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Yoshida K, Morishima Y, Ishii Y, Mastuzaka T, Shimano H, Hizawa N. Abnormal saturated fatty acids and sphingolipids metabolism in asthma. Respir Investig 2024; 62:526-530. [PMID: 38640569 DOI: 10.1016/j.resinv.2024.04.006] [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: 02/08/2024] [Revised: 03/26/2024] [Accepted: 04/11/2024] [Indexed: 04/21/2024]
Abstract
Recent advances in fatty acid analysis have highlighted the links between lipid disruption and disease development. Lipid abnormalities are well-established risk factors for many of the most common chronic illnesses, and their involvement in asthma is also becoming clear. Here, we review research demonstrating the role of abnormal lipid metabolism in asthma, with a focus on saturated fatty acids and sphingolipids. High levels of palmitic acid, the most abundant saturated fatty acid in the human body, have been found in the airways of asthmatic patients with obesity, and were shown to worsen eosinophilic airway inflammation in asthma model mice on a high-fat diet. Aside from being a building block of longer-chain fatty acids, palmitic acid is also the starting point for de novo synthesis of ceramides, a class of sphingolipids. We outline the three main pathways for the synthesis of ceramides, which have been linked to the severity of asthma and act as precursors for the dynamic lipid mediator sphingosine 1-phosphate (S1P). S1P signaling is involved in allergen-induced eosinophilic inflammation, airway hyperresponsiveness, and immune-cell trafficking. A recent study of mice with mutations for the elongation of very long-chain fatty acid family member 6 (Elovl6), an enzyme that elongates fatty acid chains, has highlighted the potential role of palmitic acid composition, and thus lipid balance, in the pathophysiology of allergic airway inflammation. Elovl6 may be a potential therapeutic target in severe asthma.
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Affiliation(s)
- Kazufumi Yoshida
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Yuko Morishima
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yukio Ishii
- Department of Respiratory Medicine, National Hospital Organization Ibaraki Higashi National Hospital, 825 Terunuma, Tokai-Mura, Naka-Gun, Ibaraki, 319-1113, Japan
| | - Takashi Mastuzaka
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Nobuyuki Hizawa
- Department of Pulmonary Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
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Demkova L, Bugajev V, Adamcova MK, Kuchar L, Grusanovic S, Alberich-Jorda M, Draber P, Halova I. Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis. Front Immunol 2024; 15:1376629. [PMID: 38715613 PMCID: PMC11074395 DOI: 10.3389/fimmu.2024.1376629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/08/2024] [Indexed: 06/04/2024] Open
Abstract
ORMDL3 is a prominent member of a family of highly conserved endoplasmic reticulum resident proteins, ORMs (ORM1 and ORM2) in yeast, dORMDL in Drosophila and ORMDLs (ORMDL1, ORMDL2, and ORMDL3) in mammals. ORMDL3 mediates feedback inhibition of de novo sphingolipid synthesis. Expression levels of ORMDL3 are associated with the development of inflammatory and autoimmune diseases including asthma, systemic lupus erythematosus, type 1 diabetes mellitus and others. It has been shown that simultaneous deletions of other ORMDL family members could potentiate ORMDL3-induced phenotypes. To understand the complex function of ORMDL proteins in immunity in vivo, we analyzed mice with single or double deletions of Ormdl genes. In contrast to other single and double knockouts, simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupted blood homeostasis and reduced immune cell content in peripheral blood and spleens of mice. The reduced number of splenocytes was not caused by aberrant immune cell homing. A competitive bone marrow transplantation assay showed that the development of Ormdl1-/-/Ormdl3-/- B cells was dependent on lymphocyte intrinsic factors. Highly increased sphingolipid production was observed in the spleens and bone marrow of Ormdl1-/-/Ormdl3-/- mice. Slight, yet significant, increase in some sphingolipid species was also observed in the spleens of Ormdl3-/- mice and in the bone marrow of both, Ormdl1-/- and Ormdl3-/- single knockout mice. Taken together, our results demonstrate that the physiological expression of ORMDL proteins is critical for the proper development and circulation of lymphocytes. We also show cell-type specific roles of individual ORMDL family members in the production of different sphingolipid species.
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Affiliation(s)
- Livia Demkova
- Laboratory of Signal Transduction, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Viktor Bugajev
- Laboratory of Signal Transduction, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Miroslava K. Adamcova
- Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Ladislav Kuchar
- Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Srdjan Grusanovic
- Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Meritxell Alberich-Jorda
- Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Petr Draber
- Laboratory of Signal Transduction, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Ivana Halova
- Laboratory of Signal Transduction, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
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3
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Sharma J, Khan S, Singh NC, Sahu S, Raj D, Prakash S, Bandyopadhyay P, Sarkar K, Bhosale V, Chandra T, Kumaravelu J, Barthwal MK, Gupta SK, Srivastava M, Guha R, Ammanathan V, Ghoshal UC, Mitra K, Lahiri A. ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome. J Biol Chem 2024; 300:107120. [PMID: 38417794 PMCID: PMC11065740 DOI: 10.1016/j.jbc.2024.107120] [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: 08/27/2023] [Revised: 02/06/2024] [Accepted: 02/20/2024] [Indexed: 03/01/2024] Open
Abstract
Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1β cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1β release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.
