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Liu C, Wang K, Liu W, Zhang J, Fan Y, Sun Y. ALOX15 + M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 2024; 154:592-608. [PMID: 38705258 DOI: 10.1016/j.jaci.2024.04.019] [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: 01/29/2024] [Revised: 03/30/2024] [Accepted: 04/16/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND Epithelial remodeling is a prominent feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP), and infiltration of M2 macrophages plays a pivotal role in the pathogenesis of eCRSwNP, but the underlying mechanisms remain undefined. OBJECTIVE We sought to investigate the role of ALOX15+ M2 macrophages in the epithelial remodeling of eCRSwNP. METHODS Digital spatial transcriptomics and single-cell sequencing analyses were used to characterize the epithelial remodeling and cellular infiltrate in eCRSwNP. Hematoxylin and eosin staining, immunohistochemical staining, and immunofluorescence staining were used to explore the relationship between ALOX15+ M2 (CD68+CD163+) macrophages and epithelial remodeling. A coculture system of primary human nasal epithelial cells (hNECs) and the macrophage cell line THP-1 was used to determine the underlying mechanisms. RESULTS Spatial transcriptomics analysis showed the upregulation of epithelial remodeling-related genes, such as Vimentin and matrix metalloproteinase 10, and enrichment of epithelial-mesenchymal transition (EMT)-related pathways, in the epithelial areas in eCRSwNP, with more abundance of epithelial basal, goblet, and glandular cells. Single-cell analysis identified that ALOX15+, rather than ALOX15-, M2 macrophages were specifically highly expressed in eCRSwNP. CRSwNP with high ALOX15+ M2THP-1-IL-4+IL-13 macrophages had more obvious epithelial remodeling features and increased genes associated with epithelial remodeling and integrity of epithelial morphology versus that with low ALOX15+ M2THP-1-IL-4+IL-13 macrophages. IL-4/IL-13-polarized M2THP-1-IL-4+IL-13 macrophages upregulated expressions of EMT-related genes in hNECs, including Vimentin, TWIST1, Snail, and ZEB1. ALOX15 inhibition in M2THP-1-IL-4+IL-13 macrophages resulted in reduction of the EMT-related transcripts in hNECs. Blocking chemokine (C-C motif) ligand 13 signaling inhibited M2THP-1-IL-4+IL-13 macrophage-induced EMT alteration in hNECs. CONCLUSIONS ALOX15+ M2 macrophages are specifically increased in eCRSwNP and may contribute to the pathogenesis of epithelial remodeling via production of chemokine (C-C motif) ligand 13.
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Affiliation(s)
- Chang Liu
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Kanghua Wang
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Wenqin Liu
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jinxiu Zhang
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yunping Fan
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
| | - Yueqi Sun
- Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
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Zhou Q, Ma J, Biswal S, Rowan NR, London NR, Riley CA, Lee SE, Pinto JM, Ahmed OG, Su M, Liang Z, Du R, Ramanathan M, Zhang Z. Air pollution, genetic factors, and chronic rhinosinusitis: A prospective study in the UK Biobank. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 940:173526. [PMID: 38825199 DOI: 10.1016/j.scitotenv.2024.173526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) is a prevalent upper respiratory condition that manifests in two primary subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). While previous studies indicate a correlation between air pollution and CRS, the role of genetic predisposition in this relationship remains largely unexplored. We hypothesized that higher air pollution exposure would lead to the development of CRS, and that genetic susceptibility might modify this association. METHODS This cohort study involving 367,298 adult participants from the UK Biobank, followed from March 2006 to October 2021. Air pollution metrics were estimated at residential locations using land-use regression models. Cox proportional hazard models were employed to explore the associations between air pollution exposure and CRS, CRSwNP, and CRSsNP. A polygenic risk score (PRS) was constructed to evaluate the joint effect of air pollution and genetic predisposition on the development of CRS. RESULTS We found that the risk of CRS increased under long-term exposure to PM2.5 [the hazard ratios (HRs) with 95 % CIs: 1.59 (1.26-2.01)], PM10 [1.64 (1.26-2.12)], NO2 [1.11 (1.04-1.17)], and NOx [1.18 (1.12-1.25)], respectively. These effects were more pronounced among participants with CRSwNP, although the differences were not statistically significant. Additionally, we found that the risks for CRS and CRSwNP increased in a graded manner among participants with higher PRS or higher exposure to PM2.5, PM10, or NOx concentrations. However, no multiplicative or additive interactions were observed. CONCLUSIONS Long-term exposure to air pollution increases the risk of CRS, particularly CRSwNP underscoring the need to prioritize clean air initiatives and environmental regulations.
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Affiliation(s)
- Qinfeng Zhou
- Department of Global Health, The Peking University School of Public Health, Beijing, China
| | - Junxiong Ma
- Department of Global Health, The Peking University School of Public Health, Beijing, China
| | - Shyam Biswal
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Nicholas R Rowan
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Nyall R London
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Charles A Riley
- Department of Otolaryngology-Head and Neck Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Stella E Lee
- Division of Otolaryngology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jayant M Pinto
- Section of Otolaryngology, Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Omar G Ahmed
- Department of Otolaryngology, Houston Methodist Academic Institute, Houston, TX, USA
| | - Mintao Su
- Department of Global Health, The Peking University School of Public Health, Beijing, China
| | - Zhisheng Liang
- Department of Global Health, The Peking University School of Public Health, Beijing, China
| | - Runming Du
- Department of Global Health, The Peking University School of Public Health, Beijing, China
| | - Murugappan Ramanathan
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Zhenyu Zhang
- Department of Global Health, The Peking University School of Public Health, Beijing, China; Institute for Global Health and Development, Peking University, Beijing, China; Institute of Carbon Neutrality, Peking University, Beijing, China.
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Lee SY, Park YM, Yoo HJ, Hong SJ. Metabolomic pathways in food allergy. Pediatr Allergy Immunol 2024; 35:e14133. [PMID: 38727629 DOI: 10.1111/pai.14133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 07/12/2024]
Abstract
Food allergy (FA) is a widespread issue, affecting as many as 10% of the population. Over the past two to three decades, the prevalence of FA has been on the rise, particularly in industrialized and westernized countries. FA is a complex, multifactorial disease mediated by type 2 immune responses and involving environmental and genetic factors. However, the precise mechanisms remain inadequately understood. Metabolomics has the potential to identify disease endotypes, which could beneficially promote personalized prevention and treatment. A metabolome approach would facilitate the identification of surrogate metabolite markers reflecting the disease activity and prognosis. Here, we present a literature overview of recent metabolomic studies conducted on children with FA.
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Affiliation(s)
| | - Yoon Mee Park
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyun Ju Yoo
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo-Jong Hong
- Department of Pediatrics, Childhood Respiratory Allergy Center, Humidifier Disinfectant Health Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Evans CE, Zhang X, Machireddy N, Zhao YY. The Unexpected Protective Role of Thrombosis in Sepsis-Induced Inflammatory Lung Injury Via Endothelial Alox15. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.29.23287934. [PMID: 37034726 PMCID: PMC10081399 DOI: 10.1101/2023.03.29.23287934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
BACKGROUND Patients with sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anti-coagulant therapies in sepsis and ARDS patients have failed. ARDS patients with thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in coronavirus disease 2019 (COVID-19) ARDS patients. METHODS Employing different amounts of microbeads to induce various levels of pulmonary thrombosis. Acute lung injury was induced by either lipopolysaccharide i.p. or cecal ligation and puncture. Endothelial cell (EC)-targeted nanoparticle coupled with CDH5 promoter was employed to delivery plasmid DNA expressing the CRISPR/Cas9 system for EC-specific gene knockout or expressing Alox15 for EC-specific overexpression. Additionally, thrombocytopenia was induced by genetic depletion of platelets using DTR Pf4Cre mice by breeding Pf4 Cre mice into the genetic background of DTR mice. RESULTS We show that while severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces endothelial cell (EC) apoptosis, ALI, and mortality via sustained expression of endothelial arachidonate 15-lipoxygenase (Alox15). Endothelial Alox15 knockout via EC-targeted nanoparticle delivery of CRISPR/Cas9 plasmid DNA in adult mice abolished the protective impact of mild lung thrombosis. Conversely, overexpression of endothelial Alox15 inhibited the increases in ALI caused by severe pulmonary thrombosis. The clinical relevance of the findings was validated by the observation of reduced ALOX15-expressing ECs in lung autopsy samples of ARDS patients. Additionally, restoration of pulmonary thrombosis in thrombocytopenic mice also normalized endotoxemia-induced ALI. CONCLUSION We have demonstrated that moderate levels of thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of Alox5 inhibits severe pulmonary thrombosis-induced increase of ALI. Thus, activation of ALOX15 signaling represents a promising therapeutic strategy for treatment of ARDS, especially in sub-populations of patients with thrombocytopenia and/or severe pulmonary thrombosis.
