-prostaglandin J2 (15-deoxy-PGJ2)] or β-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARγ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized (days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than β-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than β-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPARγ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to β-adrenoceptor agonists is limited.
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Affiliation(s)
- Chantal Donovan
- Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Simon R Bailey
- Faculty of Veterinary Science, University of Melbourne, Parkville, Australia; and
| | - Jenny Tran
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Gertruud Haitsma
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Zaridatul A Ibrahim
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Simon R Foster
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Mimi L K Tang
- Department of Allergy and Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
| | - Simon G Royce
- Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia; Department of Allergy and Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
| | - Jane E Bourke
- Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
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Stolarz AJ, Farris RA, Wiley CA, O'Brien CE, Price ET. Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis. Clin Transl Sci 2015; 8:696-701. [PMID: 26258991 DOI: 10.1111/cts.12310] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
A hallmark of cystic fibrosis (CF) lung disease is neutrophilic airway inflammation. Elevated neutrophil counts have been associated with decreased forced expiratory volume in 1 second and poor clinical measures in patients with CF. Interleukin 8 (IL-8), epithelial neutrophil activating protein 78 (ENA-78), tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) contribute to neutrophil activation and disease pathogenesis in the airways of patients with CF. Drugs that modify the production of these chemokines in the airways could potentially benefit CF patients. Thus, we determined the effects of fenofibrate on their production in cell populations obtained from the airways. Human small airway epithelial cells and CF bronchial epithelial cells were treated with IL-1β to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 μM to determine if this drug could attenuate the inflammation. IL-8, ENA-78, TNF-α, GM-CSF, and G-CSF production were measured from the cell culture supernates by ELISA. ANOVA statistical testing was conducted using SPSS 17.0. IL-1β increased the production of each of the chemokines by several fold. Fenofibrate reduced IL-1β induced production of each of these neutrophilic chemokines at the concentrations used. IL-1β increases the production of neutrophilic chemokines in airway epithelial cells. Cotreatment with fenofibrate blunts these processes. Fenofibrate should be explored as a therapeutic option to modulate the abundant neutrophilic inflammation observed in CF.
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Affiliation(s)
- Amanda J Stolarz
- Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA
| | - Ryan A Farris
- Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA
| | - Charla A Wiley
- Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA
| | - Catherine E O'Brien
- Department of Pharmacy Practice, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA
| | - Elvin T Price
- Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA
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Alexandrova E, Miglino N, Hashim A, Nassa G, Stellato C, Tamm M, Baty F, Brutsche M, Weisz A, Borger P. Small RNA profiling reveals deregulated phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway in bronchial smooth muscle cells from asthmatic patients. J Allergy Clin Immunol 2015; 137:58-67. [PMID: 26148798 DOI: 10.1016/j.jaci.2015.05.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 05/20/2015] [Accepted: 05/26/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Aberrant expression of small noncoding RNAs (sncRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) in particular, define several pathologic processes. Asthma is characterized by airway hyperreactivity, chronic inflammation, and airway wall remodeling. Asthma-specific miRNA profiles were reported for bronchial epithelial cells, whereas sncRNA expression in asthmatic bronchial smooth muscle (BSM) cells is almost completely unexplored. OBJECTIVE We sought to determine whether the primary BSM sncRNA expression profile is altered in asthmatic patients and identify targets of differentially expressed sncRNAs. METHODS Small RNA sequencing was used for sncRNA profiling in BSM cells (from 8 asthmatic and 6 nonasthmatic subjects). sncRNA identification and differential expression analysis was performed with iMir software. Experimentally validated miRNA targets were identified by using Ingenuity Pathway Analysis, and putative piRNA targets were identified by using miRanda software. RESULTS BSM cells from asthmatic patients showed abnormal expression of 32 sncRNAs (26 miRNAs, 5 piRNAs, and 1 small nucleolar RNA). Target prediction for deregulated miRNAs and piRNAs revealed experimentally validated and predicted mRNA targets expressed in the BSM cells. Thirty-eight of these mRNAs represent major targets for deregulated miRNAs and might play important roles in the pathophysiology of asthma. Interestingly, 6 of these mRNAs were previously associated with asthma, considered as novel therapeutic targets for treatment of this disease, or both. Signaling pathway analysis revealed involvement of 38 miRNA-targeted mRNAs in increased cell proliferation through phosphatase and tensin homolog and phosphoinositide 3-kinase/Akt signaling pathways. CONCLUSIONS BSM cells of asthmatic patients are characterized by aberrant sncRNA expression that recapitulates multiple pathologic phenotypes of these cells.
