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Chen S, Wang S, Liao S, Blakney AK. Exploring the Effects of Incorporating Different Bioactive Phospholipids into Messenger Ribonucleic Acid Lipid Nanoparticle (mRNA LNP) Formulations. ACS BIO & MED CHEM AU 2025; 5:154-165. [PMID: 39990935 PMCID: PMC11843334 DOI: 10.1021/acsbiomedchemau.4c00085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 09/01/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 02/25/2025]
Abstract
The current rapid advancement in ribonucleic acid (RNA) therapeutics research depends on innovations in drug delivery, especially the development of a lipid-nanoparticle (LNP)-based system. The conventional LNP formulation typically contains four components, including an ionizable cationic lipid, a phospholipid, cholesterol or a cholesterol derivative, and poly(ethylene glycol) (PEG)-lipid, with each contributing to the formulation's overall stability and effectiveness. Among these four types of lipids, the phospholipid component is often known to provide structural support for the nanoparticles but is also a class of bioactive molecules with strong cell signaling potential. This study explores the possibility of incorporating some known structurally related bioactive phospholipids as the fifth component of a conventional four-component LNP formulation and assesses the impacts of such an approach on the physicochemical properties and biological functions of the mRNA LNP formulation. We screened a library of mRNA LNP formulations containing 7 different structurally related bioactive phospholipids at molar concentrations of 5%, 15% and 30% in addition to a conventional four-component LNP formulation (base). We observed differences in physicochemical properties between the mRNA LNP formulations that could be attributed to both the types of phospholipids examined and the molar concentrations used. Cryo-EM analysis revealed structural similarity between the Base formulation and the other formulations. We also characterized the protein expression level in HeLa cells and picked up a distinct cytokine panel signature for each formulation in human peripheral blood mononuclear cells (hPBMCs). Further immunophenotyping analysis showed that most cells that were transfected were CD4+ T cells, and the addition of the different bioactive phospholipids slightly altered cellular tropism. This exploratory study illustrates how adding the bioactive phospholipid can be used to modulate the LNP function, further expanding the design space for RNA LNP formulations and potentiating LNPs for use as RNA therapeutics.
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Affiliation(s)
- Sunny
P. Chen
- School
of Biomedical Engineering, University of
British Columbia, Vancouver V6T 1Z3, Canada
- Michael
Smith Laboratories, University of British
Columbia, Vancouver V6T 1Z4, Canada
| | - Shuangyu Wang
- Department
of Biochemistry and Molecular Biology, University
of British Columbia, Vancouver V6T 2A1, Canada
| | - Suiyang Liao
- School
of Biomedical Engineering, University of
British Columbia, Vancouver V6T 1Z3, Canada
- Michael
Smith Laboratories, University of British
Columbia, Vancouver V6T 1Z4, Canada
- Department
of Biochemistry and Molecular Biology, University
of British Columbia, Vancouver V6T 2A1, Canada
| | - Anna K. Blakney
- School
of Biomedical Engineering, University of
British Columbia, Vancouver V6T 1Z3, Canada
- Michael
Smith Laboratories, University of British
Columbia, Vancouver V6T 1Z4, Canada
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2
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Kume H, Kazama K, Sato R, Sato Y. Possible Involvement of Lysophospholipids in Severe Asthma as Novel Lipid Mediators. Biomolecules 2025; 15:182. [PMID: 40001485 DOI: 10.3390/biom15020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/08/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 02/27/2025] Open
Abstract
In severe asthma, symptoms are unstable despite intensive treatment based on high doses of inhaled corticosteroids and on-demand use of oral corticosteroids. Although, recently, various biological agents related to Th2 cytokines have been added to intensive controller medications for severe asthma, a significant progress has not been observed in the management for symptoms (dyspnea, wheezing and cough). Medical treatment focused on Type 2 inflammation is probably insufficient to maintain good long-term management for severe asthma. Airway eosinophilia and decreased reversibility in forced expiratory volume in 1 second (FEV1) are listed as major predictors for exacerbation-prone asthma. However, it is generally considered that asthma is complex and heterogeneous. It is necessary to establish precision medicine using treatable traits based on a multidimensional approach related to asthma. Since phospholipids generate lysophospholipids and arachidonic acid by phospholipases, lysophospholipids can be associated with the pathogenesis of this disease via action on smooth muscle, endothelium, and epithelium in the airways. Lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosine 1-phosphate (S1P) are increased in bronchoalveolar fluid after allergen challenge. LPA, LPC, and S1P recruit eosinophils to the lungs and cause β2-adrenergic desensitization. LAP and S1P cause contraction and hyperresponsiveness in airway smooth muscle. Moreover, lysophosphatidylserine and S1P are associated with the allergic reaction related to IgE/FcεRI in mast cells. Lysophospholipid action is probably comprised of corticosteroid resistance and is independent of Type 2 inflammation, and may be corelated with oxidative stress. Lysophospholipids may be a novel molecular target in advancing the management and treatment of asthma. This review discusses the clinical relevance of lysophospholipids in asthma.
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Affiliation(s)
- Hiroaki Kume
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Kentaro Kazama
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Riko Sato
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
| | - Yuki Sato
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan
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3
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Zhang W, Chen W, Shan C, Wang R, Li L, Wang J, Meng J. IL-13 Activates Cutaneous Schwann Cells to Promote CCL7-Dependent Pruritic Signaling in Atopic Dermatitis. J Invest Dermatol 2023; 143:2322-2327.e9. [PMID: 37187410 DOI: 10.1016/j.jid.2023.04.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/28/2022] [Revised: 03/20/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023]
Affiliation(s)
- Wenhao Zhang
- School of Life Sciences, Henan University, Henan, China
| | - Weiwei Chen
- School of Life Sciences, Henan University, Henan, China
| | - Chunxu Shan
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland; National Institute for Cellular Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Ruizhen Wang
- School of Life Sciences, Henan University, Henan, China
| | - Lianlian Li
- School of Life Sciences, Henan University, Henan, China
| | - Jiafu Wang
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Jianghui Meng
- School of Life Sciences, Henan University, Henan, China; School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland; National Institute for Cellular Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland.
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4
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Jiang S, Yang H, Li M. Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases. Int J Mol Sci 2023; 24:12524. [PMID: 37569902 PMCID: PMC10419859 DOI: 10.3390/ijms241512524] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
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Affiliation(s)
- Shufan Jiang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huili Yang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
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5
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He Y, Zhou H, Huang X, Qu Y, Wang Y, Pei W, Zhang R, Chen S, You H. Infiltration of LPAR5 + macrophages in osteosarcoma tumor microenvironment predicts better outcomes. Front Immunol 2022; 13:909932. [PMID: 36591220 PMCID: PMC9797602 DOI: 10.3389/fimmu.2022.909932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/31/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. Methods Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. Results Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. Conclusion We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.