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Schebb NH, Kühn H, Kahnt AS, Rund KM, O’Donnell VB, Flamand N, Peters-Golden M, Jakobsson PJ, Weylandt KH, Rohwer N, Murphy RC, Geisslinger G, FitzGerald GA, Hanson J, Dahlgren C, Alnouri MW, Offermanns S, Steinhilber D. Formation, Signaling and Occurrence of Specialized Pro-Resolving Lipid Mediators-What is the Evidence so far? Front Pharmacol 2022; 13:838782. [PMID: 35308198 PMCID: PMC8924552 DOI: 10.3389/fphar.2022.838782] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 02/02/2022] [Indexed: 12/14/2022] Open
Abstract
Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.
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Affiliation(s)
- Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Hartmut Kühn
- Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Astrid S. Kahnt
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
| | - Katharina M. Rund
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Valerie B. O’Donnell
- School of Medicine, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Nicolas Flamand
- Département de Médecine, Faculté de Médecine, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Marc Peters-Golden
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Per-Johan Jakobsson
- Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Karsten H. Weylandt
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, Ruppin General Hospital, Brandenburg Medical School, Neuruppin, Germany
| | - Nadine Rohwer
- Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, Ruppin General Hospital, Brandenburg Medical School, Neuruppin, Germany
- Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Robert C. Murphy
- Department of Pharmacology, University of Colorado-Denver, Aurora, CO, United States
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, University Hospital of Goethe-University, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology, ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases, CIMD, Frankfurt, Germany
| | - Garret A. FitzGerald
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Julien Hanson
- Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium
- Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium
| | - Claes Dahlgren
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mohamad Wessam Alnouri
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Stefan Offermanns
- Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology, ITMP and Fraunhofer Cluster of Excellence for Immune Mediated Diseases, CIMD, Frankfurt, Germany
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Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners. Cells 2022; 11:cells11010141. [PMID: 35011703 PMCID: PMC8750928 DOI: 10.3390/cells11010141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/13/2022] Open
Abstract
High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.
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Jang H, Kim EG, Kim M, Kim SY, Kim YH, Sohn MH, Kim KW. Metabolomic profiling revealed altered lipid metabolite levels in childhood food allergy. J Allergy Clin Immunol 2021; 149:1722-1731.e9. [PMID: 34843802 DOI: 10.1016/j.jaci.2021.10.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/26/2021] [Accepted: 10/26/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND The pathophysiology of childhood food allergy (FA) and its natural history are poorly understood. Clarification of the underlying mechanism may help identify novel biomarkers and strategies for clinical intervention in children with FA. OBJECTIVE This study aimed to identify metabolites associated with the development and resolution of FA. METHODS The metabolomic profiles of 20 children with FA and 20 healthy controls were assessed by liquid chromatography-tandem mass spectrometry. Comparative analysis was performed to identify metabolites associated with FA and FA resolution. For subjects with FA, serum samples were collected at the time of diagnosis and after resolution to identify the changes in metabolite levels. The selected metabolites were then quantified in a quantification cohort to validate the results. Finally, genome-wide association analysis of the metabolite levels was performed. RESULTS The study demonstrated a significantly higher level of sphingolipid metabolites and a lower level of acylcarnitine metabolites in children with FA than those in healthy controls. At diagnosis, subjects with resolving FA had a significantly high level of omega-3 metabolites and a low level of platelet-activating factors compared to persistent FA. However, the level of omega-3 metabolites decreased in children with resolving FA but increased in children with persistent FA during the same time. The quantification data of omega-3-derived resolvins, platelet-activating factor, and platelet-activating factor acetylhydrolase activity further supported these results. CONCLUSION The lipid metabolite profile is closely related to childhood FA and FA resolution. This study suggests potential predictive biomarkers and provides insight into the mechanisms underlying childhood FA.
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Affiliation(s)
- Haerin Jang
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea
| | - Eun Gyul Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea
| | - Mina Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea
| | - Soo Yeon Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea
| | - Yoon Hee Kim
- Department of Pediatrics, Gangnam Severance Hospital, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Myung Hyun Sohn
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea
| | - Kyung Won Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
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Lyly A, Laidlaw TM, Lundberg M. Pathomechanisms of AERD—Recent Advances. FRONTIERS IN ALLERGY 2021; 2:734733. [PMID: 35387030 PMCID: PMC8974777 DOI: 10.3389/falgy.2021.734733] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
The pathomechanisms behind NSAID-exacerbated respiratory disease are complex and still largely unknown. They are presumed to involve genetic predisposition and environmental triggers that lead to dysregulation of fatty acid and lipid metabolism, altered cellular interactions involving transmetabolism, and continuous and chronic inflammation in the respiratory track. Here, we go through the recent advances on the topic and sum up the current understanding of the background of this illness that broadly effects the patients' lives.
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Affiliation(s)
- Annina Lyly
- Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Inflammation Center, Skin and Allergy Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- *Correspondence: Annina Lyly
| | - Tanya M. Laidlaw
- Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Marie Lundberg
- Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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Berman R, Min E, Huang J, Kopf K, Downey GP, Riemondy K, Smith HA, Rose CS, Seibold MA, Chu HW, Day BJ. Single-Cell RNA Sequencing Reveals a Unique Monocyte Population in Bronchoalveolar Lavage Cells of Mice Challenged With Afghanistan Particulate Matter and Allergen. Toxicol Sci 2021; 182:297-309. [PMID: 34051097 DOI: 10.1093/toxsci/kfab065] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Upon returning from deployment to Afghanistan, a substantial number of U.S. military personnel report deployment-related lung disease (DRLD) symptoms, including those consistent with an asthma-like airways disease. DRLD is thought to be caused by prolonged inhalation of toxic desert particulate matter, which can persist in the postdeployment setting such as exposure to common household allergens. The goal of this study was to define the transcriptomic responses of lung leukocytes of mice exposed to Afghanistan desert particulate matter (APM) and house dust mite (HDM). C57BL/6 mice (n = 15/group) were exposed to filtered air or aerosolized APM for 12 days, followed by intranasal PBS or HDM allergen challenges for 24 h. Bronchoalveolar lavage (BAL) cells were collected for single-cell RNA sequencing (scRNAseq), and assessment of inflammation and airway hyper-responsiveness. Unsupervised clustering of BAL cell scRNAseq data revealed a unique monocyte population induced only by both APM and allergen treatments. This population of monocytes is characterized by the expression of genes involved in allergic asthma, including Alox15. We validated Alox15 expression in monocytes via immunostaining of lung tissue. APM pre-exposure, followed by the HDM challenge, led to significantly increased total respiratory system resistance compared with filtered air controls. Using this mouse model to mimic DRLD, we demonstrated that inhalation of airborne PM during deployment may prime airways to be more responsive to allergen exposure after returning home, which may be linked to dysregulated immune responses such as induction of a unique lung monocyte population.
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Affiliation(s)
- Reena Berman
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Elysia Min
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Jie Huang
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Katrina Kopf
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Gregory P Downey
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Kent Riemondy
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Harry A Smith
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Cecile S Rose
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Max A Seibold
- Center for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206, USA
| | - Hong Wei Chu
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Brian J Day
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
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Kulkarni A, Nadler JL, Mirmira RG, Casimiro I. Regulation of Tissue Inflammation by 12-Lipoxygenases. Biomolecules 2021; 11:717. [PMID: 34064822 PMCID: PMC8150372 DOI: 10.3390/biom11050717] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells-a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.
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Affiliation(s)
- Abhishek Kulkarni
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA;
| | - Jerry L. Nadler
- Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA;
| | | | - Isabel Casimiro
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA;
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11
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Sokolowska M, Rovati GE, Diamant Z, Untersmayr E, Schwarze J, Lukasik Z, Sava F, Angelina A, Palomares O, Akdis CA, O’Mahony L, Sanak M, Dahlen S, Woszczek G. Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I. Allergy 2021; 76:114-130. [PMID: 32279330 DOI: 10.1111/all.14295] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/13/2020] [Accepted: 03/25/2020] [Indexed: 12/25/2022]
Abstract
Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.