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Affiliation(s)
- Elena Alexandrova
- Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy; Genomix4Life Srl, Campus of Medicine, University of Salerno, Baronissi, Italy
| | - Nicola Miglino
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Adnan Hashim
- Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Claudia Stellato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Michael Tamm
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Florent Baty
- Division of Molecular Pathology and Medical Genomics, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Martin Brutsche
- Division of Molecular Pathology and Medical Genomics, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy; Molecular Pathology and Medical Genomics Unit, "SS. Giovanni di Dio e Ruggi d'Aragona-Schuola Medica Salernitana" University Hospital, Salerno, Italy.
| | - Pieter Borger
- Department of Biomedicine, University of Basel, Basel, Switzerland.
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Abstract
The incidence of allergic diseases is increasing, both in developed and developing countries, concomitantly with the rise in living standards and the adoption of a 'western lifestyle'. For two decades, the hygiene hypothesis - which proposes that the lack of early childhood exposure to infectious agents increases susceptibility to allergic diseases in later life - provided the conceptual framework for unravelling the mechanisms that could account for the increased incidence of allergic diseases. In this Review, we discuss recent evidence that highlights the role of diet as a key factor influencing immune homeostasis and the development of allergic diseases through a complex interplay between nutrients, their metabolites and immune cell populations. Although further investigations are still required to understand these complex relationships, recent data have established a possible connection between metabolic homeostasis and allergic diseases.
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30
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Yang L, Lewkowich I, Apsley K, Fritz JM, Wills-Karp M, Weaver TE. Haploinsufficiency for Stard7 is associated with enhanced allergic responses in lung and skin. THE JOURNAL OF IMMUNOLOGY 2015; 194:5635-43. [PMID: 25980009 DOI: 10.4049/jimmunol.1500231] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 04/19/2015] [Indexed: 11/19/2022]
Abstract
Allergic asthma is a chronic inflammatory disorder that affects ∼20% of the population worldwide. Microarray analyses of nasal epithelial cells from acute asthmatic patients detected a 50% decrease in expression of Stard7, an intracellular phosphatidylcholine transport protein. To determine whether loss of Stard7 expression promotes allergic responses, mice were generated in which one allele of the Stard7 locus was globally disrupted (Stard7 (+/-) mice). OVA sensitization and challenge of Stard7(+/-) mice resulted in a significant increase in pulmonary inflammation, mucous cell metaplasia, airway hyperresponsiveness, and OVA-specific IgE compared with OVA-sensitized/challenged wild-type (WT) mice. This exacerbation was largely Th2-mediated with a significant increase in CD4(+)IL-13(+) T cells and IL-4, IL-5, and IL-13 cytokines. The loss of Stard7 was also associated with increased lung epithelial permeability and activation of proinflammatory dendritic cells in sensitized and/or challenged Stard7 (+/-) mice. Notably, OVA-pulsed dendritic cells from Stard7(+/-) mice were sufficient to confer an exaggerated allergic response in OVA-challenged WT mice, although airway hyperresponsiveness was greater in Stard7(+/-) recipients compared with WT recipients. Enhanced allergic responses in the lung were accompanied by age-dependent development of spontaneous atopic dermatitis. Overall, these data suggest that Stard7 is an important component of a novel protective pathway in tissues exposed to the extracellular environment.
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Affiliation(s)
- Li Yang
- Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Ian Lewkowich
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229; and
| | - Karen Apsley
- Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Jill M Fritz
- Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Marsha Wills-Karp
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205
| | - Timothy E Weaver
- Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229;
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31
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Smith SG, Hill M, Oliveria JP, Watson BM, Baatjes AJ, Dua B, Howie K, Campbell H, Watson RM, Sehmi R, Gauvreau GM. Evaluation of peroxisome proliferator-activated receptor agonists on interleukin-5-induced eosinophil differentiation. Immunology 2014; 142:484-91. [PMID: 24628018 DOI: 10.1111/imm.12280] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 02/26/2014] [Accepted: 03/07/2014] [Indexed: 12/30/2022] Open
Abstract
Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) -induced eosinophil differentiation from haemopoietic progenitor cells. Non-adherent mononuclear cells or CD34(+) cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult(®) cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1-1000 nm PPARα agonist (GW9578), PPARβ/δ agonist (GW501516), PPARγ agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34(+) cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0·01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal-regulated kinase 1/2 signalling pathway. These findings indicate that the PPARγ agonist can attenuate tissue eosinophilia by interfering with local differentiative responses.