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Affiliation(s)
- Jyotsna Sharma
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shaziya Khan
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Nishakumari C Singh
- Sophisticated Analytical Instrument Facility and Research Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Shikha Sahu
- Department of Gastroenterology, Sanjay Gandhi postgraduate institute of medical sciences, Lucknow, India
| | - Desh Raj
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shakti Prakash
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | | | - Kabita Sarkar
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Vivek Bhosale
- Toxicology and Experimental Medicine Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Tulika Chandra
- Department of Transfusion Medicine, Kings George Medical University, Lucknow, India
| | - Jagavelu Kumaravelu
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Manoj Kumar Barthwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shashi Kumar Gupta
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Mrigank Srivastava
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Molecular Parasitology and Immunology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajdeep Guha
- Lab Animal Facility, CSIR-Central Drug Research Institute, Lucknow, India
| | - Veena Ammanathan
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi postgraduate institute of medical sciences, Lucknow, India
| | - Kalyan Mitra
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Sophisticated Analytical Instrument Facility and Research Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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James BN, Weigel C, Green CD, Brown RDR, Palladino END, Tharakan A, Milstien S, Proia RL, Martin RK, Spiegel S. Neutrophilia in severe asthma is reduced in Ormdl3 overexpressing mice. FASEB J 2023; 37:e22799. [PMID: 36753412 PMCID: PMC9990076 DOI: 10.1096/fj.202201821r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/11/2023] [Accepted: 01/20/2023] [Indexed: 02/09/2023]
Abstract
Genome-wide association studies have linked the ORM (yeast)-like protein isoform 3 (ORMDL3) to asthma severity. Although ORMDL3 is a member of a family that negatively regulates serine palmitoyltransferase (SPT) and thus biosynthesis of sphingolipids, it is still unclear whether ORMDL3 and altered sphingolipid synthesis are causally related to non-Th2 severe asthma associated with a predominant neutrophil inflammation and high interleukin-17 (IL-17) levels. Here, we examined the effects of ORMDL3 overexpression in a preclinical mouse model of allergic lung inflammation that is predominantly neutrophilic and recapitulates many of the clinical features of severe human asthma. ORMDL3 overexpression reduced lung and circulating levels of dihydrosphingosine, the product of SPT. However, the most prominent effect on sphingolipid levels was reduction of circulating S1P. The LPS/OVA challenge increased markers of Th17 inflammation with a predominant infiltration of neutrophils into the lung. A significant decrease of neutrophil infiltration was observed in the Ormdl3 transgenic mice challenged with LPS/OVA compared to the wild type and concomitant decrease in IL-17, that plays a key role in the pathogenesis of neutrophilic asthma. LPS decreased survival of murine neutrophils, which was prevented by co-treatment with S1P. Moreover, S1P potentiated LPS-induced chemotaxis of neutrophil, suggesting that S1P can regulate neutrophil survival and recruitment following LPS airway inflammation. Our findings reveal a novel connection between ORMDL3 overexpression, circulating levels of S1P, IL-17 and neutrophil recruitment into the lung, and questions the potential involvement of ORMDL3 in the pathology, leading to development of severe neutrophilic asthma.
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Affiliation(s)
- Briana N. James
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Cynthia Weigel
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Christopher D. Green
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Ryan D. R. Brown
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Elisa N. D. Palladino
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Anuj Tharakan
- Department of Microbiology and ImmunologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Sheldon Milstien
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Richard L. Proia
- Genetics and Biochemistry BranchNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Rebecca K. Martin
- Department of Microbiology and ImmunologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular BiologyVirginia Commonwealth University School of MedicineRichmondVirginiaUSA
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5
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Lee JH, Son SH, Kim NJ, Im DS. NJK14047 Suppression of the p38 MAPK Ameliorates OVA-Induced Allergic Asthma during Sensitization and Challenge Periods. Biomol Ther (Seoul) 2023; 31:183-192. [PMID: 36171179 PMCID: PMC9970832 DOI: 10.4062/biomolther.2022.078] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/15/2022] [Accepted: 08/01/2022] [Indexed: 11/05/2022] Open
Abstract
p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.
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Affiliation(s)
- Ju-Hyun Lee
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Seung-Hwan Son
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Nam-Jung Kim
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
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Jo H, Shim K, Jeoung D. The Crosstalk between FcεRI and Sphingosine Signaling in Allergic Inflammation. Int J Mol Sci 2022; 23:ijms232213892. [PMID: 36430378 PMCID: PMC9695510 DOI: 10.3390/ijms232213892] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/09/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Sphingolipid molecules have recently attracted attention as signaling molecules in allergic inflammation diseases. Sphingosine-1-phosphate (S1P) is synthesized by two isoforms of sphingosine kinases (SPHK 1 and SPHK2) and is known to be involved in various cellular processes. S1P levels reportedly increase in allergic inflammatory diseases, such as asthma and anaphylaxis. FcεRI signaling is necessary for allergic inflammation as it can activate the SPHKs and increase the S1P level; once S1P is secreted, it can bind to the S1P receptors (S1PRs). The role of S1P signaling in various allergic diseases is discussed. Increased levels of S1P are positively associated with asthma and anaphylaxis. S1P can either induce or suppress allergic skin diseases in a context-dependent manner. The crosstalk between FcεRI and S1P/SPHK/S1PRs is discussed. The roles of the microRNAs that regulate the expression of the components of S1P signaling in allergic inflammatory diseases are also discussed. Various reports suggest the role of S1P in FcεRI-mediated mast cell (MC) activation. Thus, S1P/SPHK/S1PRs signaling can be the target for developing anti-allergy drugs.