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Affiliation(s)
- Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - G. Enrico Rovati
- Department of Pharmaceutical Sciences University of Milan Milan Italy
| | - Zuzana Diamant
- Department of Respiratory Medicine & Allergology Skane University Hospital Lund Sweden
- Department of Respiratory Medicine First Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic
| | - Eva Untersmayr
- Institute of Pathophysiology and Allergy Research Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
| | - Jargen Schwarze
- Child Life and Health and Centre for Inflammation Research The University of Edinburgh Edinburgh UK
| | - Zuzanna Lukasik
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
| | - Florentina Sava
- London North Genomic Laboratory Hub Great Ormond Street Hospital for Children NHS Foundation Trust London UK
| | - Alba Angelina
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - Liam O’Mahony
- Departments of Medicine and Microbiology APC Microbiome Ireland University College Cork Cork Ireland
| | - Marek Sanak
- Department of Medicine Jagiellonian University Medical College Krakow Poland
| | - Sven‐Erik Dahlen
- Institute of Environmental Medicine Karolinska Institute Stockholm Sweden
- Centre for Allergy Research Karolinska Institute Stockholm Sweden
| | - Grzegorz Woszczek
- MRC/Asthma UK Centre in Allergic Mechanisms of Asthma School of Immunology & Microbial Sciences King's College London London UK
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12
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Töröcsik D, Weise C, Gericke J, Szegedi A, Lucas R, Mihaly J, Worm M, Rühl R. Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non-affected skin of human atopic dermatitis patients. Exp Dermatol 2020; 28:177-189. [PMID: 30575130 DOI: 10.1111/exd.13867] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/28/2018] [Accepted: 12/13/2018] [Indexed: 01/06/2023]
Abstract
Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio-active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro-inflammatory or pro-resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non-affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non-affected skin were found; in addition, n3/n6-PUFA ratios were lower in affected and non-affected skin and serum. Mono-hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non-affected skin. COX1 and ALOX12B expression, COX and 12/15-LOX metabolites as well as various lipids, which are known to induce itch (12-HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro-inflammatory vs pro-resolving lipid mediators in non-affected and affected skin as well as in the serum of AD patients were increased, while n3/n6-PUFAs and metabolite ratios were lower in non-affected and affected AD skin. Expression of COX1 and COX-metabolites was even higher in non-affected AD skin. To conclude, 12/15-LOX and COX pathways were mainly upregulated, while n3/n6-PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro-inflammatory and non-resolving environment in affected and partly in non-affected skin of AD patients.
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Affiliation(s)
- Daniel Töröcsik
- Faculty of Medicine, Department of Dermatology, University of Debrecen, Debrecen, Hungary
| | - Christin Weise
- Department of Dermatology and Allergology, Allergy-Center-Charité, Charité - Universitätsmedizin, Berlin, Germany
| | - Janine Gericke
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary
| | - Andrea Szegedi
- Faculty of Medicine, Department of Dermatology, University of Debrecen, Debrecen, Hungary
| | - Renata Lucas
- Faculty of Medicine, Department of Dermatology, University of Debrecen, Debrecen, Hungary
| | - Johanna Mihaly
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary
| | - Margitta Worm
- Department of Dermatology and Allergology, Allergy-Center-Charité, Charité - Universitätsmedizin, Berlin, Germany
| | - Ralph Rühl
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.,Paprika Bioanalytics BT, Debrecen, Hungary
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13
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Chung EJ, Reedy JL, Kwon S, Patil S, Valle L, White AO, Citrin DE. 12-Lipoxygenase is a Critical Mediator of Type II Pneumocyte Senescence, Macrophage Polarization and Pulmonary Fibrosis after Irradiation. Radiat Res 2019; 192:367-379. [PMID: 31373871 PMCID: PMC6816027 DOI: 10.1667/rr15356.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of type II pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-type mice. Conditioned media from irradiated or 12S-HETE-treated primary pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 type polarization when AECIIs were derived from wild-type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.
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Affiliation(s)
- Eun Joo Chung
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Jessica L. Reedy
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Seokjoo Kwon
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Shilpa Patil
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Luca Valle
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Ayla O. White
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
| | - Deborah E. Citrin
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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14
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Rao Z, Pace S, Jordan PM, Bilancia R, Troisi F, Börner F, Andreas N, Kamradt T, Menche D, Rossi A, Serhan CN, Gerstmeier J, Werz O. Vacuolar (H +)-ATPase Critically Regulates Specialized Proresolving Mediator Pathways in Human M2-like Monocyte-Derived Macrophages and Has a Crucial Role in Resolution of Inflammation. THE JOURNAL OF IMMUNOLOGY 2019; 203:1031-1043. [PMID: 31300512 DOI: 10.4049/jimmunol.1900236] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 06/16/2019] [Indexed: 12/21/2022]
Abstract
Alternative (M2)-polarized macrophages possess high capacities to produce specialized proresolving mediators (SPM; i.e., resolvins, protectins, and maresins) that play key roles in resolution of inflammation and tissue regeneration. Vacuolar (H+)-ATPase (V-ATPase) is fundamental in inflammatory cytokine trafficking and secretion and was implicated in macrophage polarization toward the M2 phenotype, but its role in SPM production and lipid mediator biosynthesis in general is elusive. In this study, we show that V-ATPase activity is required for the induction of SPM-biosynthetic pathways in human M2-like monocyte-derived macrophages (MDM) and consequently for resolution of inflammation. Blockade of V-ATPase by archazolid during IL-4-induced human M2 polarization abrogated 15-lipoxygenase-1 expression and prevented the related biosynthesis of SPM in response to pathogenic Escherichia coli, assessed by targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics. In classically activated proinflammatory M1-like MDM, however, the biosynthetic machinery for lipid mediator formation was independent of V-ATPase activity. Targeting V-ATPase in M2 influenced neither IL-4-triggered JAK/STAT6 nor the mTOR complex 1 signaling but strongly suppressed the ERK-1/2 pathway. Accordingly, the ERK-1/2 pathway contributes to 15-lipoxygenase-1 expression and SPM formation in M2-like MDM. Targeting V-ATPase in vivo delayed resolution of zymosan-induced murine peritonitis accompanied by decreased SPM levels without affecting proinflammatory leukotrienes or PGs. Together, our data propose that V-ATPase regulates 15-lipoxygenase-1 expression and consequent SPM biosynthesis involving ERK-1/2 during M2 polarization, implying a crucial role for V-ATPase in the resolution of inflammation.
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Affiliation(s)
- Zhigang Rao
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany
| | - Simona Pace
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany
| | - Paul M Jordan
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany
| | - Rossella Bilancia
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Fabiana Troisi
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany
| | - Friedemann Börner
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany
| | - Nico Andreas
- Institute of Immunology, Jena University Hospital, 07743 Jena, Germany
| | - Thomas Kamradt
- Institute of Immunology, Jena University Hospital, 07743 Jena, Germany
| | - Dirk Menche
- Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany; and
| | - Antonietta Rossi
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
| | - Jana Gerstmeier
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany;
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany;
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15
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Werner M, Jordan PM, Romp E, Czapka A, Rao Z, Kretzer C, Koeberle A, Garscha U, Pace S, Claesson HE, Serhan CN, Werz O, Gerstmeier J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J 2019; 33:6140-6153. [PMID: 30735438 DOI: 10.1096/fj.201802509r] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: 1) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.
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Affiliation(s)
- Markus Werner
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Paul M Jordan
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Erik Romp
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Anna Czapka
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Zhigang Rao
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Christian Kretzer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Andreas Koeberle
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Ulrike Garscha
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Simona Pace
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Hans-Erik Claesson
- Division of Hematology, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Charles N Serhan
- Department of Anesthesia, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital-Harvard Medical School, Boston, Massachusetts, USA
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Jana Gerstmeier
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
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16
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Kristjansson RP, Benonisdottir S, Davidsson OB, Oddsson A, Tragante V, Sigurdsson JK, Stefansdottir L, Jonsson S, Jensson BO, Arthur JG, Arnadottir GA, Sulem G, Halldorsson BV, Gunnarsson B, Halldorsson GH, Stefansson OA, Oskarsson GR, Deaton AM, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Onundarson PT, Gislason D, Gislason T, Ludviksson BR, Ludviksdottir D, Olafsdottir TA, Rafnar T, Masson G, Zink F, Bjornsdottir G, Magnusson OT, Bjornsdottir US, Thorleifsson G, Norddahl GL, Gudbjartsson DF, Thorsteinsdottir U, Jonsdottir I, Sulem P, Stefansson K. A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Nat Genet 2019; 51:267-276. [PMID: 30643255 DOI: 10.1038/s41588-018-0314-6] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022]
Abstract
Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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Affiliation(s)
| | | | | | | | - Vinicius Tragante
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | | | | | | | | | | | | | | | - Bjarni V Halldorsson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,School of Science and Engineering, Reykjavik University, Reykjavik, Iceland
| | | | | | | | | | | | - Isleifur Olafsson
- Department of Clinical Biochemistry, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland
| | | | | | - Pall T Onundarson
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Laboratory Hematology, Landspítali, the National University Hospital of Iceland, Reykjavik, Iceland
| | - David Gislason
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland
| | - Thorarinn Gislason
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Sleep, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland
| | - Bjorn R Ludviksson
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland
| | - Dora Ludviksdottir
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Respiratory Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland
| | - Thorunn A Olafsdottir
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | | | | | | | | | - Unnur S Bjornsdottir
- Department of Medicine, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.,The Medical Center Mjodd, Reykjavik, Iceland
| | | | | | - Daniel F Gudbjartsson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Unnur Thorsteinsdottir
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Ingileif Jonsdottir
- deCODE genetics/Amgen Inc., Reykjavik, Iceland.,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | | | - Kari Stefansson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland. .,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
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17
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Kim D, McAlees JW, Bischoff LJ, Kaur D, Houshel LK, Gray J, Hargis J, Davis X, Dudas PL, Deshmukh H, Lewkowich IP. Combined administration of anti-IL-13 and anti-IL-17A at individually sub-therapeutic doses limits asthma-like symptoms in a mouse model of Th2/Th17 high asthma. Clin Exp Allergy 2018; 49:317-330. [PMID: 30353972 DOI: 10.1111/cea.13301] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 09/17/2018] [Accepted: 10/08/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2-effector cytokines results in elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17-associated effector cytokines, clinical trials of anti-IL-17/IL-17RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine-blocking therapies with the goal of reducing the potential emergence of infection-related complications is a translationally relevant goal. OBJECTIVE In the current report, we examine whether combined blockade of IL-13 and IL-17A, at individually sub-therapeutic levels, can limit the development of allergic asthma while sparing expression of IL-17A-associated anti-microbial effectors. METHODS House dust mite was given intratracheally to A/J mice. Anti-IL-13 and anti-IL-17A antibodies were administered individually, or concomitantly at sub-therapeutic doses. Airway hyper-reactivity, lung inflammation, magnitude of Th2- and Th17-associated cytokine production and expression of IL-13- and IL-17A-induced genes in the lungs was assessed. RESULTS Initial dosing studies identified sub-therapeutic levels of IL-13 and IL-17A blocking mAbs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub-therapeutic dosing with IL-13 and IL-17A blocking mAbs resulted in significant improvement in airway hyperresponsiveness (AHR) and expression of IL-13-induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17-associated cytokines, or IL-17A-associated gene expression. CONCLUSION This study suggests that combining blockade of individual Th2 and Th17 effector cytokines, even at individually sub-therapeutic levels, may be sufficient to limit disease development while preserving important anti-microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.