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Affiliation(s)
- Steven G Smith
- Department of Medicine, McMaster University, Hamilton, ON, Canada
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Malekinejad H, Khoramjouy M, Hobbenaghi R, Amniattalab A. Atorvastatin attenuates the paraquat-induced pulmonary inflammation via PPARγ receptors: a new indication for atorvastatin. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2014; 114:79-89. [PMID: 25175654 DOI: 10.1016/j.pestbp.2014.06.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 02/08/2023]
Abstract
This study was carried out to highlight the role of PPARγ receptors and atorvastatin's protective effect on paraquat (PQ)-induced inflammation in the lungs. Forty-two male Wistar rats were exposed either against saline as control or PQ (3.5 mg/kg, IP) as test groups for 14 days. The test groups were nominated as: PQ, pioglitazone (PGT, 10 mg/kg, orally), atorvastatin (STN, 10 mg/kg, orally), PGT+STN, PGT+GW9662 (1 mg/kg) and STN+GW9662 (1 mg/kg). PGT and STN significantly (P<0.05) reduced the PQ-elevated myeloperoxidase activity, nitric oxide and malondialdehyde contents of the lungs and IL-6 and TNF-α concentrations in serum. Histopathological studies revealed alveolar edema and hemorrhages along with hyaline exudates in alveoli confirming that PGT and STN reduced the damages. Immunohistochemistry studies showed that the PQ-induced inflammation resulted in a severe recruitment of CD68(+) macrophages, which PGT and STN remarkably diminished them. STN regulated the PQ-up-regulated COX-2 expression. The antagonistic effect of GW9662 as an absolute antagonist of PPARγ receptors on anti-inflammatory effect of STN in the regulation of COX-2 expression was observed. These data provide a molecular proof(s) of the STN-produced protective effects on the PQ-induced pulmonary inflammation, which is antagonized by PPARγ antagonist indicating its anti-inflammatory effects via PPARγ receptors. Moreover, a new indication for atorvastatin is suggested.
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Affiliation(s)
- Hassan Malekinejad
- Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
| | - Mona Khoramjouy
- Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Rahim Hobbenaghi
- Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Amir Amniattalab
- Department of Pathology, Islamic Azad University, Urmia Branch, Urmia, Iran
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Rinne ST, Feemster LC, Collins BF, Au DH, Perkins M, Bryson CL, O’Riordan TG, Liu CF. Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study. ALLERGY, ASTHMA, AND CLINICAL IMMUNOLOGY : OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF ALLERGY AND CLINICAL IMMUNOLOGY 2014; 10:34. [PMID: 25024717 PMCID: PMC4094895 DOI: 10.1186/1710-1492-10-34] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 06/19/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Thiazolidinediones are oral diabetes medications that selectively activate peroxisome proliferator-activated receptor gamma and have potent anti-inflammatory properties. While a few studies have found improvements in pulmonary function with exposure to thiazolidinediones, there are no studies of their impact on asthma exacerbations. Our objective was to assess whether exposure to thiazolidinediones was associated with a decreased risk of asthma exacerbation. METHODS We performed a cohort study of diabetic Veterans who had a diagnosis of asthma and were taking oral diabetes medications during the period of 10/1/2005 - 9/30/2006. The risk of asthma exacerbations and oral steroid use during 10/1/2006 - 9/30/2007 was compared between patients who were prescribed thiazolidinediones and patients who were on alternative oral diabetes medications. Multivariable logistic regression and negative binomial regression analyses were used to characterize this risk. A sensitivity analysis was performed, restricting our evaluation to patients who were adherent to diabetes therapy. RESULTS We identified 2,178 patients who were on thiazolidinediones and 10,700 who were not. Exposure to thiazolidinediones was associated with significant reductions in the risk of asthma exacerbation (OR = 0.79, 95% CI, 0.62 - 0.99) and oral steroid prescription (OR = 0.73, 95% CI 0.63 - 0.84). Among patients who were adherent to diabetes medications, there were more substantial reductions in the risks for asthma exacerbation (OR = 0.64, 95% CI 0.47 - 0.85) and oral steroid prescription (OR = 0.68, 95% CI 0.57 - 0.81). CONCLUSIONS Thiazolidinediones may provide a novel anti-inflammatory approach to asthma management by preventing exacerbations and decreasing the use of oral steroids.