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Worgall TS. Sphingolipids and Asthma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1372:145-155. [DOI: 10.1007/978-981-19-0394-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Wasserman E, Gomi R, Sharma A, Hong S, Bareja R, Gu J, Balaji U, Veerappan A, Kim BI, Wu W, Heras A, Perez-Zoghbi J, Sung B, Gueye-Ndiaye S, Worgall TS, Worgall S. Human Rhinovirus Infection of the Respiratory Tract Affects Sphingolipid Synthesis. Am J Respir Cell Mol Biol 2021; 66:302-311. [PMID: 34851798 DOI: 10.1165/rcmb.2021-0443oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The 17q21 asthma susceptibility locus includes asthma risk alleles associated with decreased sphingolipid synthesis, likely resulting from increased expression of ORMDL3. ORMDL3 inhibits serine-palmitoyl transferase (SPT), the rate limiting enzyme of de novo sphingolipid synthesis. There is evidence that decreased sphingolipid synthesis is critical to asthma pathogenesis. Children with asthma and 17q21 asthma risk alleles display decreased sphingolipid synthesis in blood cells. Reduced SPT activity results in airway hyperreactivity, a hallmark feature of asthma. 17q21 asthma risk alleles are also linked to childhood infections with human rhinovirus (RV). This study evaluates the interaction of RV with the de novo sphingolipid synthesis pathway, and the alterative effects of concurrent SPT inhibition in SPT-deficient mice and human airway epithelial cells. In mice, RV infection shifted lung sphingolipid synthesis gene expression to a pattern that resembles genetic SPT deficiency, including decreased expression of Sptssa, a small SPT subunit. This pattern was pronounced in lung EpCAM+ epithelial cells and reproduced in human bronchial epithelial cells. RV did not affect Sptssa expression in lung CD45+ immune cells. RV increased sphingolipids unique to the de novo synthesis pathway in mouse lung and human airway epithelial cells. Interestingly, these de novo sphingolipid species were reduced in the blood of RV infected, wild-type mice. RV exacerbated SPT-deficiency-associated airway hyperreactivity. Airway inflammation was similar in RV-infected wild-type and SPT deficient mice. This study reveals the effects of RV infection on the de novo sphingolipid synthesis pathway, elucidating a potential mechanistic link between 17q21 asthma risk alleles and rhinoviral infection.
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Affiliation(s)
- Emily Wasserman
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Rika Gomi
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Anurag Sharma
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Seunghee Hong
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Rohan Bareja
- Weill Cornell Medical College, 12295, Precision Medicine, New York, New York, United States
| | - Jinghua Gu
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Uthra Balaji
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Arul Veerappan
- New York University, 5894, Medicine, New York, New York, United States
| | - Benjamin I Kim
- Columbia University, 5798, Pathology, New York, New York, United States
| | - Wenzhu Wu
- Weill Cornell Medical College, 12295, New York, New York, United States
| | - Andrea Heras
- Weill Cornell Medical College, 12295, Pediatrics , New York, New York, United States
| | - Jose Perez-Zoghbi
- Columbia University, 5798, Department of Anesthesiology , New York, New York, United States
| | - Biin Sung
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Seyni Gueye-Ndiaye
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States
| | - Tilla S Worgall
- Columbia University Irving Medical Center, 21611, Dept. of Pathology, New York, New York, United States
| | - Stefan Worgall
- Weill Cornell Medical College, 12295, Pediatrics, New York, New York, United States;
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Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
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Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
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10
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Rago D, Pedersen CET, Huang M, Kelly RS, Gürdeniz G, Brustad N, Knihtilä H, Lee-Sarwar KA, Morin A, Rasmussen MA, Stokholm J, Bønnelykke K, Litonjua AA, Wheelock CE, Weiss ST, Lasky-Su J, Bisgaard H, Chawes BL. Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype. Am J Respir Crit Care Med 2021; 203:853-863. [PMID: 33535020 PMCID: PMC8017574 DOI: 10.1164/rccm.202008-3206oc] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 02/03/2021] [Indexed: 12/21/2022] Open
Abstract
Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data.Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
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Affiliation(s)
- Daniela Rago
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Casper-Emil T. Pedersen
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Mengna Huang
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Rachel S. Kelly
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Gözde Gürdeniz
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Nicklas Brustad
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Hanna Knihtilä
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Kathleen A. Lee-Sarwar
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Andréanne Morin
- Department of Human Genetics, University of Chicago, Chicago, Illinois
| | - Morten A. Rasmussen
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Jakob Stokholm
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Klaus Bønnelykke
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Augusto A. Litonjua
- Division of Pediatric Pulmonary Medicine, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, New York; and
| | - Craig E. Wheelock
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Scott T. Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Jessica Lasky-Su
- Channing Division of Network Medicine, Brigham and Women’s Hospital–Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Hans Bisgaard
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
| | - Bo L. Chawes
- Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital–University of Copenhagen, Gentofte, Denmark
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11
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Raby BA, Weiss ST. Diversity and the Splice of Life: Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African American Individuals. Am J Respir Crit Care Med 2021; 203:401-403. [PMID: 33108222 PMCID: PMC7885835 DOI: 10.1164/rccm.202010-3802ed] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Benjamin A Raby
- Department of Pediatrics Boston Children's Hospital and Harvard Medical School Boston, Massachusetts and
- Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts
| | - Scott T Weiss
- Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts
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12
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Heras AF, Veerappan A, Silver RB, Emala CW, Worgall TS, Perez-Zoghbi J, Worgall S. Increasing Sphingolipid Synthesis Alleviates Airway Hyperreactivity. Am J Respir Cell Mol Biol 2020; 63:690-698. [PMID: 32706610 DOI: 10.1165/rcmb.2020-0194oc] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity (AHR). The objective was to investigate whether sphingolipid synthesis could be a target for asthma therapeutics. The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on AHR was evaluated in mice deficient in SPT (serine palmitoyl-CoA transferase), the rate-limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth-muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth-muscle cells, decreased the intracellular calcium concentration in airway smooth-muscle cells, and decreased agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased AHR in SPT-deficient mice in vivo. This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate AHR.