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Affiliation(s)
- Yi He
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haiting Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaojian Huang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yunkun Qu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yingguang Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenbin Pei
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Chen
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongbo You
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Hongbo You,
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6
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Lee YJ, Im DS. Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice. Int J Mol Sci 2022; 23:ijms23179745. [PMID: 36077141 PMCID: PMC9456302 DOI: 10.3390/ijms23179745] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2022] [Revised: 08/19/2022] [Accepted: 08/26/2022] [Indexed: 11/30/2022] Open
Abstract
Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA2) has been reported as a therapeutic target for asthma. However, results with LPA2 agonist and antagonist along with LPA2 gene deficient mice have been controversial and contradictory. We compared the effects of LPA2 antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA2 in asthmatic responses. We suggest that the development of LPA2 antagonists would achieve better therapeutic efficacy against asthma than agonists.
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LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation. Proc Natl Acad Sci U S A 2022; 119:e2118816119. [PMID: 35394866 PMCID: PMC9169816 DOI: 10.1073/pnas.2118816119] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/26/2023] Open
Abstract
Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-specific T cell:target cell formation, IP3R1 localizes to the IS by a process dependent on mDia1 and actin and microtubule polymerization. LPA not only inhibited IP3R1 from reaching the IS but also altered T cell receptor (TCR)–induced localization of RhoA and mDia1 impairing F-actin accumulation and altering the tubulin code. Consequently, LPA impeded calcium store release and IS-directed cytokine secretion. Thus, targeting LPA signaling in chronic inflammatory conditions may rescue T cell function and promote antiviral and antitumor immunity.
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8
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Abstract
Lysophosphatidic acid (LPA) is a versatile lysolipid, and activates a variety of signaling cascades in many cell types. Extracellular LPA is produced from lysophosphatidylcholine (LPC) by the enzyme autotaxin (ATX), and binds to a family of G-protein coupled receptors on its target cells. Research by many groups continues to support the idea that LPA, and the ATX-LPA axis, have important roles in asthma and allergic airway inflammation. In vitro studies have shown that LPA activates many cell types implicated in airway inflammation, including eosinophils, mast cells, dendritic cells, lymphocytes, airway epithelial cells, and airway smooth muscle cells. In animal models ATX and LPA receptor antagonists have been shown to attenuate allergic airway inflammation and hyperreactivity, cardinal features of asthma in humans. ATX and LPA antagonists are currently under active development to treat lung fibrosis, cancer, and other conditions. If compounds with acceptable safety profiles can be identified, then it seems likely that they will be useful in inflammatory lung diseases like asthma.
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Affiliation(s)
- Steve N Georas
- University of Rochester Medical Center, Rochester, NY, USA.
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9
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Lysophospholipids in Lung Inflammatory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:373-391. [PMID: 33788203 DOI: 10.1007/978-3-030-63046-1_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Academic Contribution Register] [Indexed: 01/21/2023]
Abstract
The lysophospholipids (LPLs) belong to a group of bioactive lipids that play pivotal roles in several physiological and pathological processes. LPLs are derivatives of phospholipids and consist of a single hydrophobic fatty acid chain, a hydrophilic head, and a phosphate group with or without a large molecule attached. Among the LPLs, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are the simplest, and have been shown to be involved in lung inflammatory symptoms and diseases such as acute lung injury, asthma, and chronic obstructive pulmonary diseases. G protein-coupled receptors (GPCRs) mediate LPA and S1P signaling. In this chapter, we will discuss on the role of LPA, S1P, their metabolizing enzymes, inhibitors or agonists of their receptors, and their GPCR-mediated signaling in lung inflammatory symptoms and diseases, focusing specially on acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease.
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10
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Mathew D, Torres RM. Lysophosphatidic Acid Is an Inflammatory Lipid Exploited by Cancers for Immune Evasion via Mechanisms Similar and Distinct From CTLA-4 and PD-1. Front Immunol 2021; 11:531910. [PMID: 33584637 PMCID: PMC7873449 DOI: 10.3389/fimmu.2020.531910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
Immunological tolerance has evolved to curtail immune responses against self-antigens and prevent autoimmunity. One mechanism that contributes to immunological tolerance is the expression of inhibitory receptors by lymphocytes that signal to dampen immune responses during the course of an infection and to prevent immune-mediated collateral damage to the host. The understanding that tumors exploit these physiological mechanisms to avoid elimination has led to remarkable, but limited, success in the treatment of cancer through the use of biologics that interfere with the ability of cancers to suppress immune function. This therapy, based on the understanding of how T lymphocytes are normally activated and suppressed, has led to the development of therapeutic blocking antibodies, referred to as immune checkpoint blockade, which either directly or indirectly promote the activation of CD8 T cells to eradicate cancer. Here, we highlight the distinct signaling mechanisms, timing and location of inhibition used by the CTLA-4 and PD-1 inhibitory receptors compared to a novel inhibitory signaling axis comprised of the bioactive lipid, lysophosphatidic acid (LPA), signaling via the LPA5 receptor expressed by CD8 T cells. Importantly, abundant evidence indicates that an LPA-LPA5 signaling axis is also exploited by diverse cancers to suppress T cell activation and function. Clearly, a thorough molecular and biochemical understanding of how diverse T cell inhibitory receptors signal to suppress T cell antigen receptor signaling and function will be important to inform the choice of which complimentary checkpoint blockade modalities might be used for a given cancer.
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Affiliation(s)
| | - Raul M. Torres
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
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Kondo M, Tezuka T, Ogawa H, Koyama K, Bando H, Azuma M, Nishioka Y. Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation. Int Arch Allergy Immunol 2020; 182:1-13. [PMID: 32846422 DOI: 10.1159/000509804] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/27/2019] [Accepted: 06/30/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. OBJECT We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. METHODS We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4+ T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. RESULTS The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. CONCLUSION These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.
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Affiliation(s)
- Mayo Kondo
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Toshifumi Tezuka
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Hirohisa Ogawa
- Department of Pathology and Laboratory Medicine, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Kazuya Koyama
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Hiroki Bando
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Masahiko Azuma
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.,Department of Medical Education, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yasuhiko Nishioka
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan,
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12
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Feng Y, Xiao M, Zhang Z, Cui R, Jiang X, Wang S, Bai H, Liu C, Zhang Z. Potential interaction between lysophosphatidic acid and tumor-associated macrophages in ovarian carcinoma. JOURNAL OF INFLAMMATION-LONDON 2020; 17:23. [PMID: 32774171 PMCID: PMC7405460 DOI: 10.1186/s12950-020-00254-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 05/09/2019] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
Ovarian carcinoma is the deadliest type of gynecological cancer. The unique tumor microenvironment enables specific and efficient metastasis, weakens immunological monitoring, and mediates drug resistance. Tumor associated macrophages (TAMs) are a crucial part of the TME and are involved in various aspects of tumor behavior. Lysophosphatidic acid (LPA) is elevated in the blood of ovarian carcinoma patients, as well as in the tumor tissues and ascites, which make it a useful biomarker and a potential therapeutic target. Recent studies have shown that LPA transforms monocytes into macrophages and regulates the formation of macrophages through the AKT/mTOR pathway, and PPAR γ is a major regulator of LPA-derived macrophages. In addition, TAMs synthesize and secrete LPA and express LPA receptor (LPAR) on the surface. With these data in mind, we hypothesize that LPA can convert monocytes directly into TAMs in the microenvironment of ovarian cancer. LPA may mediate TAM formation by activating the PI3K/AKT/mTOR signaling pathway through LPAR on the cell surface, which may also affect the function of PPAR γ, leading to increased LPA production by TAMs. Thus, LPA and TAMs form a vicious circle that affects the malignant behavior of ovarian cancer.