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Affiliation(s)
- Seppo T Rinne
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Department of Pulmonary and Cri Care, University of Washington, Seattle, WA, USA
| | - Laura C Feemster
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Department of Pulmonary and Cri Care, University of Washington, Seattle, WA, USA
| | - Bridget F Collins
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Department of Pulmonary and Cri Care, University of Washington, Seattle, WA, USA
| | - David H Au
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Department of Pulmonary and Cri Care, University of Washington, Seattle, WA, USA
| | - Mark Perkins
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
| | - Christopher L Bryson
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Chuan-Fen Liu
- Health Services Research and Development, VA Puget Sound Health Care System, Department of Veterans Affairs, 1100 Olive Way Suite 1400, 98104-3801 Seattle, WA, USA
- Department of Health Services, University of Washington, Seattle, WA, USA
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Kiss M, Czimmerer Z, Nagy L. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology. J Allergy Clin Immunol 2013; 132:264-86. [PMID: 23905916 DOI: 10.1016/j.jaci.2013.05.044] [Citation(s) in RCA: 125] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Revised: 05/16/2013] [Accepted: 05/30/2013] [Indexed: 02/06/2023]
Abstract
Nuclear receptors are ligand-activated transcription factors linking lipid signaling to the expression of the genome. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells (DCs), essential members of the innate immune system. In this review we focus on the role of retinoid X receptor, retinoic acid receptor, peroxisome proliferator-associated receptor γ, liver X receptor, and vitamin D receptor in shaping the immune and metabolic functions of macrophages and DCs. We also provide an overview of the contribution of macrophage- and DC-expressed nuclear receptors to various immunopathologic conditions, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, asthma, and some others. We suggest that systematic analyses of the roles of these receptors and their activating lipid ligands in immunopathologies combined with complementary and focused translational and clinical research will be crucial for the development of new therapies using the many molecules available to target nuclear receptors.
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Affiliation(s)
- Mate Kiss
- Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
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Zappavigna S, Luce A, Vitale G, Merola N, Facchini S, Caraglia M. Autophagic cell death: A new frontier in cancer research. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/abb.2013.42034] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Seidel P, Alkhouri H, Lalor DJ, Burgess JK, Armour CL, Hughes JM. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies. Respir Res 2012; 13:90. [PMID: 23034049 PMCID: PMC3503570 DOI: 10.1186/1465-9921-13-90] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 09/27/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. METHODS Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher's post-hoc test. RESULTS Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix). The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1 nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM) inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production. CONCLUSIONS Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.
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Affiliation(s)
- Petra Seidel
- Respiratory Research Group, Faculty of Pharmacy, The University of Sydney, A15, Science Rd, Sydney, NSW 2006, Australia
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Bhatt KH, Sodhi A, Chakraborty R. Peptidoglycan induced expression of peroxisome proliferator-activated receptor γ in mouse peritoneal macrophages: role of ERK and JNK MAP kinases. Cytokine 2012; 60:778-86. [PMID: 22925536 DOI: 10.1016/j.cyto.2012.07.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 07/07/2012] [Accepted: 07/29/2012] [Indexed: 01/28/2023]
Abstract
The peroxisome proliferator-activated receptor (PPAR) γ plays an important role in macrophage inflammatory homeostasis. Here we investigate the cross talk between PPARγ and TLR2 signaling pathway in mouse peritoneal macrophages. Real time RT-PCR and immunoblot analysis revealed that peptidoglycan (PGN) treatment of macrophages leads to biphasic effect on PPARγ expression i.e. an early upregulation and a late suppression. Inhibition of ERK MAP kinase by PD98059 abolished the early and rapid induction of PPARγ, while the inhibition of JNK MAP kinase by SP600125 nullifies the late inhibitory effect on the PPARγ expression in a dose-dependent manner. Furthermore, PPARγ knockdown macrophages showed enhanced NF-κB activity after PGN treatment. PGN treatment also enhances PPARγ interaction with p65 as observed by immunoprecipitation. This interaction may inhibit NF-κB (p65) activity as increased nuclear localization of p65 was observed in PPARγ knockdown macrophages after PGN treatment. PPARγ knockdown also increased the PGN-induced inflammatory cytokines (TNF-α, IL-1β, IL-12p40) production. Thus, our observations suggest that PGN induces PPARγ expression which is regulated by MAPKs activation and this enhanced PPARγ in turn attenuate NF-κB activity probably via enhancing p65 nuclear export. These results provide insight into how these pathways could be modulated in inflammatory diseases.