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Affiliation(s)
| | | | | | | | - Tilla S Worgall
- Department of Pathology and Cell Biology, Columbia University, New York, New York
| | | | - Stefan Worgall
- Department of Pediatrics.,Department of Genetic Medicine, and.,Drukier Institute for Children's Health, Weill Cornell Medicine, New York, New York; and
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13
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Mechanisms of non-type 2 asthma. Curr Opin Immunol 2020; 66:123-128. [PMID: 33160187 DOI: 10.1016/j.coi.2020.10.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/04/2020] [Indexed: 12/17/2022]
Abstract
Non-type 2 inflammation (Non-T2)-mediated asthma is difficult to define due to lack of signature biomarkers. It exists in the absence of T2-high or eosinophilic inflammation and includes neutrophilic and paucigranulocytic subtypes. Several cell types and cytokines, including Th1, Th17, IL-6, and IL-17, contribute to mechanisms of non-T2 asthma. Neutrophil extracellular traps (NETs) and inflammasome activation likely play a role in severe neutrophilic asthma. Several mechanisms lead to uncoupling of airway hyperresponsiveness and remodeling from airway inflammation in paucigranulocytic asthma. Recent research on transcriptomics and proteomics in non-T2 asthma is discussed in this review. Investigations of specific drug therapies for non-T2 asthma have been disappointing, and remain an important area for future clinical studies.
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14
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Liu Y, Bochkov YA, Eickhoff JC, Hu T, Zumwalde NA, Tan JW, Lopez C, Fichtinger PS, Reddy TR, Overmyer KA, Gumperz JE, Coon J, Mathur SK, Gern JE, Smith JA. Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells. Am J Respir Cell Mol Biol 2020; 62:783-792. [PMID: 32078788 DOI: 10.1165/rcmb.2019-0237oc] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Polymorphism at the 17q21 gene locus and wheezing responses to rhinovirus (RV) early in childhood conspire to increase the risk of developing asthma. However, the mechanisms mediating this gene-environment interaction remain unclear. In this study, we investigated the impact of one of the 17q21-encoded genes, ORMDL3 (orosomucoid-like 3), on RV replication in human epithelial cells. ORMDL3 knockdown inhibited RV-A16 replication in HeLa, BEAS-2B, A549, and NCI-H358 epithelial cell lines and primary nasal and bronchial epithelial cells. Inhibition varied by RV species, as both minor and major group RV-A subtypes RV-B52 and RV-C2 were inhibited but not RV-C15 or RV-C41. ORMDL3 siRNA did not affect expression of the major group RV-A receptor ICAM-1 or initial internalization of RV-A16. The two major outcomes of ORMDL3 activity, SPT (serine palmitoyl-CoA transferase) inhibition and endoplasmic reticulum (ER) stress induction, were further examined: silencing ORMDL3 decreased RV-induced ER stress and IFN-β mRNA expression. However, pharmacologic induction of ER stress and concomitant increased IFN-β inhibited RV-A16 replication. Conversely, blockade of ER stress with tauroursodeoxycholic acid augmented replication, pointing to an alternative mechanism for the effect of ORMDL3 knockdown on RV replication. In comparison, the SPT inhibitor myriocin increased RV-A16 but not RV-C15 replication and negated the inhibitory effect of ORMDL3 knockdown. Furthermore, lipidomics analysis revealed opposing regulation of specific sphingolipid species (downstream of SPT) by myriocin and ORMDL3 siRNA, correlating with the effect of these treatments on RV replication. Together, these data revealed a requirement for ORMDL3 in supporting RV replication in epithelial cells via SPT inhibition.
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Affiliation(s)
| | | | | | | | | | | | | | - Paul S Fichtinger
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | | | - Katherine A Overmyer
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin; and.,Morgridge Institute for Research, Madison, Wisconsin
| | | | - Joshua Coon
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin; and.,Morgridge Institute for Research, Madison, Wisconsin
| | - Sameer K Mathur
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | | | - Judith A Smith
- Department of Pediatrics.,Department of Medical Microbiology and Immunology, and
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15
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Ban GY, Youn DY, Ye YM, Park HS. Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease. PLoS One 2020; 15:e0240334. [PMID: 33031402 PMCID: PMC7544079 DOI: 10.1371/journal.pone.0240334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 09/23/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood. OBJECTIVE We aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA). METHODS A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of ORMDL3 SNP (rs7216389) was performed. RESULTS Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTE4 (all P<0.05). The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC (P = 0.033, r = -0.274; P = 0.019, r = -0.299, respectively). Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030). CONCLUSION & CLINICAL RELEVANCE This is the first study that shows the dysregulated de novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.