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Affiliation(s)
- Dasom Kim
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jaclyn W McAlees
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Lindsay J Bischoff
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Davinder Kaur
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Lauren K Houshel
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jerilyn Gray
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Julie Hargis
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Xenia Davis
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Paul L Dudas
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Hitesh Deshmukh
- Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Ian P Lewkowich
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
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18
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Yan B, Wang Y, Li Y, Wang C, Zhang L. Inhibition of arachidonate 15-lipoxygenase reduces the epithelial-mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 2018; 9:270-280. [PMID: 30452122 DOI: 10.1002/alr.22243] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/05/2018] [Accepted: 10/17/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Bing Yan
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital; Capital Medical University; Beijing China
- Beijing Key Laboratory of Nasal Diseases; Beijing Institute of Otolaryngology; Beijing China
| | - Yang Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital; Capital Medical University; Beijing China
- Beijing Key Laboratory of Nasal Diseases; Beijing Institute of Otolaryngology; Beijing China
| | - Ying Li
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital; Capital Medical University; Beijing China
- Beijing Key Laboratory of Nasal Diseases; Beijing Institute of Otolaryngology; Beijing China
| | - Chengshuo Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital; Capital Medical University; Beijing China
| | - Luo Zhang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital; Capital Medical University; Beijing China
- Beijing Key Laboratory of Nasal Diseases; Beijing Institute of Otolaryngology; Beijing China
- Department of Allergy, Beijing TongRen Hospital; Capital Medical University; Beijing China
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19
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Abstract
Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.
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Affiliation(s)
- Renata Nascimento Gomes
- Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, Universidade de São Paulo, SP, BR
| | - Souza Felipe da Costa
- Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, Universidade de São Paulo, SP, BR
| | - Alison Colquhoun
- Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, Universidade de São Paulo, SP, BR
- *Corresponding author. E-mail:
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20
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Zhao J, Minami Y, Etling E, Coleman JM, Lauder SN, Tyrrell V, Aldrovandi M, O'Donnell V, Claesson HE, Kagan V, Wenzel S. Preferential Generation of 15-HETE-PE Induced by IL-13 Regulates Goblet Cell Differentiation in Human Airway Epithelial Cells. Am J Respir Cell Mol Biol 2017; 57:692-701. [PMID: 28723225 DOI: 10.1165/rcmb.2017-0031oc] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Type 2-associated goblet cell hyperplasia and mucus hypersecretion are well known features of asthma. 15-Lipoxygenase-1 (15LO1) is induced by the type 2 cytokine IL-13 in human airway epithelial cells (HAECs) in vitro and is increased in fresh asthmatic HAECs ex vivo. 15LO1 generates a variety of products, including 15-hydroxyeicosatetraenoic acid (15-HETE), 15-HETE-phosphatidylethanolamine (15-HETE-PE), and 13-hydroxyoctadecadienoic acid (13-HODE). In this study, we investigated the 15LO1 metabolite profile at baseline and after IL-13 treatment, as well as its influence on goblet cell differentiation in HAECs. Primary HAECs obtained from bronchial brushings of asthmatic and healthy subjects were cultured under air-liquid interface culture supplemented with arachidonic acid and linoleic acid (10 μM each) and exposed to IL-13 for 7 days. Short interfering RNA transfection and 15LO1 inhibition were applied to suppress 15LO1 expression and activity. IL-13 stimulation induced expression of 15LO1 and preferentially generated 15-HETE-PE in vitro, both of which persisted after removal of IL-13. 15LO1 inhibition (by short interfering RNA and chemical inhibitor) decreased IL-13-induced forkhead box protein A3 (FOXA3) expression and enhanced FOXA2 expression. These changes were associated with reductions in both mucin 5AC and periostin. Exogenous 15-HETE-PE stimulation (alone) recapitulated IL-13-induced FOXA3, mucin 5AC, and periostin expression. The results of this study confirm the central importance of 15LO1 and its primary product, 15-HETE-PE, for epithelial cell remodeling in HAECs.
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Affiliation(s)
- Jinming Zhao
- 1 University of Pittsburgh Asthma Institute at UPMC, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yoshinori Minami
- 1 University of Pittsburgh Asthma Institute at UPMC, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Emily Etling
- 1 University of Pittsburgh Asthma Institute at UPMC, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - John M Coleman
- 2 Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Sarah N Lauder
- 3 Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Victoria Tyrrell
- 3 Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Maceler Aldrovandi
- 3 Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Valerie O'Donnell
- 3 Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | | | - Valerian Kagan
- 5 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sally Wenzel
- 1 University of Pittsburgh Asthma Institute at UPMC, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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21
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Chen X, Ji N, Qin N, Tang SA, Wang R, Qiu Y, Duan H, Kong D, Jin M. 1,6-O,O-Diacetylbritannilactone Inhibits Eotaxin-1 and ALOX15 Expression Through Inactivation of STAT6 in A549 Cells. Inflammation 2017; 40:1967-1974. [DOI: 10.1007/s10753-017-0637-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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22
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Lauder SN, Tyrrell VJ, Allen-Redpath K, Aldrovandi M, Gray D, Collins P, Jones SA, Taylor PR, O'Donnell V. Myeloid 12/15-LOX regulates B cell numbers and innate immune antibody levels in vivo. Wellcome Open Res 2017; 2:1. [PMID: 28239665 PMCID: PMC5321417 DOI: 10.12688/wellcomeopenres.10308.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background. The myeloid enzyme 12/15-lipoxygenase (LOX), which generates bioactive oxidized lipids, has been implicated in numerous inflammatory diseases, with several studies demonstrating an improvement in pathology in mice lacking the enzyme. However, the ability of 12/15-LOX to directly regulate B cell function has not been studied. Methods. The influence of 12/15-LOX on B cell phenotype and function, and IgM generation, was compared using wildtype (WT) and 12/15-LOX (
Alox15-/-) deficient mice. The proliferative and functional capacity of splenic CD19
+ B cells was measured
in vitro in response to various toll-like receptor agonists. Results. WT and
Alox15-/- displayed comparable responses. However
in vivo, splenic B cell numbers were significantly elevated in
Alox15-/- mice with a corresponding elevation in titres of total IgM in lung, gut and serum, and lower serum IgM directed against the 12/15-LOX product, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (HETE-PE). Discussion. Myeloid 12/15-LOX can regulate B cell numbers and innate immune antibody levels
in vivo, potentially contributing to its ability to regulate inflammatory disease. Furthermore, the alterations seen in 12/15-LOX deficiency likely result from changes in the equilibrium of the immune system that develop from birth. Further studies in disease models are warranted to elucidate the contribution of 12/15-LOX mediated alterations in B cell numbers and innate immune antibody generation to driving inflammation
in vivo.
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Affiliation(s)
- Sarah N Lauder
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Victoria J Tyrrell
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Keith Allen-Redpath
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Maceler Aldrovandi
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - David Gray
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
| | - Peter Collins
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Simon A Jones
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Philip R Taylor
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
| | - Valerie O'Donnell
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK.,Institute of Infection & Immunity, Cardiff University, Cardiff, UK
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23
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Han H, Liang X, Ekberg M, Kritikou JS, Brunnström Å, Pelcman B, Matl M, Miao X, Andersson M, Yuan X, Schain F, Parvin S, Melin E, Sjöberg J, Xu D, Westerberg LS, Björkholm M, Claesson HE. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation. FASEB J 2016; 31:491-504. [PMID: 27825104 DOI: 10.1096/fj.201600679rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 10/04/2016] [Indexed: 01/20/2023]
Abstract
Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnström, Å., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjöberg, J., Xu, D., Westerberg, L. S., Björkholm, M., Claesson, H.-E. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.