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Affiliation(s)
- Ying Feng
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Meizhu Xiao
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Zihan Zhang
- Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ran Cui
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Xuan Jiang
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Shuzhen Wang
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Huimin Bai
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Chongdong Liu
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
| | - Zhenyu Zhang
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China
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13
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The roles of autotaxin/lysophosphatidic acid in immune regulation and asthma. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158641. [PMID: 32004685 DOI: 10.1016/j.bbalip.2020.158641] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/18/2019] [Revised: 12/26/2019] [Accepted: 01/23/2020] [Indexed: 12/18/2022]
Abstract
Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.
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14
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Xu Y. Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside. Cancers (Basel) 2019; 11:E1523. [PMID: 31658655 PMCID: PMC6826372 DOI: 10.3390/cancers11101523] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/28/2019] [Revised: 10/02/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022] Open
Abstract
Since the clear demonstration of lysophosphatidic acid (LPA)'s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications.
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Affiliation(s)
- Yan Xu
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA.
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15
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Nojiri T, Kurano M, Araki O, Nakawatari K, Nishikawa M, Shimamoto S, Igarashi K, Kano K, Aoki J, Kihara S, Murakami M, Yatomi Y. Serum autotaxin levels are associated with Graves' disease. Endocr J 2019; 66:409-422. [PMID: 30814442 DOI: 10.1507/endocrj.ej18-0451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/23/2022] Open
Abstract
Graves' Disease is a representative autoimmune thyroid disease that presents with hyperthyroidism. Emerging evidence has shown the involvement of lysophosphatidic acid (LPA) and its producing enzyme, autotaxin (ATX), in the pathogenesis of various diseases; among them, the involvement of the ATX/LPA axis in some immunological disturbances has been proposed. In this study, we investigated the association between serum ATX levels and Graves' disease. We measured the levels of serum total ATX and ATX isoforms (classical ATX and novel ATX) in patients with untreated Graves' disease, Graves' disease treated with anti-thyroid drugs, patients with subacute thyroiditis, silent thyroiditis, Plummer's disease, or Hashimoto's thyroiditis, and patients who had undergone a total thyroidectomy, as well as normal subjects. The serum total ATX and ATX isoform levels were higher in the patients with Graves' disease, compared with the levels in the healthy subjects and the patients with subacute thyroiditis. Treatment with anti-thyroid drugs significantly decreased the serum ATX levels. The serum ATX levels and the changes in serum ATX levels during treatment were moderately or strongly correlated with the serum concentrations or the changes in thyroid hormones. However, the administration of T3 or T4 did not increase the expression or serum levels of ATX in 3T3L1 adipocytes or wild-type mice. In conclusion, the serum ATX levels were higher in subjects with Graves' disease, possibly because of a mechanism that does not involve hyperthyroidism. These results suggest the possible involvement of the ATX/LPA axis in the pathogenesis of Graves' disease.
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Affiliation(s)
- Takahiro Nojiri
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Osamu Araki
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Kazuki Nakawatari
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Masako Nishikawa
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | - Kuniyuki Kano
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Shinji Kihara
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masami Murakami
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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16
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Zhang X, Biagini Myers JM, Yadagiri VK, Ulm A, Chen X, Weirauch MT, Khurana Hershey GK, Ji H. Nasal DNA methylation differentiates corticosteroid treatment response in pediatric asthma: A pilot study. PLoS One 2017; 12:e0186150. [PMID: 29028809 PMCID: PMC5640236 DOI: 10.1371/journal.pone.0186150] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2017] [Accepted: 09/26/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Treatment response to systemic corticosteroid in asthmatic children is heterogeneous and may be mediated by epigenetic mechanism(s). We aim to identify DNA methylation (DNAm) changes responsive to steroid, and DNAm biomarkers that distinguish treatment response. MATERIALS AND METHODS We followed 33 children (ages 5-18) presenting to the Emergency Department (ED) for asthma exacerbation. Based on whether they met discharge criteria in ≤24 hours, participants were grouped into good and poor responders to steroid treatment. Nasal samples were collected upon presentation to the ED (T0) and 18-24 hours later (T1). Genome-wide DNAm was measured for both time points in 20 subjects, and compared between T0 and T1 in good and poor responders respectively. DNAm at T1 was also compared between two responder groups. DNAm of selected CpGs was verified in the complete cohort, and expression of associated genes was examined. Interactions between DNAm, common single nucleotide polymorphism (SNP) located at the CpG sites and treatment responses were assessed. RESULTS Three CpGs located in the OTX2 promoter showed responder-specific DNAm changes from T0 to T1, in which DNAm decreased in good but not in poor responders. Good and poor responders showed differential DNAm at T1 in 127 CpGs without and 182 CpGs with common SNP co-localization. Negative correlations between DNAm and gene expression were observed at CpGs located within the LDHC promoter, suggesting an impact of DNAm on gene regulation. Interactions between SNPs, DNAm and treatment response were detected. CONCLUSION Acute systemic steroid treatment modifies nasal DNAm in good responders. Nasal DNAm, dependent or independent of SNPs, can differentiate response to treatment in acute asthmatic children.
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Affiliation(s)
- Xue Zhang
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Jocelyn M. Biagini Myers
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Veda K. Yadagiri
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Ashley Ulm
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Xiaoting Chen
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Matthew T. Weirauch
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Gurjit K. Khurana Hershey
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Hong Ji
- Pyrosequencing lab for genomic and epigenomic research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
- * E-mail:
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17
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Sun S, Zhang X, Lyu L, Li X, Yao S, Zhang J. Autotaxin Expression Is Regulated at the Post-transcriptional Level by the RNA-binding Proteins HuR and AUF1. J Biol Chem 2016; 291:25823-25836. [PMID: 27784781 DOI: 10.1074/jbc.m116.756908] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/04/2016] [Revised: 10/24/2016] [Indexed: 01/20/2023] Open
Abstract
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a lysophospholipid mediator that regulates cellular activities through its specific G protein-coupled receptors. The ATX-LPA axis plays an important role in various physiological and pathological processes, especially in inflammation and cancer development. Although the transcriptional regulation of ATX has been widely studied, the post-transcriptional regulation of ATX is largely unknown. In this study, we identified conserved adenylate-uridylate (AU)-rich elements in the ATX mRNA 3'-untranslated region (3'UTR). The RNA-binding proteins HuR and AUF1 directly bound to the ATX mRNA 3'UTR and had antagonistic functions in ATX expression. HuR enhanced ATX expression by increasing ATX mRNA stability, whereas AUF1 suppressed ATX expression by promoting ATX mRNA decay. HuR and AUF1 were involved in ATX regulation in Colo320 human colon cancer cells and the LPS-stimulated human monocytic THP-1 cells. HuR knockdown suppressed ATX expression in B16 mouse melanoma cells, leading to inhibition of cell migration. This effect was reversed by AUF1 knockdown to recover ATX expression or by the addition of LPA. These results suggest that the post-transcriptional regulation of ATX expression by HuR and AUF1 modulates cancer cell migration. In summary, we identified HuR and AUF1 as novel post-transcriptional regulators of ATX expression, thereby elucidating a novel mechanism regulating the ATX-LPA axis.