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Affiliation(s)
- Ga-Young Ban
- Department of Pulmonary, Allergy and Critical Care Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
- Allergy and Clinical Immunology Research Center, Hallym University College of Medicine, Seoul, Korea
| | - Dong-Ye Youn
- Department of Pulmonary, Allergy and Critical Care Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Young-Min Ye
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Hae-Sim Park
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
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16
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Hur GY, Pham A, Miller M, Weng N, Hu J, Kurten RC, Broide DH. ORMDL3 but not neighboring 17q21 gene LRRC3C is expressed in human lungs and lung cells of asthmatics. Allergy 2020; 75:2061-2065. [PMID: 32086831 DOI: 10.1111/all.14243] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/11/2020] [Accepted: 02/15/2020] [Indexed: 12/26/2022]
Affiliation(s)
- Gyu Young Hur
- Department of Medicine University of California San Diego La Jolla CA USA
- Department of Internal Medicine Korea University College of Medicine Seoul Korea
| | - Alexa Pham
- Department of Medicine University of California San Diego La Jolla CA USA
| | - Marina Miller
- Department of Medicine University of California San Diego La Jolla CA USA
| | - Ning Weng
- Department of Medicine University of California San Diego La Jolla CA USA
| | - Jingwen Hu
- Department of Medicine University of California San Diego La Jolla CA USA
| | - Richard C. Kurten
- Department of Physiology and Biophysics Arkansas Children's Research Institute University of Arkansas for Medical Sciences Little Rock AR USA
| | - David H. Broide
- Department of Medicine University of California San Diego La Jolla CA USA
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17
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Crestani E, Harb H, Charbonnier LM, Leirer J, Motsinger-Reif A, Rachid R, Phipatanakul W, Kaddurah-Daouk R, Chatila TA. Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma. J Allergy Clin Immunol 2020; 145:897-906. [PMID: 31669435 PMCID: PMC7062570 DOI: 10.1016/j.jaci.2019.10.014] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/10/2019] [Accepted: 10/01/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Novel disease biomarkers and curative treatment options are strongly needed. OBJECTIVE We sought to apply untargeted metabolomic profiling to identify pathogenic mechanisms and candidate disease biomarkers in patients with FA. METHODS Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone, or both FA and asthma, as well as healthy pediatric control subjects. RESULTS In this pilot study patients with FA exhibited a disease-specific metabolomic signature compared with both control subjects and asthmatic patients. In particular, FA was uniquely associated with a marked decrease in sphingolipid levels, as well as levels of a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T cells. Specific comparison of patients with FA and asthmatic patients revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, the history of severe systemic reactions and the presence of multiple FAs were associated with changes in levels of tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids. CONCLUSIONS Children with FA have a disease-specific metabolomic profile that is informative of disease mechanisms and severity and that dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in children with FA might reflect the interplay between an altered microbiota and immune cell subsets in the gut.
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Affiliation(s)
- Elena Crestani
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Hani Harb
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Louis-Marie Charbonnier
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Jonathan Leirer
- Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC
| | - Alison Motsinger-Reif
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC
| | - Rima Rachid
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Wanda Phipatanakul
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioral Sciences and the Duke Institute for Brain Sciences, Duke University, Durham, NC
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass.
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18
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Ono JG, Kim BI, Zhao Y, Christos PJ, Tesfaigzi Y, Worgall TS, Worgall S. Decreased sphingolipid synthesis in children with 17q21 asthma-risk genotypes. J Clin Invest 2020; 130:921-926. [PMID: 31929190 PMCID: PMC6994114 DOI: 10.1172/jci130860] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/31/2019] [Indexed: 02/06/2023] Open
Abstract
Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.
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Affiliation(s)
- Jennie G. Ono
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Benjamin I. Kim
- Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Yize Zhao
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA
| | - Paul J. Christos
- Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York, USA
| | - Yohannes Tesfaigzi
- Department of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Tilla S. Worgall
- Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Stefan Worgall
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
- Department of Genetic Medicine, Weill Cornell Medicine, New York, New York, USA
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19
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De Cunto G, Brancaleone V, Riemma MA, Cerqua I, Vellecco V, Spaziano G, Cavarra E, Bartalesi B, D'Agostino B, Lungarella G, Cirino G, Lucattelli M, Roviezzo F. Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice. Br J Pharmacol 2019; 177:267-281. [PMID: 31499592 DOI: 10.1111/bph.14861] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 07/16/2019] [Accepted: 08/13/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
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Affiliation(s)
- Giovanna De Cunto
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | | | | | - Ida Cerqua
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Giuseppe Spaziano
- Department of Experimental Medicine L. Donatelli, Section of Pharmacology, School of Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Eleonora Cavarra
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Barbara Bartalesi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Bruno D'Agostino
- Department of Experimental Medicine L. Donatelli, Section of Pharmacology, School of Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giuseppe Lungarella
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Monica Lucattelli
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
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20
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Zhu Z, Camargo CA, Hasegawa K. Metabolomics in the prevention and management of asthma. Expert Rev Respir Med 2019; 13:1135-1138. [PMID: 31561725 DOI: 10.1080/17476348.2019.1674650] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Zhaozhong Zhu
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Carlos A Camargo
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Kohei Hasegawa
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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21
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Wang HC, Wong TH, Wang LT, Su HH, Yu HY, Wu AH, Lin YC, Chen HL, Suen JL, Hsu SH, Chen LC, Zhou Y, Huang SK. Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cell Mol Immunol 2019; 16:783-790. [PMID: 29572542 PMCID: PMC6804566 DOI: 10.1038/s41423-018-0022-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 02/16/2018] [Accepted: 02/18/2018] [Indexed: 01/17/2023] Open
Abstract
Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3-S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR-ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.