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Affiliation(s)
- Hongya Han
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; .,Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Xiuming Liang
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Monica Ekberg
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Joanna S Kritikou
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Åsa Brunnström
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Benjamin Pelcman
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden
| | - Maria Matl
- Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Xinyan Miao
- Clinical Pharmacology Group, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden; and
| | - Margareta Andersson
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Xiaotian Yuan
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Frida Schain
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Selina Parvin
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Eva Melin
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
| | - Jan Sjöberg
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Dawei Xu
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Lisa S Westerberg
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Björkholm
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Hans-Erik Claesson
- Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
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24
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Ban GY, Cho K, Kim SH, Yoon MK, Kim JH, Lee HY, Shin YS, Ye YM, Cho JY, Park HS. Metabolomic analysis identifies potential diagnostic biomarkers for aspirin-exacerbated respiratory disease. Clin Exp Allergy 2016; 47:37-47. [PMID: 27533637 DOI: 10.1111/cea.12797] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/13/2016] [Accepted: 08/09/2016] [Indexed: 11/28/2022]
Abstract
BACKGROUND To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). OBJECTIVE To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. METHODS An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/Q-ToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. RESULTS A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE4 and LTE4 /PGF2 α ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE4 and LTE4 /PGF2 α ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE4 levels were significantly correlated with the fall in FEV1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). CONCLUSIONS AND CLINICAL RELEVANCE Serum metabolite level of LTE4 and LTE4 /PGF2 α ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/Q-ToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.
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Affiliation(s)
- G-Y Ban
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - K Cho
- Department of Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.,Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea
| | - S-H Kim
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - M K Yoon
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - J-H Kim
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - H Y Lee
- Department of Statistics, Clinical Trial Center, Ajou University Medical Center, Suwon, Korea
| | - Y S Shin
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Y-M Ye
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - J-Y Cho
- Department of Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H-S Park
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
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25
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Ackermann JA, Hofheinz K, Zaiss MM, Krönke G. The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:371-381. [PMID: 27480217 DOI: 10.1016/j.bbalip.2016.07.014] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 07/01/2016] [Accepted: 07/28/2016] [Indexed: 01/18/2023]
Abstract
12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder.
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Affiliation(s)
- Jochen A Ackermann
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Katharina Hofheinz
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Mario M Zaiss
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany
| | - Gerhard Krönke
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany; Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.
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26
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Sacharzewska E, Bielecki P, Bernatowicz P, Niklinski J, Kowal-Bielecka O, Kowal K. The role of 12/15-lipoxygenase in production of selected eicosanoids in allergic airway inflammation. Adv Med Sci 2016; 61:141-6. [PMID: 26686860 DOI: 10.1016/j.advms.2015.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE To evaluate the role of 12/15-lipoxygenase (LOX) in regulation of synthesis of selected eicosanoids in mice sensitized and challenged with Dermatophagoides pteronyssinus (Dp) allergen extract. MATERIALS AND METHODS Both C57Bl and 12/15-LOX knockout mice were sensitized by 2 intraperitoneal injections and subsequently challenged by inhalation with Dp allergen extract. Sham sensitized and challenged mice were used as controls. Samples of bronchoalveolar lavage (BAL) were used for assessment of prostaglandin E2 (PGE2), cysteinyl leukotreienes (cysLT), lipoxin A4 (LXA4) and 15-hydroxyeicosatetraenoic acid (15-HETE) concentration using ELISA method. Whole lung samples were used for isolation of RNA and evaluation of selected genes involved in eicosanoid metabolism, including cyclooxygenase-2 (COX-2), 12/15-LOX, 5-LOX and 5-LOX activated protein (FLAP). RESULTS Allergen-induced airway inflammation was associated with significant (9-fold, 95% CI 8.068-9.932-fold; p<0.05) up-regulation of 12/15-LOX in wild type but not in the 12/15-LOX knockout mice in which 12/15-LOX mRNA remained undetectable. Lack of 12/15-LOX was associated with significant attenuation of production of 15-HETE in response to allergen challenge. On the contrary, the greatest up-regulation of COX-2 after allergen exposure was demonstrated in the 12/15-LOX knockout mice (4.3-fold vs sham group) and was significantly greater than in the wild type counterparts (5.185-fold, 95% CI 4.723-6.309-fold; p<0.05 vs wild type mice). Also, allergen challenged 12/15-LOX knockout mice were characterized by greater production of PGE2 and cysLT. CONCLUSION The 12/15-LOX plays an important role in the metabolism of eicosanoids in response to allergen-induced airway inflammation.
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27
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Sun L, Tang XJ, Luo FM. Forkhead box protein A2 and T helper type 2-mediated pulmonary inflammation. World J Methodol 2015; 5:223-229. [PMID: 26713283 PMCID: PMC4686420 DOI: 10.5662/wjm.v5.i4.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/24/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The transcription factor forkhead box protein A2 (FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2 (Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
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28
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IL-4 and IL-13 signaling in allergic airway disease. Cytokine 2015; 75:68-78. [PMID: 26070934 DOI: 10.1016/j.cyto.2015.05.014] [Citation(s) in RCA: 346] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/15/2015] [Indexed: 12/12/2022]
Abstract
Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
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29
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Brunnström Å, Tryselius Y, Feltenmark S, Andersson E, Leksell H, James A, Mannervik B, Dahlén B, Claesson HE. On the biosynthesis of 15-HETE and eoxin C4 by human airway epithelial cells. Prostaglandins Other Lipid Mediat 2015; 121:83-90. [PMID: 26026713 DOI: 10.1016/j.prostaglandins.2015.04.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 04/24/2015] [Accepted: 04/29/2015] [Indexed: 01/18/2023]
Abstract
Several lines of evidence indicate that 15-lipoxygenase type 1 (15-LO-1) plays a pathophysiological role in asthma. The aim for this study was to investigate the 15-LO-1 expression and activity in primary human airway epithelial cells cultivated on micro-porous filters at air-liquid interface. Incubation of human airway epithelial cells with arachidonic acid led to the formation of 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and exposing the cells to bacteria or physical injury markedly increased their production of 15-HETE. The cells were also found to convert arachidonic acid to eoxin C4 (EXC4). Subcellular fractionation revealed that the conversion of EXA4 to EXC4 was catalyzed by a soluble glutathione transferase (GST). The GST P1-1 enzyme was found to possess the highest activity of the investigated soluble GSTs. Following IL-4 treatment of airway epithelial cells, microarray analysis confirmed high expression of 15-LO-1 and GST P1-1, and immunohistochemical staining of bronchial biopsies revealed co-localization of 15-LO-1 and GST P1-1 in airway epithelial cells. These results indicate that respiratory infection and cell injury may activate the 15-LO pathway in airway epithelial cells. Furthermore, we also demonstrate that airway epithelial cells have the capacity to produce EXC4.
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Affiliation(s)
- Åsa Brunnström
- Department of Medicine, Karolinska University Hospital and Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | | | | | | | - Helene Leksell
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden
| | - Anna James
- Institute of Environmental Medicine, Karolinska Institutet, Sweden; The Centre for Allergy Research, Sweden
| | - Bengt Mannervik
- Department of Neurochemistry, Stockholm University, SE-10691 Stockholm, Sweden
| | - Barbro Dahlén
- The Centre for Allergy Research, Sweden; Department of Medicine, Karolinska University Hospital Huddinge, Sweden
| | - Hans-Erik Claesson
- Department of Medicine, Karolinska University Hospital and Karolinska Institutet, SE-171 76 Stockholm, Sweden.