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Affiliation(s)
- Shuhong Sun
- From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
| | - Xiaotian Zhang
- From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
| | - Lin Lyu
- From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
| | - Xixi Li
- the Key Laboratory of Biodiversity Science and Ecological Engineering, Ministry of Education, College of Life Science, Beijing Normal University, Beijing 100875, China
| | - Siliang Yao
- From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
| | - Junjie Zhang
- From the Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, and
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18
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Ackerman SJ, Park GY, Christman JW, Nyenhuis S, Berdyshev E, Natarajan V. Polyunsaturated lysophosphatidic acid as a potential asthma biomarker. Biomark Med 2016; 10:123-35. [PMID: 26808693 PMCID: PMC4881841 DOI: 10.2217/bmm.15.93] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/04/2015] [Accepted: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Lysophosphatidic acid (LPA), a lipid mediator in biological fluids and tissues, is generated mainly by autotaxin that hydrolyzes lysophosphatidylcholine to LPA and choline. Total LPA levels are increased in bronchoalveolar lavage fluid from asthmatic lung, and are strongly induced following subsegmental bronchoprovocation with allergen in subjects with allergic asthma. Polyunsaturated molecular species of LPA (C22:5 and C22:6) are selectively synthesized in the airways of asthma subjects following allergen challenge and in mouse models of allergic airway inflammation, having been identified and quantified by LC/MS/MS lipidomics. This review discusses current knowledge of LPA production in asthmatic lung and the potential utility of polyunsaturated LPA molecular species as novel biomarkers in bronchoalveolar lavage fluid and exhaled breath condensate of asthma subjects.
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Affiliation(s)
- Steven J Ackerman
- Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
- Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
| | - Gye Young Park
- Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
| | - John W Christman
- Department of Medicine, Ohio State University School of Medicine, Columbus, OH 43210, USA
| | - Sharmilee Nyenhuis
- Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
| | - Evgeny Berdyshev
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Viswanathan Natarajan
- Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
- Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA
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19
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Song J, Guan M, Zhao Z, Zhang J. Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation. PLoS One 2015; 10:e0136629. [PMID: 26313906 PMCID: PMC4552386 DOI: 10.1371/journal.pone.0136629] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/01/2015] [Accepted: 08/05/2015] [Indexed: 12/30/2022] Open
Abstract
Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation.
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Affiliation(s)
- Jianwen Song
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Ming Guan
- Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing, China
| | - Zhenwen Zhao
- Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences, Beijing, China
| | - Junjie Zhang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
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20
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Oda SK, Strauch P, Fujiwara Y, Al-Shami A, Oravecz T, Tigyi G, Pelanda R, Torres RM. Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression. Cancer Immunol Res 2015; 1:245-55. [PMID: 24455753 DOI: 10.1158/2326-6066.cir-13-0043-t] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/21/2023]
Abstract
CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immune surveillance. However, multiple inhibitory mechanisms within the tumor microenvironment have been described that impede tumor rejection by CD8 T cells, including increased signaling by inhibitory receptors. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that has been shown repeatedly to promote diverse cellular processes benefiting tumorigenesis. Accordingly, the increased expression of LPA and LPA receptors is a common feature of diverse tumor cell lineages and can result in elevated systemic LPA levels. LPA is recognized by at least 6 distinct G-protein-coupled receptors and several of which are expressed by T cells, although the precise role of LPA signaling in CD8 T cell activation and function has not been defined. Here, we demonstrate that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells. Together, these data suggest that the production of LPA by tumors serves not only in an autocrine manner to promote tumorigenesis but also as a mechanism to suppress adaptive immunity and highlights a potential novel target for cancer treatment.
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Affiliation(s)
- Shannon K Oda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado
| | - Pamela Strauch
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado
| | - Yuko Fujiwara
- Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, Tennessee
| | | | | | - Gabor Tigyi
- Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, Tennessee
| | - Roberta Pelanda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado
| | - Raul M Torres
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado
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21
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Shlyonsky V, Naeije R, Mies F. Possible role of lysophosphatidic acid in rat model of hypoxic pulmonary vascular remodeling. Pulm Circ 2015; 4:471-81. [PMID: 25621161 DOI: 10.1086/677362] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/21/2013] [Accepted: 02/20/2014] [Indexed: 01/12/2023] Open
Abstract
Pulmonary hypertension is characterized by cellular and structural changes in the vascular wall of pulmonary arteries. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling in a rat model of hypoxic pulmonary hypertension. Exposure of Wistar rats to 10% O2 for 3 weeks induced an increase in the mean serum levels of LPA, to 40.9 (log-detransformed standard deviations: 23.4-71.7) μM versus 21.6 (11.0-42.3) μM in a matched control animal group (P = 0.037). We also observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats colocalized with the secreted lysophospholipase D autotaxin (ATX). Moreover, ATX colocalized with mast cell tryptase, suggesting implication of these cells in perivascular LPA production. Hypoxic rat lungs expressed more ATX transcripts (2.4-fold) and more transcripts of proteins implicated in cell migration: β2 integrin (1.74-fold), intracellular adhesion molecule 1 (ICAM-1; 1.84-fold), and αM integrin (2.70-fold). Serum from the hypoxic group of animals had significantly higher chemoattractant properties toward rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonists. LPA also increased adhesive properties of human pulmonary artery endothelial cells as well as those of human peripheral blood mononuclear cells, via the activation of LPA receptor 1 or 3 followed by the stimulation of gene expression of ICAM-1, β-1, E-selectin, and vascular cell adhesion molecule integrins. In conclusion, chronic hypoxia increases circulating and tissue levels of LPA, which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature, both of which contribute to pulmonary vascular remodeling.
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Affiliation(s)
- Vadim Shlyonsky
- Department of Physiology, Université Libre de Bruxelles, Brussels, Belgium
| | - Robert Naeije
- Department of Physiology, Université Libre de Bruxelles, Brussels, Belgium
| | - Frédérique Mies
- Department of Physiology, Université Libre de Bruxelles, Brussels, Belgium
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22
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Kihara Y, Maceyka M, Spiegel S, Chun J. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol 2014; 171:3575-94. [PMID: 24602016 PMCID: PMC4128058 DOI: 10.1111/bph.12678] [Citation(s) in RCA: 253] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/27/2013] [Revised: 02/03/2014] [Accepted: 02/12/2014] [Indexed: 12/11/2022] Open
Abstract
Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7-transmembrane GPCRs, constituent members of which have continued to be identified after their initial discovery in the mid-1990s. Here we briefly review this class of receptors, with a particular emphasis on their protein and gene nomenclatures that reflect their cognate ligands. There are six lysophospholipid receptors that interact with lysophosphatidic acid (LPA): protein names LPA1 - LPA6 and italicized gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human). There are five sphingosine 1-phosphate (S1P) receptors: protein names S1P1 -S1P5 and italicized gene names S1PR1-S1PR5 (human) and S1pr1-S1pr5 (non-human). Recent additions to the lysophospholipid receptor family have resulted in the proposed names for a lysophosphatidyl inositol (LPI) receptor - protein name LPI1 and gene name LPIR1 (human) and Lpir1 (non-human) - and three lysophosphatidyl serine receptors - protein names LyPS1 , LyPS2 , LyPS3 and gene names LYPSR1-LYPSR3 (human) and Lypsr1-Lypsr3 (non-human) along with a variant form that does not appear to exist in humans that is provisionally named LyPS2L . This nomenclature incorporates previous recommendations from the International Union of Basic and Clinical Pharmacology, the Human Genome Organization, the Gene Nomenclature Committee, and the Mouse Genome Informatix.