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Affiliation(s)
- Kunal H Bhatt
- School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
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PPARγ Ligands Regulate Noncontractile and Contractile Functions of Airway Smooth Muscle: Implications for Asthma Therapy. PPAR Res 2012; 2012:809164. [PMID: 22966222 PMCID: PMC3431171 DOI: 10.1155/2012/809164] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 06/12/2012] [Indexed: 01/22/2023] Open
Abstract
In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptor γ (PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγ ligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASM in vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγ ligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse trachea in vitro through a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity to β2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotine in utero or following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγ agonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.
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The Effect of PPAR Agonists on the Migration of Mature and Immature Eosinophils. PPAR Res 2012; 2012:235231. [PMID: 22966220 PMCID: PMC3395269 DOI: 10.1155/2012/235231] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/07/2012] [Indexed: 01/21/2023] Open
Abstract
PPARγ agonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis) and random cell movement (chemokinesis). To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα, δ, and γ agonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγ agonist), GW9578 (PPARα agonist), GW501516 (PPARδ agonist), or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P = 0.0038), and SDF-1α-induced migration of immature eosinophils (P = 0.0538). Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P = 0.0042). The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function.
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Diez D, Goto S, Fahy JV, Erle DJ, Woodruff PG, Wheelock ÅM, Wheelock CE. Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics. BMC Med Genomics 2012; 5:27. [PMID: 22713245 PMCID: PMC3408345 DOI: 10.1186/1755-8794-5-27] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 06/19/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium. METHODS Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment. RESULTS Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs. CONCLUSIONS Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.
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Affiliation(s)
- Diego Diez
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
- Laboratory of Bioinformatics and Genomics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan
| | - Susumu Goto
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
| | - John V Fahy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - David J Erle
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Lung Biology Center, University of California San Francisco, San Francisco, CA, USA
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Prescott G Woodruff
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
| | - Åsa M Wheelock
- Respiratory Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Craig E Wheelock
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan
- Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden
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PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases. PPAR Res 2012; 2012:256874. [PMID: 22761606 PMCID: PMC3385647 DOI: 10.1155/2012/256874] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 03/19/2012] [Accepted: 05/08/2012] [Indexed: 02/05/2023] Open
Abstract
Airway mucus hypersecretion (AMH) is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγ is expressed in structural, immune, and inflammatory cells in the lung. PPARγ is involved in mucin production, and PPARγ agonists can inhibit mucin synthesis both in vitro and in vivo. These findings suggest that PPARγ is a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.
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The modulation of PPARγ1 and PPARγ2 mRNA expression by ciglitazone in CD3/CD28-activated naïve and memory CD4+ T cells. Clin Dev Immunol 2012; 2012:849195. [PMID: 22548115 PMCID: PMC3323850 DOI: 10.1155/2012/849195] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 01/24/2012] [Accepted: 01/26/2012] [Indexed: 01/10/2023]
Abstract
Given their roles in immune regulation, the expression of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 1 and 2 isoforms was investigated in human naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells. Stimulation of both types of cells via the CD3/CD28 pathway resulted in high expression of both PPARγ receptors as measured by real-time PCR. Treatment with the PPARγ agonist, ciglitazone, increased PPARγ1 expression but decreased PPARγ2 expression in stimulated naïve and memory cells. Furthermore, when present, the magnitude of both PPARγ receptors expression was lower in naïve cells, perhaps suggesting a lower regulatory control of these cells. Similar profiles of selected proinflammatory cytokines were expressed by the two cell types following stimulation. The induction of PPARγ1 and suppression of PPARγ2 expressions in naïve and memory CD4+ T cells in the presence of ciglitazone suggest that the PPARγ subtypes may have different roles in the regulation of T-cell function.