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30
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Pelcman B, Sanin A, Nilsson P, Schaal W, Olofsson K, Krog-Jensen C, Forsell P, Hallberg A, Larhed M, Boesen T, Kromann H, Claesson HE. N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase. Bioorg Med Chem Lett 2015; 25:3017-23. [PMID: 26037319 DOI: 10.1016/j.bmcl.2015.05.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 05/05/2015] [Accepted: 05/06/2015] [Indexed: 11/30/2022]
Abstract
High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
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Affiliation(s)
- Benjamin Pelcman
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
| | - Andrei Sanin
- Biolipox AB, Berzelius väg 3, SE-171 65 Solna, Sweden
| | - Peter Nilsson
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden; Biolipox AB, Berzelius väg 3, SE-171 65 Solna, Sweden
| | - Wesley Schaal
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden; Biolipox AB, Berzelius väg 3, SE-171 65 Solna, Sweden
| | | | | | | | - Anders Hallberg
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
| | - Mats Larhed
- Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
| | - Thomas Boesen
- MedChem ApS, Fruebjergvej 3, DK-2100 Copenhagen, Denmark
| | - Hasse Kromann
- MedChem ApS, Fruebjergvej 3, DK-2100 Copenhagen, Denmark
| | - Hans-Erik Claesson
- Biolipox AB, Berzelius väg 3, SE-171 65 Solna, Sweden; Department of Medicine, Building A3:02, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, Sweden
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Abstract
The inflammatory response plays an important role in host defense and maintenance of homeostasis, while imbalances in these responses can also lead to pathologic disease processes. Emerging data show that RKIP interacts with multiple signaling molecules that may potentiate multiple functions during inflammatory processes. Here, we review the interaction of RKIP with both the MAPK and NF-κB pathways in relation to chronic inflammatory diseases. In these settings, it can both inhibit inflammatory pathways as well contribute to pro-inflammatory signaling, often depending on the interactions with multiple proteins and perhaps lipids. The interactions of RKIP with proteins, phospholipids, fatty acids, and their enzymes thus could play a substantial role in diseases like asthma and diabetes. Targeting interactions of RKIP with these pathways could lead to novel approaches to treatment.
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Affiliation(s)
- Jinming Zhao
- University of Pittsburgh Asthma Institute at UPMC/Pulmonary Allergy and Critical Care Medicine Division, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sally Wenzel
- University of Pittsburgh Asthma Institute at UPMC/Pulmonary Allergy and Critical Care Medicine Division, University of Pittsburgh, Pittsburgh, Pennsylvania
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Rothenberg ME, Wen T, Greenberg A, Alpan O, Enav B, Hirano I, Nadeau K, Kaiser S, Peters T, Perez A, Jones I, Arm JP, Strieter RM, Sabo R, Gunawardena KA. Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. J Allergy Clin Immunol 2015; 135:500-7. [PMID: 25226850 DOI: 10.1016/j.jaci.2014.07.049] [Citation(s) in RCA: 231] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/04/2014] [Accepted: 07/29/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options. OBJECTIVE We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE. METHODS Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers. RESULTS Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated. CONCLUSIONS QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE in a sustained manner.
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Affiliation(s)
- Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
| | - Ting Wen
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Allison Greenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; Office of Clinical and Translational Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | - Benjamin Enav
- O & O Alpan LLC, Fairfax, Va; Pediatric Gastroenterology of Northern Virginia, Fairfax, Va
| | - Ikuo Hirano
- Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Kari Nadeau
- Division of Immunology and Allergy, Stanford University Medical Center, Stanford, Calif
| | - Sergio Kaiser
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Thomas Peters
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Antonio Perez
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Ieuan Jones
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Jonathan P Arm
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | - Ronald Sabo
- Novartis Institutes for Biomedical Research, Cambridge, Mass
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Tang X, Liu XJ, Tian C, Su Q, Lei Y, Wu Q, He Y, Whitsett JA, Luo F. Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation. Am J Respir Cell Mol Biol 2014; 49:960-70. [PMID: 23822876 DOI: 10.1165/rcmb.2013-0122oc] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene-targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.
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Hegab AE, Ha VL, Bisht B, Darmawan DO, Ooi AT, Zhang KX, Paul MK, Kim YS, Gilbert JL, Attiga YS, Alva-Ornelas JA, Nickerson DW, Gomperts BN. Aldehyde dehydrogenase activity enriches for proximal airway basal stem cells and promotes their proliferation. Stem Cells Dev 2014; 23:664-75. [PMID: 24171691 DOI: 10.1089/scd.2013.0295] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Both basal and submucosal gland (SMG) duct stem cells of the airway epithelium are capable of sphere formation in the in vitro sphere assay, although the efficiency at which this occurs is very low. We sought to improve this efficiency of sphere formation by identifying subpopulations of airway basal stem cells (ABSC) and SMG duct cells based on their aldehyde dehydrogenase (ALDH) activity. ALDH(hi) ABSCs and SMG duct cells were highly enriched for the population of cells that could make spheres, while the co-culture of ALDH(hi) differentiated cells with the ALDH(hi) ABSCs increased their sphere-forming efficiency. Specific ALDH agonists and antagonists were used to show that airway specific ALDH isozymes are important for ABSC proliferation. Pathway analysis of gene expression profiling of ALDH(hi) and ALDH(lo) ABSCs revealed a significant upregulation of the arachidonic acid (AA) metabolism pathway in ALDH(hi) ABSCs. We confirmed the importance of this pathway in the metabolism of proliferating ALDH(hi) ABSCs using bioenergetics studies as well as agonists and antagonists of the AA pathway. These studies could lead to the development of novel strategies for altering ABSC proliferation in the airway epithelium.
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Affiliation(s)
- Ahmed E Hegab
- 1 Department of Pediatrics, Children's Discovery and Innovation Institute, David Geffen School of Medicine at UCLA, Mattel Children's Hospital , Los Angeles, California
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Mihály J, Gericke J, Törőcsik D, Gáspár K, Szegedi A, Rühl R. Reduced lipoxygenase and cyclooxygenase mediated signaling in PBMC of atopic dermatitis patients. Prostaglandins Other Lipid Mediat 2013; 107:35-42. [DOI: 10.1016/j.prostaglandins.2013.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 03/04/2013] [Accepted: 03/06/2013] [Indexed: 10/26/2022]
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Bhowmick R, Maung N, Hurley BP, Ghanem EB, Gronert K, McCormick BA, Leong JM. Systemic disease during Streptococcus pneumoniae acute lung infection requires 12-lipoxygenase-dependent inflammation. THE JOURNAL OF IMMUNOLOGY 2013; 191:5115-23. [PMID: 24089193 DOI: 10.4049/jimmunol.1300522] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Acute pulmonary infection by Streptococcus pneumoniae is characterized by high bacterial numbers in the lung, a robust alveolar influx of polymorphonuclear cells (PMNs), and a risk of systemic spread of the bacterium. We investigated host mediators of S. pneumoniae-induced PMN migration and the role of inflammation in septicemia following pneumococcal lung infection. Hepoxilin A3 (HXA3) is a PMN chemoattractant and a metabolite of the 12-lipoxygenase (12-LOX) pathway. We observed that S. pneumoniae infection induced the production of 12-LOX in cultured pulmonary epithelium and in the lungs of infected mice. Inhibition of the 12-LOX pathway prevented pathogen-induced PMN transepithelial migration in vitro and dramatically reduced lung inflammation upon high-dose pulmonary challenge with S. pneumoniae in vivo, thus implicating HXA3 in pneumococcus-induced pulmonary inflammation. PMN basolateral-to-apical transmigration in vitro significantly increased apical-to-basolateral transepithelial migration of bacteria. Mice suppressed in the expression of 12-LOX exhibited little or no bacteremia and survived an otherwise lethal pulmonary challenge. Our data suggest that pneumococcal pulmonary inflammation is required for high-level bacteremia and systemic infection, partly by disrupting lung epithelium through 12-LOX-dependent HXA3 production and subsequent PMN transepithelial migration.
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Affiliation(s)
- Rudra Bhowmick
- Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA
| | - Nang Maung
- Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Bryan P Hurley
- Mucosal Immunology Laboratory, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA
| | - Elsa Bou Ghanem
- Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA
| | - Karsten Gronert
- Vision Science Program, School of Optometry, University of California, Berkeley, CA 94720, USA
| | - Beth A McCormick
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - John M Leong
- Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA
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James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE. The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma. Int Arch Allergy Immunol 2013; 162:135-42. [PMID: 23921438 DOI: 10.1159/000351422] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 04/12/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The effect of aspirin on the release of key arachidonic acid metabolites in activated eosinophils from subjects with aspirin-intolerant asthma (AIA) has not been investigated previously, despite the characteristic eosinophilia in AIA. METHODS Peripheral blood eosinophils were isolated from four groups of subjects: healthy volunteers (HV; n = 8), mild asthma (MA; n = 8), severe asthma (SA; n = 9) and AIA (n = 7). In the absence or presence of lysine-aspirin, eosinophils were stimulated with arachidonic acid or calcium ionophore to trigger the 15-lipoxygenase-1 (15-LO) and 5-lipoxygenase (5-LO) pathways, respectively. 15(S)-hydroxy-eicosatetraenoic acid (15-HETE) and eoxin C4 (EXC4) were measured as 15-LO products and leukotriene (LT)C4 as a product of the 5-LO pathway. RESULTS Activated eosinophils from patients with SA and AIA produced approximately five times more 15-HETE than eosinophils from HV or MA patients. In the presence of lysine-aspirin, eosinophils from AIA, MA and SA patients generated higher levels of 15-HETE than in the absence of lysine-aspirin. Furthermore, in the presence of lysine-aspirin, formation of EXC4 was also significantly increased in eosinophils from AIA patients, and LTC4 synthesis was increased both in AIA and SA patients. CONCLUSIONS Taken together, this study shows an increased release of the recently discovered lipid mediator EXC4, as well as the main indicator of 15-LO activity, 15-HETE, in activated eosinophils from severe and aspirin-intolerant asthmatics, and also elevated EXC4 and LTC4 formation in eosinophils from AIA patients after cellular activation in the presence of lysine-aspirin. The findings support a pathophysiological role of the 15-LO pathway in SA and AIA.