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Affiliation(s)
- Yasuyuki Kihara
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research InstituteLa Jolla, CA, USA
| | - Michael Maceyka
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, School of Medicine, Virginia Commonwealth UniversityRichmond, VA, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology and the Massey Cancer Center, School of Medicine, Virginia Commonwealth UniversityRichmond, VA, USA
| | - Jerold Chun
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research InstituteLa Jolla, CA, USA
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23
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Hu J, Oda SK, Shotts K, Donovan EE, Strauch P, Pujanauski LM, Victorino F, Al-Shami A, Fujiwara Y, Tigyi G, Oravecz T, Pelanda R, Torres RM. Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response. THE JOURNAL OF IMMUNOLOGY 2014; 193:85-95. [PMID: 24890721 DOI: 10.4049/jimmunol.1300429] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
Lysophospholipids have emerged as biologically important chemoattractants capable of directing lymphocyte development, trafficking, and localization. Lysophosphatidic acid (LPA) is a major lysophospholipid found systemically, and its levels are elevated in certain pathological settings, such as cancer and infections. In this study, we demonstrate that BCR signal transduction by mature murine B cells is inhibited upon LPA engagement of the LPA5 (GPR92) receptor via a Gα12/13-Arhgef1 pathway. The inhibition of BCR signaling by LPA5 manifests by impaired intracellular calcium store release and most likely by interfering with inositol 1,4,5-triphosphate receptor activity. We further show that LPA5 also limits Ag-specific induction of CD69 and CD86 expression and that LPA5-deficient B cells display enhanced Ab responses. Thus, these data show that LPA5 negatively regulates BCR signaling, B cell activation, and immune response. Our findings extend the influence of lysophospholipids on immune function and suggest that alterations in LPA levels likely influence adaptive humoral immunity.
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Affiliation(s)
- Jiancheng Hu
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Shannon K Oda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Kristin Shotts
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Erin E Donovan
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Pamela Strauch
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Lindsey M Pujanauski
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Francisco Victorino
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Amin Al-Shami
- Lexicon Pharmaceuticals, Inc, The Woodlands, TX, 77381 USA.,Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Yuko Fujiwara
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Gabor Tigyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Tamas Oravecz
- Lexicon Pharmaceuticals, Inc, The Woodlands, TX, 77381 USA
| | - Roberta Pelanda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Raul M Torres
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
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24
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Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res 2014; 55:1192-214. [PMID: 24643338 DOI: 10.1194/jlr.r046458] [Citation(s) in RCA: 530] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/20/2013] [Indexed: 12/18/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1-6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets.
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Affiliation(s)
- Yun C Yung
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
| | - Nicole C Stoddard
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037 Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
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25
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Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions. FEBS Lett 2014; 588:2712-27. [PMID: 24560789 DOI: 10.1016/j.febslet.2014.02.009] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/15/2014] [Revised: 02/11/2014] [Accepted: 02/12/2014] [Indexed: 02/07/2023]
Abstract
Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.
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Park GY, Lee YG, Berdyshev E, Nyenhuis S, Du J, Fu P, Gorshkova IA, Li Y, Chung S, Karpurapu M, Deng J, Ranjan R, Xiao L, Jaffe HA, Corbridge SJ, Kelly EAB, Jarjour NN, Chun J, Prestwich GD, Kaffe E, Ninou I, Aidinis V, Morris AJ, Smyth SS, Ackerman SJ, Natarajan V, Christman JW. Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir Crit Care Med 2013; 188:928-40. [PMID: 24050723 DOI: 10.1164/rccm.201306-1014oc] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022] Open
Abstract
RATIONALE Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis. OBJECTIVES To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. METHODS We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. MEASUREMENTS AND MAIN RESULTS Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. CONCLUSIONS The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.
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Affiliation(s)
- Gye Young Park
- 1 Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Plasma proteome analysis reveals overlapping, yet distinct mechanisms of immune activation in chronic HCV and HIV infections. J Acquir Immune Defic Syndr 2013; 63:563-71. [PMID: 23507661 DOI: 10.1097/qai.0b013e3182909847] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND HIV infection contributes to accelerated rates of progression of liver fibrosis during hepatitis C virus (HCV) infection, and HCV liver disease contributes to mortality during HIV infection. Although mechanisms underlying these interactions are not well known, soluble and cellular markers of immune activation associate with disease progression during both infections. METHODS We identified proteins varying in expression across the plasma proteomes of subjects with untreated HIV infection, untreated HCV infection with low aspartate transaminase/platelet ratio index, untreated HCV infection with high aspartate transaminase/platelet ratio index, HIV-HCV coinfection, and controls. We examined correlations between dysregulated proteins and markers of immune activation to uncover biomarkers specific to disease states. RESULTS We observed the anticipated higher frequencies of HLA-DRCD38CD4 and CD8 T cells, higher serum soluble CD14 levels, and higher serum interleukin-6 levels for HCV- and HIV-infected groups compared with controls. Plasma proteome analysis identified 2297 peptides mapping to 227 proteins, and quantitative analysis of peptide intensity identified significant changes in 85 proteins across the 5 groups. Abundance for 7 of these proteins was validated by enzyme-linked immunosorbent assay. Forty-three of these proteins correlated with markers of immune activation, including at least 2 proteins that may directly drive T-cell activation. As a functional validation, we tested the enzymatic pathway product (lysophosphatidic acid, LPA) of one such protein, ecotonucleotide pyrophosphatase/phosphodiesterase-2, for ability to activate T cells in vitro. LPA activated T cells to express CD38 and HLA-DR. CONCLUSIONS These data indicate that elevated levels of ecotonucleotide pyrophosphatase/phosphodiesterase-2 and LPA during advanced HCV disease may play a role in exacerbating immune activation during HCV-HIV coinfection.
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Abstract
Lysophosphatidic acid (LPA) is a class of bioactive phospholipid that displays a wide range of cellular effects via LPA receptors, of which six have been identified (LPAR1–6). In serum and plasma, LPA production occurs mainly by the hydrolysis of lysophosphatidylcholine by the phospholipase D activity of autotaxin (ATX). The involvement of the LPA pathway in driving chronic wound-healing conditions, such as idiopathic pulmonary fibrosis, has suggested targets in this pathway could provide potential therapeutic approaches. Mice with LPAR1 knockout or tissue-specific ATX deletion have demonstrated reduced lung fibrosis following bleomycin challenge. Therefore, strategies aimed at antagonizing LPA receptors or inhibiting ATX have gained considerable attention. This Review will summarize the current status of identifying small-molecule modulators of the LPA pathway. The therapeutic utility of LPA modulators for the treatment of fibrotic diseases will soon be revealed as clinical trials are already in progress in this area.