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Helyes Z, Hajna Z. Endotoxin-Induced Airway Inflammation and Asthma Models. METHODS IN PHARMACOLOGY AND TOXICOLOGY 2012. [DOI: 10.1007/978-1-62703-077-9_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Legutko A, Marichal T, Fiévez L, Bedoret D, Mayer A, de Vries H, Klotz L, Drion PV, Heirman C, Cataldo D, Louis R, Thielemans K, Andris F, Leo O, Lekeux P, Desmet CJ, Bureau F. Sirtuin 1 promotes Th2 responses and airway allergy by repressing peroxisome proliferator-activated receptor-γ activity in dendritic cells. THE JOURNAL OF IMMUNOLOGY 2011; 187:4517-29. [PMID: 21948987 DOI: 10.4049/jimmunol.1101493] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sirtuins are a unique class of NAD(+)-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-κB. In contrast, we report in this study that pharmacological inhibition of sirtuins dampens adaptive Th2 responses and subsequent allergic inflammation by interfering with lung dendritic cell (DC) function in a mouse model of airway allergy. Using genetic engineering, we demonstrate that sirtuin 1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of DC function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins.
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Affiliation(s)
- Agnieszka Legutko
- Laboratory of Cellular and Molecular Physiology, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research), University of Liège, Liège B-4000, Belgium
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Peroxisome proliferator activated receptor ligands as regulators of airway inflammation and remodelling in chronic lung disease. PPAR Res 2011; 2007:14983. [PMID: 18000530 PMCID: PMC2065911 DOI: 10.1155/2007/14983] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2007] [Accepted: 06/11/2007] [Indexed: 11/20/2022] Open
Abstract
Inflammation is a major component in the pathology of chronic lung diseases, including asthma. Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic options are required to control diverse cellular functions that are currently not optimally targeted by these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, and cell proliferation and survival. In murine models of allergen-induced inflammation, PPARα and PPARγ ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to mimimise the contribution of inflammation to airway remodelling and dysfunction.
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Macredmond R, Dorscheid DR. Conjugated linoleic acid (CLA): is it time to supplement asthma therapy? Pulm Pharmacol Ther 2011; 24:540-8. [PMID: 21530672 DOI: 10.1016/j.pupt.2011.03.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 03/15/2011] [Accepted: 03/20/2011] [Indexed: 01/08/2023]
Abstract
The limitations and side effects of existing asthma therapies prompt interest in complementary and alternative therapies. Conjugated linoleic acids (CLA) are a family of natural fatty acids found primarily in beef and dairy products. These molecules have a variety of biological properties which suggest potential benefit in asthma, including effects on energy regulation, lipid metabolism, inflammation and immune function. Here we review the evidence for these effects from pre-clinical and clinical studies, their significance in the context of human asthma, and discuss the potential role for CLA supplementation in asthma management.
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Affiliation(s)
- Ruth Macredmond
- Providence Healthcare Heart + Lung Institute, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
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Sahebkar A. Potential benefits of supplementation with auraptene in cystic fibrosis. Clin Nutr 2011; 30:259-60. [DOI: 10.1016/j.clnu.2010.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Revised: 07/13/2010] [Accepted: 07/14/2010] [Indexed: 10/19/2022]
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Wang W, Zhu Z, Zhu B, Ma Z. Pioglitazone attenuates allergic inflammation and induces production of regulatory T lymphocytes. Am J Rhinol Allergy 2011; 24:454-8. [PMID: 21144225 DOI: 10.2500/ajra.2010.24.3522] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists have been shown to be involved in the regulation of allergic inflammatory responses. The molecular mechanisms by which PPAR-gamma activation inhibits the inflammatory process have not been well understood. METHODS BALB/c mice received ovalbumin (OVA) sensitization followed by OVA intranasal challenge. Mice in the treatment group received intragastric administration with pioglitazone (PIO; 30 mg/kg) before each OVA challenge. Various allergic responses were then assessed. RESULTS The frequencies of sneezing and nose-scratching and eosinophil infiltration decreased significantly in the PIO treatment group compared with the OVA group (p < 0.05). The PIO treatment also showed that the levels of nasal cavity lavage fluid interleukin (IL)-5 and sera OVA-specific immunoglobulin E (IgE) were markedly reduced (p < 0.05). PIO significantly increased the expression of Foxp3 mRNA (p < 0.05) and induced production of regulatory T lymphocyte (p < 0.01) compared with the OVA group. CONCLUSION Given the potent effectiveness shown by PIO, we conclude that PPAR-gamma agonists deserve investigation as potential therapies for human allergic upper airway inflammation.