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Affiliation(s)
- Hsueh-Chun Wang
- Department of Medical Research, China Medical University Hospital, China Medical University, 40402, Taichung, Taiwan, China
| | - Tzu-Hsuan Wong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
| | - Li-Ting Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
| | - Hsiang-Han Su
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
| | - Hsiu-Yueh Yu
- Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, China
| | - Ai-Hsuan Wu
- Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, China
| | - Yu-Chun Lin
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, China
| | - Hua-Ling Chen
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, China
| | - Jau-Ling Suen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
- Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
- Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung, Taiwan, China
| | - Shih-Hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
- Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China
| | - Li-Chen Chen
- Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, China
- Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan, China
- Department of Pediatrics, Xiamen Chang Gung Hospital, Xiamen, China
| | - Yufeng Zhou
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Key Laboratory of Neonatal Disease, Children's Hospital and Institute of Biomedical Sciences, Ministry of Health, Fudan University, 201102, Shanghai, China
| | - Shau-Ku Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China.
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, China.
- Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China.
- Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Lou-Hu Hospital, Shen-Zhen University, Shen-Zhen, China.
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22
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James B, Milstien S, Spiegel S. ORMDL3 and allergic asthma: From physiology to pathology. J Allergy Clin Immunol 2019; 144:634-640. [PMID: 31376405 DOI: 10.1016/j.jaci.2019.07.023] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/18/2019] [Accepted: 07/26/2019] [Indexed: 01/10/2023]
Abstract
There is a strong genetic component to asthma, and numerous genome-wide association studies have identified ORM1 (yeast)-like protein 3 (ORMDL3) as a gene associated with asthma susceptibility. However, how ORMDL3 contributes to asthma pathogenesis and its physiologic functions is not well understood and a matter of great debate. This rostrum describes recent advances and new insights in understanding of the multifaceted functions of ORMDL3 in patients with allergic asthma. We also suggest a potential unifying paradigm and discuss molecular mechanisms for the pathologic functions of ORMDL3 in asthma related to its evolutionarily conserved role in regulation of sphingolipid homeostasis. Finally, we briefly survey the utility of sphingolipid metabolites as potential biomarkers for allergic asthma.
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Affiliation(s)
- Briana James
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va
| | - Sheldon Milstien
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
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23
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Debeuf N, Zhakupova A, Steiner R, Van Gassen S, Deswarte K, Fayazpour F, Van Moorleghem J, Vergote K, Pavie B, Lemeire K, Hammad H, Hornemann T, Janssens S, Lambrecht BN. The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice. J Allergy Clin Immunol 2019; 144:1648-1659.e9. [PMID: 31330218 DOI: 10.1016/j.jaci.2019.06.041] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/27/2019] [Accepted: 06/28/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk. OBJECTIVE We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma. METHODS Ormdl3-LacZ reporter mice, gene-deficient Ormdl3-/- mice, and overexpressing Ormdl3Tg/wt mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma. Mass spectrometry-based sphingolipidomics were performed, and airway eosinophilia, TH2 cytokine production, immunoglobulin synthesis, airway remodeling, and bronchial hyperreactivity were measured. RESULTS HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3Tg/wt mice the allergen-induced increase in lung ceramide levels was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, levels of total sphingolipids, including ceramides, were increased in Ormdl3-/- mice, whereas they were decreased in Ormdl3Tg/wt mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wild-type, Ormdl3Tg/wt, and Ormdl3-/- mice across several models of experimental asthma. CONCLUSION ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma.
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Affiliation(s)
- Nincy Debeuf
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Assem Zhakupova
- Institute of Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland
| | - Regula Steiner
- Institute of Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland
| | - Sofie Van Gassen
- Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | - Kim Deswarte
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Farzaneh Fayazpour
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
| | - Justine Van Moorleghem
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Karl Vergote
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Benjamin Pavie
- VIB Bioimaging Core, VIB Center for Inflammation Research, Ghent, Belgium; Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kelly Lemeire
- Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB Center for Inflammation Research, Ghent, Belgium
| | - Hamida Hammad
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Thorsten Hornemann
- Institute of Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland
| | - Sophie Janssens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory for ER Stress and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
| | - Bart N Lambrecht
- Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
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24
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Miller M, Broide DH. Why Is ORMDL3 on Chromosome 17q21 Highly Linked to Asthma? Am J Respir Crit Care Med 2019; 199:404-406. [PMID: 30365391 DOI: 10.1164/rccm.201810-1941ed] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Marina Miller
- 1 Department of Medicine University of California San Diego La Jolla, California
| | - David H Broide
- 1 Department of Medicine University of California San Diego La Jolla, California
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25
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Wang H, Liu Y, Shi J, Cheng Z. ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway. Biochem Biophys Res Commun 2019; 516:739-746. [PMID: 31255288 DOI: 10.1016/j.bbrc.2019.06.122] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 06/21/2019] [Indexed: 12/27/2022]
Abstract
Orosomucoid-like protein 3 (ORMDL3) is a common mutation in many asthma patients and its effects on the specific pathogenesis of asthma are still unclear. Therefore, in this study, we used a mouse that specifically knockout the mouse ORDML3 gene to further study the mechanism. We used ovalbumin (OVA) to induce asthma in wild-type mice and ORMDL3 knockout mice. Lung ventilation resistance, airway inflammation, mucus hypersecretion, collagen deposition, the levels of inflammatory factors and the expression of ORDML3 and JNK1/2-MMP-9 pathway were detected. The results showed that ORMDL3 gene was highly expressed in clinical asthmatic children and mouse asthma model. Knocking down the ORMDL3 gene in the lung tissue of asthmatic mice can reduce airway hyperresponsiveness, airway inflammation, mucus secretion, and collagen deposition around the airway. After knocking down the lung tissue of mice, the IL-4, IL-5 and IL-13 concentrations in broncho alveolar lavage fluid of asthmatic mice were significantly decreased, and the activation of JNK1/2-MMP-9 pathway was inhibited in mouse lung tissue. Collectively, our results demonstrate that the ORMDL3 gene may aggravate asthma symptoms by activating the JNK1/2-MMP-9 pathway, which indicates that the ORMDL3 gene may be the key molecule for the next step of asthma targeted therapy.