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Lysoglycerophospholipids in chronic inflammatory disorders: The PLA2/LPC and ATX/LPA axes. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:42-60. [DOI: 10.1016/j.bbalip.2012.07.019] [Citation(s) in RCA: 172] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/18/2012] [Revised: 07/20/2012] [Accepted: 07/24/2012] [Indexed: 02/08/2023]
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Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 2012; 47:566-74. [PMID: 22744859 DOI: 10.1165/rcmb.2012-0004oc] [Citation(s) in RCA: 196] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/21/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults. Increased lysophosphatidic acid (LPA) concentrations have been reported in the alveolar space of both idiopathic pulmonary fibrosis patients and a corresponding animal model, whereas the genetic deletion or pharmacological inhibition of LPA receptor 1 attenuated the development of the modeled disease, suggesting a direct involvement of LPA in disease pathogenesis. In this report, increased concentrations of autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular LPA production, were detected in both murine and human fibrotic lungs. The genetic deletion of ATX from bronchial epithelial cells or macrophages attenuated disease severity, establishing ATX as a novel player in IPF pathogenesis. Furthermore, the pharmacological inhibition of ATX attenuated the development of the modeled disease, suggesting that ATX is a possible therapeutic target in IPF.
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Affiliation(s)
- Nikos Oikonomou
- Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Athens, Greece
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Emo J, Meednu N, Chapman TJ, Rezaee F, Balys M, Randall T, Rangasamy T, Georas SN. Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation. THE JOURNAL OF IMMUNOLOGY 2012; 188:3784-90. [PMID: 22427635 DOI: 10.4049/jimmunol.1102956] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2(-/-) mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF-κB-driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2(-/-) DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2(-/-) mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation.
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Affiliation(s)
- Jason Emo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14610, USA
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Singla A, Kumar A, Priyamvada S, Tahniyath M, Saksena S, Gill RK, Alrefai WA, Dudeja PK. LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway. Am J Physiol Gastrointest Liver Physiol 2012; 302:G618-27. [PMID: 22159277 PMCID: PMC3311307 DOI: 10.1152/ajpgi.00172.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
DRA (downregulated in adenoma) or SLC26A3 is the major apical anion exchanger mediating Cl(-) absorption in intestinal epithelial cells. Disturbances in DRA function and expression have been implicated in diarrheal conditions such as congenital chloride diarrhea and inflammatory bowel diseases. Previous studies have shown that DRA is subject to regulation by short-term and transcriptional mechanisms. In this regard, we have recently shown that short-term treatment by lysophosphatidic acid (LPA), an important bioactive phospholipid, stimulates Cl(-)/HCO(3)(-)(OH(-)) exchange activity via an increase in DRA surface levels in human intestinal epithelial cells. However, the long-term effects of LPA on DRA at the level of gene transcription have not been examined. The present studies were aimed at investigating the effects of LPA on DRA function and expression as well as elucidating the mechanisms underlying its transcriptional regulation. Long-term LPA treatment increased the Cl(-)/HCO(3)(-) exchange activity in Caco-2 cells. LPA treatment (50-100 μM) of Caco-2 cells significantly stimulated DRA mRNA levels and DRA promoter activity (-1183/+114). This increase in DRA promoter activity involved the LPA2 receptor and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. Progressive deletions from -1183/+114 to -790/+114 abrogated the stimulatory effects of LPA, indicating that the -1183/-790 promoter region harbors LPA response elements. Utilizing EMSA and mutational studies, our results showed that LPA induced the DRA promoter activity in a c-Fos-dependent manner. LPA also increased the protein expression of c-Fos and c-Jun in Caco-2 cells. Furthermore, overexpression of c-Fos but not c-Jun enhanced the DRA promoter activity. This increase in DRA transcription in response to LPA indicates that LPA may act as an antidiarrheal agent and could be exploited for the treatment of diarrhea associated with inflammatory or infectious diseases of the gut.
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Affiliation(s)
- Amika Singla
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and ,2Department of Physiology and Biophysics, University of Illinois at Chicago and
| | - Anoop Kumar
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and
| | | | - Maliha Tahniyath
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and
| | - Seema Saksena
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and
| | - Ravinder K. Gill
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and
| | - Waddah A. Alrefai
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and ,3Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Pradeep K. Dudeja
- 1Section of Digestive Diseases and Nutrition, Dept. of Medicine and ,3Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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Blaho VA, Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev 2011; 111:6299-320. [PMID: 21939239 PMCID: PMC3216694 DOI: 10.1021/cr200273u] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Affiliation(s)
- Victoria A. Blaho
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
| | - Timothy Hla
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
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35
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Abstract
Lysophosphatidic acid (LPA) has been found to accumulate in high concentrations in atherosclerotic lesions. LPA is a bioactive phospholipid produced by activated platelets and formed during the oxidation of LDL. Accumulating evidence suggests that this lipid mediator may serve as an important risk factor for development of atherosclerosis and thrombosis. The role of LPA in atherogenesis is supported by the evidence that LPA: stimulates endothelial cells to produce adhesion molecules and chemoattractants; induces smooth muscle cells to produce inflammatory cytokines; stimulates smooth muscle cell dedifferentiation, proliferation, and migration; increases monocyte migration and decreases monocyte-derived cell emigration from the vessel wall; induces hypertension and vascular neointimal formation in vivo; and promotes plaque progression in a mouse atherosclerosis model. The role of LPA in thrombogenesis is supported by the evidence that LPA markedly induces the aggregation of platelets and the expression of tissue factor, which is the principal initiator of blood coagulation. Recent experimental data indicate that LPA is produced by specific enzymes and that LPA binds to and activates multiple G-protein-coupled receptors, leading to intracellular signaling. Therapeutics targeting LPA biosynthesis, metabolism and signaling pathways could be viable for prevention and treatment of atherosclerosis and thrombosis.
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Affiliation(s)
- Mei-Zhen Cui
- Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA
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36
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Berdichevets IN, Tyazhelova TV, Shimshilashvili KR, Rogaev EI. Lysophosphatidic acid is a lipid mediator with wide range of biological activities. Biosynthetic pathways and mechanism of action. BIOCHEMISTRY (MOSCOW) 2011; 75:1088-97. [PMID: 21077828 DOI: 10.1134/s0006297910090026] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/29/2022]
Abstract
Lysophosphatidic acid (LPA) is a lipid mediator required for maintaining homeostasis of numerous physiological functions and also involved in development of some pathological processes through interactions with G protein-coupled receptors. Recently many data have appeared about the role of this phospholipid in humans, but pathways of LPA biosynthesis and mechanisms of its action remain unclear. This review presents modern concepts about biosynthesis, reception, and biological activity of LPA in humans. Natural and synthetic LPA analogs are considered in the view of their possible use in pharmacology as agonists and/or antagonists of G protein-coupled receptors of LPA.
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Affiliation(s)
- I N Berdichevets
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119991, Russia.