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Affiliation(s)
- Weihua Wang
- Department of Otolaryngology–Head and Neck Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, China
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Becker J, Delayre-Orthez C, Frossard N, Pons F. The peroxisome proliferator-activated receptor α agonist fenofibrate decreases airway reactivity to methacholine and increases endothelial nitric oxide synthase phosphorylation in mouse lung. Fundam Clin Pharmacol 2011; 26:340-6. [PMID: 21392098 DOI: 10.1111/j.1472-8206.2011.00935.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In the present study, we have investigated the effect of the peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate on airway reactivity and the role of the endothelial nitric oxide synthase (eNOS)/NO pathway in this effect. Airway reactivity to methacholine was assessed in C57BL/6 mice treated or not with fenofibrate by whole-body plethysmography. In some experiments, animals were administered with the NOS inhibitor L-NAME, one hour before airway reactivity measurement. Expression and phosphorylation of eNOS were evaluated in lung homogenates from fenofibrate and control animals using Western blotting. Fenofibrate dose and time dependently decreased airway reactivity to methacholine in mice. A statistically significant (P < 0.05) reduction was observed after a treatment of 10 days with a dose of 3 or 15 mg/day fenofibrate. Mice treated with fenofibrate and administered with l-NAME exhibited similar reactivity to methacholine than vehicle-treated mice administered with the NOS inhibitor, suggesting that NO mediates fenofibrate-induced decrease in airway reactivity. eNOS levels remained unchanged in the lung from mice treated with fenofibrate, but phosphorylation of the enzyme at Ser-1177 was increased by 118% (P < 0.05). Taken together, our data demonstrate that fenofibrate downregulates airway reactivity to methacholine in the mouse and suggest that this effect could involve an increase in NO generation through an enhanced eNOS phosphorylation.
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Affiliation(s)
- Julien Becker
- EA3771 Inflammation et environnement dans l'asthme, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg I, 74 route du rhin, BP 60024, 67401 Illkirch, France
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Bassaganya-Riera J, Song R, Roberts PC, Hontecillas R. PPAR-gamma activation as an anti-inflammatory therapy for respiratory virus infections. Viral Immunol 2011; 23:343-52. [PMID: 20712478 DOI: 10.1089/vim.2010.0016] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Newly emerged influenza viruses have attracted extensive attention due to their high infectivity, proinflammatory actions, and potential to induce worldwide pandemics. Frequent mutations and gene reassortments between viruses complicate the development of protective vaccines and antiviral therapeutics. In contrast, targeting the host response for the development of novel cost-effective, broad-based prophylactic or therapeutic agents holds greater promise. Since inflammation often parallels the development of productive immune responses, virus-induced pulmonary inflammation and injury represents an additional challenge to the development of broad-based immunotherapeutics. Excessive inflammatory responses to respiratory viruses, also known as "cytokine storm," are largely due to immune dysregulation that manifests as proinflammatory cytokine secretion. In addition to modulating lipid and glucose metabolism, peroxisome proliferator-activated receptors (PPAR) play important roles in antagonizing core inflammatory pathways such as NF-kappaB, AP1, and STAT. Their role in regulating inflammatory responses caused by pulmonary pathogens is receiving increasing attention, setting the stage for the discovery of novel applications for anti-diabetic and lipid-lowering drugs. This review focuses on the potential use of PPAR-gamma agonists to downregulate the inflammatory responses to respiratory virus-related pulmonary inflammation.
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Affiliation(s)
- Josep Bassaganya-Riera
- Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
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