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Affiliation(s)
- Anna James
- The Centre for Allergy Research, Stockholm, Sweden
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Mabalirajan U, Ghosh B. Mitochondrial dysfunction in metabolic syndrome and asthma. J Allergy (Cairo) 2013; 2013:340476. [PMID: 23840225 PMCID: PMC3687506 DOI: 10.1155/2013/340476] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 05/21/2013] [Indexed: 01/15/2023] Open
Abstract
Though severe or refractory asthma merely affects less than 10% of asthma population, it consumes significant health resources and contributes significant morbidity and mortality. Severe asthma does not fell in the routine definition of asthma and requires alternative treatment strategies. It has been observed that asthma severity increases with higher body mass index. The obese-asthmatics, in general, have the features of metabolic syndrome and are progressively causing a significant burden for both developed and developing countries thanks to the westernization of the world. As most of the features of metabolic syndrome seem to be originated from central obesity, the underlying mechanisms for metabolic syndrome could help us to understand the pathobiology of obese-asthma condition. While mitochondrial dysfunction is the common factor for most of the risk factors of metabolic syndrome, such as central obesity, dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, the involvement of mitochondria in obese-asthma pathogenesis seems to be important as mitochondrial dysfunction has recently been shown to be involved in airway epithelial injury and asthma pathogenesis. This review discusses current understanding of the overlapping features between metabolic syndrome and asthma in relation to mitochondrial structural and functional alterations with an aim to uncover mechanisms for obese-asthma.
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Affiliation(s)
- Ulaganathan Mabalirajan
- Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India
| | - Balaram Ghosh
- Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India
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Impact of adiponectin overexpression on allergic airways responses in mice. J Allergy (Cairo) 2013; 2013:349520. [PMID: 23861690 PMCID: PMC3686156 DOI: 10.1155/2013/349520] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 05/07/2013] [Indexed: 11/18/2022] Open
Abstract
Obesity is an important risk factor for asthma. Obese individuals have decreased circulating adiponectin, an adipose-derived hormone with anti-inflammatory properties. We hypothesized that transgenic overexpression of adiponectin would attenuate allergic airways inflammation and mucous hyperplasia in mice. To test this hypothesis, we used mice overexpressing adiponectin (Adipo Tg). Adipo Tg mice had marked increases in both serum adiponectin and bronchoalveolar lavage (BAL) fluid adiponectin. Both acute and chronic ovalbumin (OVA) sensitization and challenge protocols were used. In both protocols, OVA-induced increases in total BAL cells were attenuated in Adipo Tg versus WT mice. In the acute protocol, OVA-induced increases in several IL-13 dependent genes were attenuated in Adipo Tg versus WT mice, even though IL-13 per se was not affected. With chronic exposure, though OVA-induced increases in goblet cells numbers per millimeter of basement membrane were greater in Adipo Tg versus WT mice, mRNA abundance of mucous genes in lungs was not different. Also, adiponectin overexpression did not induce M2 polarization in alveolar macrophages. Our results indicate that adiponectin protects against allergen-induced inflammatory cell recruitment to the airspaces, but not development of goblet cell hyperplasia.
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Xu J, Zhang Y, Xiao Y, Ma S, Liu Q, Dang S, Jin M, Shi Y, Wan B, Zhang Y. Inhibition of 12/15-lipoxygenase by baicalein induces microglia PPARβ/δ: a potential therapeutic role for CNS autoimmune disease. Cell Death Dis 2013; 4:e569. [PMID: 23559003 PMCID: PMC3668632 DOI: 10.1038/cddis.2013.86] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
12/15-Lipoxygenase (12/15-LO) is an enzyme that converts polyunsaturated fatty acids into bioactive lipid derivatives. In this study, we showed that inhibition of 12/15-LO by baicalein (BA) significantly attenuated clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Inhibited migration of autoimmune T cells into the central nervous system (CNS) by BA treatment could be attributed to reduced activation of microglia, which was indicated by suppressed phagocytosis, and decreased production of proinflammatory cytokines and chemokines in the CNS. We further observed that inhibition of 12/15-LO with BA led to increased expression of peroxisome proliferator-activated receptor (PPAR)β/δ in microglia of EAE mice. This was confirmed in vitro in primary microglia and a microglia cell line, BV2. In addition, we demonstrated that BA did not affect 12/15-LO or 5-lipoxygenase (5-LO) expression in microglia, but significantly decreased 12/15-LO products without influencing the levels of 5-LO metabolites. Moreover, among these compounds only 12/15-LO metabolite 12-hydroxyeicosatetraenoic acid was able to reverse BA-mediated upregulation of PPARβ/δ in BV2 cells. We also showed that inhibition of microglia activation by PPARβ/δ was associated with repressed NF-κB and MAPK activities. Our findings indicate that inhibition of 12/15-LO induces PPARβ/δ, demonstrating important regulatory properties of 12/15-LO in CNS inflammation. This reveals potential therapeutic applications for MS.
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Affiliation(s)
- J Xu
- Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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41
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Zasłona Z, Peters-Golden M. A lipid mediator controls neutrophil recruitment in acute lung injury--should we really be surprised? CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:161. [PMID: 23102473 PMCID: PMC3682262 DOI: 10.1186/cc11519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
New therapeutic approaches are sorely needed for acute lung injury. Neutrophil recruitment is a pathological hallmark of this syndrome, and is mainly regulated by CXC chemokine receptor 2 and its ligand CXC ligand 1. Rossaint and colleagues have described a new mechanism for regulation of this axis by 12/15-lipoxygenase products. This work opens the door for new therapeutic approaches and highlights the crucial interplay between lipid mediators and chemokines, a time-honored but often-ignored concept.
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Brunnström Å, Backman L, Tryselius Y, Claesson HE. Biosynthesis of eoxin C4 by porcine leukocytes. Prostaglandins Leukot Essent Fatty Acids 2012; 87:159-63. [PMID: 22921794 DOI: 10.1016/j.plefa.2012.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 06/11/2012] [Accepted: 07/07/2012] [Indexed: 11/23/2022]
Abstract
Human 15-lipoxygenase-1 (LO) possesses mainly 15-lipoxygenase activity whereas the animal ortholog 12/15-LO possesses mainly 12-lipoxygenase activity. These findings have raised the question if studies on animals can predict the function of 15-LO-1 in human. In this study we have characterized the arachidonic acid metabolites formed by porcine 12/15-LO. Mini pigs were infected with a parasite to increase the number of blood eosinophils, which highly express 12/15-LO. Isolated porcine polymorphonuclear leukocytes (PMNL) were incubated with arachidonic acid and the produced metabolites were analysed with HPLC and mass spectrometry (MS). The cells were found to produce 15-hydroxyeicosatetraenoic acid (HETE) and 12-HETE at a ratio of 1:5. Furthermore 8,15-dihydroxyeicosatetraenoic acids (DiHETEs) and 14,15-DiHETE were formed. Based on HPLC, UV-spectroscopy and MS analysis it was found that porcine PMNL also produced eoxin (EX) C4. These results demonstrate that although porcine 12/15-LO possesses primarily 12-lipoxygenase activity, the enzyme can catalyse the formation of EXC(4).
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Affiliation(s)
- Åsa Brunnström
- Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Solna, SE-171 76 Stockholm, Sweden.
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Bickford JS, Mueller C, Newsom KJ, Barilovits SJ, Beachy DE, Herlihy JD, Keeler B, Flotte TR, Nick HS. Effect of allergy and inflammation on eicosanoid gene expression in CFTR deficiency. J Cyst Fibros 2012; 12:258-65. [PMID: 22985691 DOI: 10.1016/j.jcf.2012.08.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 08/02/2012] [Accepted: 08/10/2012] [Indexed: 11/19/2022]
Abstract
BACKGROUND Allergic bronchopulmonary aspergillosis (ABPA) is a complicating factor in cystic fibrosis (CF), affecting 2-15% of patients. We hypothesized that sensitization/challenge of CFTR(-/-) mice with an Aspergillus fumigatus (Af) extract will affect eicosanoid pathway gene expression, impacting ABPA and CF. METHODS FABP-hCFTR(+/-)-CFTR(-/-) mice were sensitized/challenged with an Af extract and gene expression of lung mRNA was evaluated for >40 genes, with correlative data in human CF (IB3.1) and CFTR-corrected (S9) bronchoepithelial cell lines. RESULTS Pla2g4c, Pla2g2c, Pla2g2d and Pla2g5 were induced in response to Af in CFTR(-/-) mice. Interestingly, PLA2G2D was induced by LPS, IL-2, IL-6, IL-13, and Af only in CFTR-deficient human IB3.1 cells. Prostanoid gene expression was relatively constant, however, several 12/15-lipoxygenase genes were induced in response to Af. Numerous cytokines also caused differential expression of ALOX15 only in IB3.1 cells. CONCLUSIONS The distinct regulation of PLA2G4C, PLA2G2D and ALOX15 genes in Aspergillus sensitization and/or cystic fibrosis could provide new insights into diagnosis and treatment of ABPA and CF.