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Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev 2010; 62:579-87. [PMID: 21079037 PMCID: PMC2993255 DOI: 10.1124/pr.110.003111] [Citation(s) in RCA: 246] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/25/2022] Open
Abstract
Lysophospholipids are cell membrane-derived lipids that include both glycerophospholipids such as lysophosphatidic acid (LPA) and sphingoid lipids such as sphingosine 1-phosphate (S1P). These and related molecules can function in vertebrates as extracellular signals by binding and activating G protein-coupled receptors. There are currently five LPA receptors, along with a proposed sixth (LPA₁-LPA₆), and five S1P receptors (S1P₁-S1P₅). A remarkably diverse biology and pathophysiology has emerged since the last review, driven by cloned receptors and targeted gene deletion ("knockout") studies in mice, which implicate receptor-mediated lysophospholipid signaling in most organ systems and multiple disease processes. The entry of various lysophospholipid receptor modulatory compounds into humans through clinical trials is ongoing and may lead to new medicines that are based on this signaling system. This review incorporates IUPHAR Nomenclature Committee guidelines in updating the nomenclature for lysophospholipid receptors ( http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=36).
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Affiliation(s)
- Jerold Chun
- Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
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38
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Abstract
Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons.
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Affiliation(s)
- Gabor Tigyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
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Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN, Chun J. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 2010; 50:157-86. [PMID: 20055701 DOI: 10.1146/annurev.pharmtox.010909.105753] [Citation(s) in RCA: 649] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein-coupled receptors (GPCRs): LPA(1)-LPA(5). They are encoded by distinct genes named LPAR1-LPAR5 in humans and Lpar1-Lpar5 in mice. The biological roles of LPA are diverse and include developmental, physiological, and pathophysiological effects. This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by cognate LPA receptors. Studies using cloned receptors and genetic knockout mice have been instrumental in uncovering the significance of this signaling system, notably involving basic cellular processes as well as multiple organ systems such as the nervous system. This has further provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.
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Affiliation(s)
- Ji Woong Choi
- Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037, USA
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He D, Su Y, Usatyuk PV, Spannhake EW, Kogut P, Solway J, Natarajan V, Zhao Y. Lysophosphatidic acid enhances pulmonary epithelial barrier integrity and protects endotoxin-induced epithelial barrier disruption and lung injury. J Biol Chem 2009; 284:24123-32. [PMID: 19586906 DOI: 10.1074/jbc.m109.007393] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022] Open
Abstract
Lysophosphatidic acid (LPA), a bioactive phospholipid, induces a wide range of cellular effects, including gene expression, cytoskeletal rearrangement, and cell survival. We have previously shown that LPA stimulates secretion of pro- and anti-inflammatory cytokines in bronchial epithelial cells. This study provides evidence that LPA enhances pulmonary epithelial barrier integrity through protein kinase C (PKC) delta- and zeta-mediated E-cadherin accumulation at cell-cell junctions. Treatment of human bronchial epithelial cells (HBEpCs) with LPA increased transepithelial electrical resistance (TER) by approximately 2.0-fold and enhanced accumulation of E-cadherin to the cell-cell junctions through Galpha(i)-coupled LPA receptors. Knockdown of E-cadherin with E-cadherin small interfering RNA or pretreatment with EGTA (0.1 mm) prior to LPA (1 microm) treatment attenuated LPA-induced increases in TER in HBEpCs. Furthermore, LPA induced tyrosine phosphorylation of focal adhesion kinase (FAK) and overexpression of the FAK inhibitor, and FAK-related non-kinase-attenuated LPA induced increases in TER and E-cadherin accumulation at cell-cell junctions. Overexpression of dominant negative protein kinase delta and zeta attenuated LPA-induced phosphorylation of FAK, accumulation of E-cadherin at cell-cell junctions, and an increase in TER. Additionally, lipopolysaccharide decreased TER and induced E-cadherin relocalization from cell-cell junctions to cytoplasm in a dose-dependent fashion, which was restored by LPA post-treatment in HBEpCs. Intratracheal post-treatment with LPA (5 microm) reduced LPS-induced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage fluids in a murine model of acute lung injury. These data suggest a protective role of LPA in airway inflammation and remodeling.
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Affiliation(s)
- Donghong He
- Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
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41
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Zhao Y, Natarajan V. Lysophosphatidic acid signaling in airway epithelium: role in airway inflammation and remodeling. Cell Signal 2009; 21:367-77. [PMID: 18996473 PMCID: PMC2660380 DOI: 10.1016/j.cellsig.2008.10.010] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2008] [Revised: 09/27/2008] [Accepted: 10/21/2008] [Indexed: 02/07/2023]
Abstract
Lysophosphatidic acid (LPA), a potent bioactive phospholipid, induces diverse cellular responses, including cell proliferation, migration, and cytokine release. LPA can be generated intracellularly and extracellularly through multiple synthetic pathways by action of various enzymes, such as phospholipase A(1/2) (PLA(1/2)), phospholipase D (PLD), acylglycerol kinase (AGK), and lysophospholipase D (lysoPLD). Metabolism of LPA is regulated by a family of lipid phosphate phosphatases (LPPs). Significant amounts of LPA have been detected in various biological fluids, including serum, saliva, and bronchoalveolar lavage fluid (BALF). The most significant effects of LPA appear to be through activation of the G-protein-coupled receptors (GPCRs), termed LPA(1-6). LPA regulates gene expression through activation of several transcriptional factors, such as nuclear factor-kappaB (NF-kappaB), AP-1, and C/EBPbeta. In addition to GPCRs, cross-talk between LPA receptors and receptor tyrosine kinases (RTKs) partly regulates LPA-induced intracellular signaling and cellular responses. Airway epithelial cells participate in innate immunity through the release of cytokines, chemokines, lipid mediators, other inflammatory mediators and an increase in barrier function in response to a variety of inhaled stimuli. Expression of LPA receptors has been demonstrated in airway epithelial cells. This review summarizes our recent observations of the role of LPA/LPA-Rs in regulation of airway epithelium, especially in relation to the secretion of pro- and anti-inflammatory mediators and regulation of airway barrier function.
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Affiliation(s)
- Yutong Zhao
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
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42
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Abstract
Lysophosphatidic acid (LPA) can affect the growth, migration, and activation of many different cell types. Research in this field has recently accelerated due to the molecular cloning of LPA receptors as well as advances in our understanding of LPA metabolism. A major pathway for LPA generation is the hydrolysis of lysophosphatidylcholine by the enzyme autotaxin (ATX). Although most research to-date has been conducted in other disciplines (e.g., neurobiology and cardiovascular diseases), emerging data point to an important role for LPA and ATX in regulating immune responses. Here we review current understanding of LPA and ATX in immunity with an emphasis on migration and activation of lymphocytes and dendritic cells. New gene-targeted and transgenic mice, receptor-specific antibodies, and pathway antagonists should rapidly enhance our understanding of this versatile lysolipid in immune responses in the near future.
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Affiliation(s)
- Steve N Georas
- Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, NY 14610, USA.