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Affiliation(s)
- Huan Wang
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ying Liu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jiang Shi
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhe Cheng
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
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26
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Identification of Zebrafish Calcium Toolkit Genes and their Expression in the Brain. Genes (Basel) 2019; 10:genes10030230. [PMID: 30889933 PMCID: PMC6471419 DOI: 10.3390/genes10030230] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 03/13/2019] [Indexed: 01/12/2023] Open
Abstract
Zebrafish are well-suited for in vivo calcium imaging because of the transparency of their larvae and the ability to express calcium probes in various cell subtypes. This model organism has been used extensively to study brain development, neuronal function, and network activity. However, only a few studies have investigated calcium homeostasis and signaling in zebrafish neurons, and little is known about the proteins that are involved in these processes. Using bioinformatics analysis and available databases, the present study identified 491 genes of the zebrafish Calcium Toolkit (CaTK). Using RNA-sequencing, we then evaluated the expression of these genes in the adult zebrafish brain and found 380 hits that belonged to the CaTK. Based on quantitative real-time polymerase chain reaction arrays, we estimated the relative mRNA levels in the brain of CaTK genes at two developmental stages. In both 5 dpf larvae and adult zebrafish, the highest relative expression was observed for tmbim4, which encodes a Golgi membrane protein. The present data on CaTK genes will contribute to future applications of zebrafish as a model for in vivo and in vitro studies of Ca2+ signaling.
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27
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Magaye RR, Savira F, Hua Y, Kelly DJ, Reid C, Flynn B, Liew D, Wang BH. The role of dihydrosphingolipids in disease. Cell Mol Life Sci 2019; 76:1107-1134. [PMID: 30523364 PMCID: PMC11105797 DOI: 10.1007/s00018-018-2984-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 11/06/2018] [Accepted: 11/26/2018] [Indexed: 12/29/2022]
Abstract
Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.
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Affiliation(s)
- Ruth R Magaye
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Feby Savira
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Yue Hua
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Darren J Kelly
- Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Bernard Flynn
- Australian Translational Medicinal Chemistry Facility, Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Bing H Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
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28
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Kowal K, Żebrowska E, Chabowski A. Altered Sphingolipid Metabolism Is Associated With Asthma Phenotype in House Dust Mite-Allergic Patients. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2019; 11:330-342. [PMID: 30912323 PMCID: PMC6439195 DOI: 10.4168/aair.2019.11.3.330] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 11/18/2018] [Accepted: 12/11/2018] [Indexed: 12/21/2022]
Abstract
Purpose Sphingolipids play an important role in cell growth, survival, inflammation and tissue remodeling. House dust mite (HDM) allergy is a major risk factor for asthma. The aim of the study was to evaluate if allergic asthma phenotype is associated with altered sphingolipid metabolism. Methods Twenty-two HDM-allergic asthmatic patients and 11 HDM-allergic rhinitis patients were challenged intrabronchially with biologically standardized Dermatophagoides pteronyssinus extract. Whole blood and platelet-poor plasma samples were collected before, during early asthmatic response (EAR), late asthmatic response (LAR) and 24 hours after the challenge. Concentrations of sphinganine (SFA), sphinganine-1-phosphate (SFA1P), ceramide, sphingosine (SFO) and sphingosine-1-phosphate (S1P) were measured using high performance liquid chromatography. Results In all house dust mite-allergic patients (HDM-APs), baseline lung function and severity of airway hyperreactivity (AHR) correlated significantly with plasma S1P and SFA1P concentrations. Exhaled nitric oxide concentration, however, correlated with SFA and ceramide, but not with S1P or SFA1P concentration. Allergen challenge increased plasma S1P concentration during EAR, but only in patients who developed both EAR and LAR. The magnitude of the increase determined during EAR correlated with the severity of subsequently developed LAR. Platelet and eosinophil counts were independent predictors of plasma S1P concentration. A significant increase in plasma SFA concentration in response to allergen challenge was seen only in patients who did not develop asthmatic response. Conclusions Altered sphingolipid metabolism, with augmented synthesis of S1P and impaired de novo sphingolipid synthesis in response to allergen challenge, may participate in the development of asthma phenotype in HDM-APs.