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Affiliation(s)
- Justin S Bickford
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, United States
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Uderhardt S, Krönke G. 12/15-lipoxygenase during the regulation of inflammation, immunity, and self-tolerance. J Mol Med (Berl) 2012; 90:1247-56. [PMID: 22983484 DOI: 10.1007/s00109-012-0954-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 08/22/2012] [Accepted: 08/27/2012] [Indexed: 12/20/2022]
Abstract
12/15-Lipoxygenase (12/15-LO) catalyzes the oxidation of free and esterified fatty acids thereby generating a whole spectrum of bioactive lipid mediators. This enzyme is involved in the regulation of various homeostatic processes as well as in the pathogenesis of multiple diseases. During the innate and adaptive immune response, 12/15-LO and its products exert both pro- and anti-inflammatory effects. Likewise, this enzyme has been implicated in the pathogenesis of autoimmune disease as well as in the maintenance of self-tolerance. This review will summarize our current knowledge about the role of 12/15-LO and will try to examine the two faces of this enzyme within the context of inflammation and immunity.
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Affiliation(s)
- Stefan Uderhardt
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
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Rossaint J, Nadler JL, Ley K, Zarbock A. Eliminating or blocking 12/15-lipoxygenase reduces neutrophil recruitment in mouse models of acute lung injury. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:R166. [PMID: 22973824 PMCID: PMC3682261 DOI: 10.1186/cc11518] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Accepted: 09/13/2012] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Acute lung injury (ALI) is a common disease in critically ill patients with a high morbidity and mortality. 12/15-lipoxygenase (12/15-LO) is an enzyme generating 12-hydroxy-eicosatetraenoic acid (12-HETE) and 15-HETE from arachidonic acid. It has been shown that 12/15-LO is involved in the regulation of vascular permeability during ALI. METHODS To test whether 12/15-LO participates in leukocyte recruitment into the lung, we investigated the role of 12/15-LO in mouse models of lipopolysaccharide (LPS)-induced pulmonary inflammation and acid-induced ALI, a clinically relevant model of acute lung injury. RESULTS The increase in neutrophil recruitment following LPS inhalation was reduced in 12/15-LO-deficient (Alox15(-/-)) mice and in wild-type (WT) mice after the blocking of 12/15-LO with a pharmacological inhibitor. Bone marrow chimeras revealed that 12/15-LO in hematopoietic cells regulates neutrophil accumulation in the interstitial and alveolar compartments, whereas the accumulation of neutrophils in the intravascular compartment is regulated by 12/15-LO in non-hematopoietic and hematopoietic cells. Mechanistically, the increased plasma levels of the chemokine CXCL1 in Alox15(-/-) mice led to a reduced response of the neutrophil chemokine receptor CXCR2 to stimulation with CXCL1, which in turn abrogated neutrophil recruitment. Alox15(-/-) mice also showed decreased edema formation, reduced neutrophil recruitment and improved gas exchange in an acid-induced ALI model. CONCLUSIONS Our findings suggest that 12/15-LO modulates neutrophil recruitment into the lung by regulating chemokine/chemokine receptor homeostasis.
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Szczeklik W, Sanak M, Mastalerz L, Sokołowska BM, Gielicz A, Soja J, Kumik J, Musiał J, Szczeklik A. 12-hydroxy-eicosatetraenoic acid (12-HETE): a biomarker of Churg-Strauss syndrome. Clin Exp Allergy 2012; 42:513-22. [PMID: 22417211 DOI: 10.1111/j.1365-2222.2011.03943.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Churg-Strauss syndrome (CSS) shares similarities with asthma and hypereosinophilic syndrome (HES). Eicosanoids--important inflammatory and signaling molecules--are present in exhaled breath condensate (EBC) and broncho-alveolar lavage fluid (BALF). OBJECTIVES To assess eicosanoid profile both in EBC and BALF of CSS subjects searching for a pattern characteristic of this syndrome. METHODS EBCs from 23 CSS patients, 30 asthmatics, 12 HES patients and 54 healthy controls (HC) were assessed quantitatively for 19 eicosanoids by a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). In addition, in 21 of 23 CSS subjects and in nine asthmatics, eicosanoids were determined in BALF. RESULTS EBC from CSS patients showed markedly elevated levels of 12-HETE as compared with other studied groups. BALF was characterized by a significant elevation of 12-HETE and its metabolite 12-tetranor HETE in CSS as compared with asthma. Clinical activity of CSS correlated with 12-HETE and its metabolites levels in BALF, but not in EBC. CONCLUSION AND CLINICAL RELEVANCE CSS is clearly distinguished from bronchial asthma, and HES by a marked increase in 12-HETE concentration in both EBC and BALF. This points to a possible new pathogenic mechanism in CSS and may help in future in establishing the diagnosis of CSS.
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Affiliation(s)
- W Szczeklik
- Department of Medicine, Jagiellonian University Medical College, ul. Skawińska 8,Krakow, Poland.
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Metabolism of anandamide into eoxamides by 15-lipoxygenase-1 and glutathione transferases. Lipids 2012; 47:781-91. [PMID: 22684912 DOI: 10.1007/s11745-012-3684-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 05/14/2012] [Indexed: 01/18/2023]
Abstract
Human 15-lipoxygenase-1 (15-LO-1) can metabolize arachidonic acid (ARA) into pro-inflammatory mediators such as the eoxins, 15-hydroperoxyeicosatetraenoic acid (HPETE), and 15-hydroxyeicosatetraenoyl-phosphatidylethanolamine. We have in this study investigated the formation of various lipid hydroperoxide by either purified 15-LO-1 or in the Hodgkin lymphoma cell line L1236, which contain abundant amount of 15-LO-1. Both purified 15-LO-1 and L1236 cells produced lipid hydroperoxides more efficiently when anandamide (AEA) or 2-arachidonoyl-glycerol ester was used as substrate than with ARA. Furthermore, L1236 cells converted AEA to a novel class of cysteinyl-containing metabolites. Based on RP-HPLC, mass spectrometry and comparison to synthetic products, these metabolites were identified as the ethanolamide of the eoxin (EX) C(4) and EXD(4). By using the epoxide EXA(4)-ethanol amide, it was also found that platelets have the capacity to produce the ethanolamide of EXC(4) and EXD(4). We suggest that the ethanolamides of the eoxins should be referred to as eoxamides, in analogy to the ethanolamides of prostaglandins which are named prostamides. The metabolism of AEA into eoxamides might engender molecules with novel biological effects. Alternatively, it might represent a new mechanism for the termination of AEA signalling.
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Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood. Mucosal Immunol 2011; 4:682-94. [PMID: 21881572 DOI: 10.1038/mi.2011.35] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.
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15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells. Proc Natl Acad Sci U S A 2011; 108:14246-51. [PMID: 21831839 DOI: 10.1073/pnas.1018075108] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Epithelial 15-lipoxygenase 1 (15LO1) and activated ERK are increased in asthma despite modest elevations in IL-13. MAPK kinase (MEK)/ERK activation is regulated by interactions of Raf-1 with phosphatidylethanolamine-binding protein 1 (PEBP1). Epithelial 15LO1 generates intracellular 15-hydroxyeicosatetraenoic acid (15HETE) conjugated to phosphatidylethanolamine (PE) (15HETE-PE). We hypothesized that (i) 15LO1 and its product 15HETE-PE serve as signaling molecules interacting with PEBP1 to activate Raf-1/MEK/ERK and that (ii) this 15LO1-15HETE-PE-regulated ERK activation amplifies IL-4Rα downstream pathways. Our results demonstrate that high epithelial 15LO1 levels correlate with ERK phosphorylation ex vivo. In vitro, IL-13 induces 15LO1, which preferentially binds to PEBP1, causing PEBP1 to dissociate from Raf-1 and activate ERK. Exogenous 15HETE-PE similarly induces dissociation of PEBP1 from Raf-1 independently of IL-13/15LO1. siRNA knockdown of 15LO1 decreases the dissociation of Raf-1 from PEBP1, and the resulting lower ERK activation leads to lower downstream IL-4Rα-related gene expression. Identical protein-protein interactions are observed in endobronchial biopsies and fresh epithelial cells from asthmatics ex vivo. Colocalization of Raf-1 to PEBP1 is low in asthmatic tissue and cells compared with normals, whereas there is striking colocalization of 15LO1 with PEBP1 in asthma. Low 15LO1 levels in normals limit its colocalization with PEBP1. The results confirm a previously unknown signaling role for 15LO1 and its PE-conjugated eicosanoid product in human airway epithelial cells. This pathway enhances critical inflammatory pathways integral to asthma pathogenesis.
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