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Affiliation(s)
- Krzysztof Kowal
- Department of Experimental Allergology and Immunology, Medical University of Bialystok, Bialystok, Poland.,Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
| | - Ewa Żebrowska
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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29
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Miller M, Vuong C, Garcia MF, Rosenthal P, Das S, Weng N, Pham A, Kim YJ, Broide DH. Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? J Allergy Clin Immunol 2018; 142:706-709.e4. [PMID: 29709669 PMCID: PMC6078789 DOI: 10.1016/j.jaci.2018.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/09/2018] [Accepted: 04/20/2018] [Indexed: 10/17/2022]
Affiliation(s)
- Marina Miller
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - Christine Vuong
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | | | - Peter Rosenthal
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - Sudipta Das
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - Ning Weng
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - Alexa Pham
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - Yu Jin Kim
- Department of Medicine, University of California San Diego, La Jolla, Calif
| | - David H Broide
- Department of Medicine, University of California San Diego, La Jolla, Calif.
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30
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Kanagaratham C, Chiwara V, Ho B, Moussette S, Youssef M, Venuto D, Jeannotte L, Bourque G, de Sanctis JB, Radzioch D, Naumova AK. Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion. Mamm Genome 2018. [PMID: 29536159 DOI: 10.1007/s00335-018-9743-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.
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Affiliation(s)
| | - Victoria Chiwara
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Bianca Ho
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Sanny Moussette
- The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Mina Youssef
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - David Venuto
- McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada
| | - Lucie Jeannotte
- Département de Biologie moléculaire, Biochimie medicale & Pathologie, Faculté de médecine, Université Laval, Québec, QC, Canada.,Centre de recherche sur le cancer de l'Université Laval, CRCHU de Québec-Université Laval, L'Hôtel-Dieu de Québec, Québec, QC, Canada
| | - Guillaume Bourque
- Department of Human Genetics, McGill University, Montreal, QC, Canada.,McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada
| | - Juan Bautista de Sanctis
- Institute of Immunology, Faculty of Medicine, Universidad Central de Venezuela, Sabana Grande, Caracas, Venezuela
| | - Danuta Radzioch
- Department of Human Genetics, McGill University, Montreal, QC, Canada.,The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.,Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program (IDIGH), The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Anna K Naumova
- Department of Human Genetics, McGill University, Montreal, QC, Canada. .,The Research Institute of the McGill University Health Centre, Montreal, QC, Canada. .,Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada.
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31
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A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 2018; 142:749-764.e3. [PMID: 29307657 PMCID: PMC6172038 DOI: 10.1016/j.jaci.2017.12.974] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/13/2017] [Accepted: 12/16/2017] [Indexed: 12/20/2022]
Abstract
Chromosome 17q12–21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12–21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus. (J Allergy Clin Immunol 2018;142:749–64.)
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32
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Vicente CT, Revez JA, Ferreira MAR. Lessons from ten years of genome-wide association studies of asthma. Clin Transl Immunology 2017; 6:e165. [PMID: 29333270 PMCID: PMC5750453 DOI: 10.1038/cti.2017.54] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/10/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022] Open
Abstract
Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10−8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.
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Affiliation(s)
| | - Joana A Revez
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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33
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Mohammed S, Harikumar KB. Sphingosine 1-Phosphate: A Novel Target for Lung Disorders. Front Immunol 2017; 8:296. [PMID: 28352271 PMCID: PMC5348531 DOI: 10.3389/fimmu.2017.00296] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 03/01/2017] [Indexed: 01/11/2023] Open
Abstract
Sphingosine 1-phosphate (S1P) is involved in a wide range of cellular processes, which include proliferation, apoptosis, lymphocyte egress, endothelial barrier function, angiogenesis, and inflammation. S1P is produced by two isoenzymes, namely, sphingosine kinase 1 and 2 (SphK1 and 2) and once produced, S1P can act both in an autocrine and paracrine manner. S1P can be dephosphorylated back to sphingosine by two phosphatases (SGPP 1 and 2) or can be irreversibly cleaved by S1P lyase. S1P has a diverse range of functions, which is mediated in a receptor dependent, through G-protein coupled receptors (S1PR1-5) or receptor independent manner, through intracellular targets such as HDACs and TRAF2. The involvement of S1P signaling has been confirmed in various disease conditions including lung diseases. The SphK inhibitors and S1PR modulators are currently under clinical trials for different pathophysiological conditions. There is a significant effort in targeting various components of S1P signaling for several diseases. This review focuses on the ways in which S1P signaling can be therapeutically targeted in lung disorders.
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Affiliation(s)
- Sabira Mohammed
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology , Thiruvananthapuram , India
| | - K B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology , Thiruvananthapuram , India
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34
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Miller M, Tam AB, Mueller JL, Rosenthal P, Beppu A, Gordillo R, McGeough MD, Vuong C, Doherty TA, Hoffman HM, Niwa M, Broide DH. Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate. THE JOURNAL OF IMMUNOLOGY 2017; 198:3017-3022. [PMID: 28275141 DOI: 10.4049/jimmunol.1601848] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/13/2017] [Indexed: 11/19/2022]
Abstract
In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challenged Ormdl3Δ2-3/Δ2-3/CC10 mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in Ormdl3Δ2-3/Δ2-3/CC10 and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3/CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3/CC10 mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.
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Affiliation(s)
- Marina Miller
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Arvin B Tam
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093
| | - James L Mueller
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093.,Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and
| | - Peter Rosenthal
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Andrew Beppu
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Matthew D McGeough
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093.,Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and
| | - Christine Vuong
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Taylor A Doherty
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Hal M Hoffman
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093.,Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and
| | - Maho Niwa
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093
| | - David H Broide
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
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