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Medoff BD, Landry AL, Wittbold KA, Sandall BP, Derby MC, Cao Z, Adams JC, Xavier RJ. CARMA3 mediates lysophosphatidic acid-stimulated cytokine secretion by bronchial epithelial cells. Am J Respir Cell Mol Biol 2008; 40:286-94. [PMID: 18757306 DOI: 10.1165/rcmb.2008-0129oc] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023] Open
Abstract
NF-kappaB activation in bronchial epithelial cells is important for the development of allergic airway inflammation, and may control the expression of critical mediators of allergic inflammation such as thymic stromal lymphopoietin (TSLP) and the chemokine CCL20. Members of the caspase recruitment domain (CARD) family of proteins are differentially expressed in tissue and help mediate NF-kappaB activity in response to numerous stimuli. Here we demonstrate that CARMA3 (CARD10) is specifically expressed in human airway epithelial cells, and that expression of CARMA3 in these cells leads to activation of NF-kappaB. CARMA3 has recently been shown to mediate NF-kappaB activation in embryonic fibroblasts after stimulation with lysophosphatidic acid (LPA), a bioactive lipid-mediator that is elevated in the lungs of individuals with asthma. Consistent with this, we demonstrate that stimulation of airway epithelial cells with LPA leads to increased expression of TSLP and CCL20. We then show that inhibition of CARMA3 activity in airway epithelial cells reduces LPA-mediated NF-kappaB activity and the production of TSLP and CCL20. In conclusion, these data demonstrate that LPA stimulates TSLP and CCL20 expression in bronchial epithelial cells via CARMA3-mediated NF-kappaB activation.
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Affiliation(s)
- Benjamin D Medoff
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Simches Research Building, Room 7222, 185 Cambridge Street, Boston, MA 02114, USA.
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Georas SN, Berdyshev E, Hubbard W, Gorshkova IA, Usatyuk PV, Saatian B, Myers AC, Williams MA, Xiao HQ, Liu M, Natarajan V. Lysophosphatidic acid is detectable in human bronchoalveolar lavage fluids at baseline and increased after segmental allergen challenge. Clin Exp Allergy 2007; 37:311-22. [PMID: 17359381 DOI: 10.1111/j.1365-2222.2006.02626.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Lysophosphatidic acid (LPA) is a biologically active lysophospholipid and a component of normal plasma. LPA binds to receptors expressed on circulating and structural lung cells and affects cell growth and activation. Whether LPA is present in the lung has not been previously reported. OBJECTIVE To develop an assay to measure LPA in bronchoalveolar lavage (BAL) fluids, and to study the association between LPA and allergic airway inflammation. METHODS Seventeen allergic subjects underwent bronchoscopy and segmental allergen challenge, followed 18 h later by BAL. Supernatants were analysed for LPA content using liquid chromatography and mass spectroscopy. Expression of LPA receptors on primary bronchial epithelial cells was analysed by immunolabelling, and the effects of LPA on epithelial cell barrier function was investigated by measuring transepithelial resistance. RESULTS LPA was detectable in BAL from control lung segments, and significantly increased 18 h after allergen challenge. Polyunsaturated species of LPA were especially increased following segmental allergen challenge. LPA levels did not strongly correlate with the number or percentages of eosinophils, neutrophils of lymphocytes, whereas MIP-3alpha (CCL20) levels correlated significantly with the allergen-driven influx of lymphocytes. The levels of LPA from control sites correlated inversely with BAL protein content, suggesting that LPA promoted epithelial barrier integrity at baseline. Experiments using primary human bronchial epithelial cells confirmed that LPA tightened the epithelial cell barrier. CONCLUSION Lysophosphatidic acid is detectable in human BAL fluids at baseline and its expression increases during allergic inflammation. LPA does not appear to be a dominant chemoattractant for eosinophils or lymphocytes during allergic airway inflammation. In the absence of ongoing inflammation, LPA may promote epithelial barrier integrity.
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Affiliation(s)
- S N Georas
- Division of Pulmonary & Critical Care Medicine, The Johns Hopkins Asthma & Allergy Center, Baltimore, MD, USA.
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Chen R, Roman J, Guo J, West E, McDyer J, Williams MA, Georas SN. Lysophosphatidic acid modulates the activation of human monocyte-derived dendritic cells. Stem Cells Dev 2007; 15:797-804. [PMID: 17253943 DOI: 10.1089/scd.2006.15.797] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a biologically active lysophospholipid that can regulate immune activation. LPA can activate T cells and dendritic cells (DCs), but the effects of LPA on the ability of DCs to influence T cell polarization are not well understood. Human monocyte-derived DCs were differentiated in vitro in the presence of interleukin-4 (IL-4) and granulocyte-macrophage colonystimulating factor (GM-CSF), and matured with LPA and lipopolysaccharide (LPS) alone or in combination. DC activation was monitored by analyzing cell-surface expression of co-stimulatory receptors and cytokine production. The ability of DCs to influence T cell activation was determined using two models of DC:T cell co-culture. Maturation with LPS induced dose-dependent DC activation characterized by enhanced expression of co-stimulatory molecules (e.g., CD86) and production of cytokines including IL-6 and IL-10. Co-incubation with LPA attenuated the LPS-induced production of IL-6, without significantly affecting IL-10 secretion or the ability of DC to promote T cell proliferation. DCs matured in the presence of both LPA and LPS enhanced the production of interferon-gamma (IFN-gamma) when co-cultured with allogeneic T cells, compared with DC matured by LPS alone. Similar results were found using a model of allogeneic naïve T cell differentiation, where LPA- plus LPS-matured DC enhanced IFN-gamma as well as IL-4 secretion after restimulation. Lysophosphatidic acid fine-tunes the effects of LPS on human myeloid DC maturation, but does not exert a dominant effect on the ability of DC to influence Th cell polarization.
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Affiliation(s)
- Rongbing Chen
- Division of Pulmonary & Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21212, USA
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Zhao Y, He D, Zhao J, Wang L, Leff AR, Spannhake EW, Georas S, Natarajan V. Lysophosphatidic acid induces interleukin-13 (IL-13) receptor alpha2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells. J Biol Chem 2007; 282:10172-9. [PMID: 17287216 PMCID: PMC2659592 DOI: 10.1074/jbc.m611210200] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023] Open
Abstract
Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor alpha1 (IL-13Ralpha1) and IL-4 receptor alpha (IL-4Ralpha). Recent studies show that a decoy receptor for IL-13, namely IL-13Ralpha2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13Ralpha2 production and release and IL-13-dependent signaling by lysophosphatidic acid (LPA) in primary cultures of human bronchial epithelial cells (HBEpCs). LPA treatment of HBEpCs in at imedependent fashion increased IL-13Ralpha2 gene expression without altering the mRNA levels of IL-13Ralpha1 and IL-4Ralpha. Pretreatment with pertussis toxin (100 ng/ml, 4 h) or transfection of c-Jun small interference RNA or an inhibitor of JNK attenuated LPA-induced IL-13Ralpha2 gene expression and secretion of soluble IL-13Ralpha2. Overexpression of catalytically inactive mutants of phospholipase D (PLD) 1 or 2 attenuated LPA-induced IL-13Ralpha2 gene expression and protein secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 microM LPA for 6 h attenuated IL-13-but not IL-4-induced phosphorylation of STAT6. Transfection of HBEpCs with IL-13Ralpha2 small interference RNA blocked the effect of LPA on IL-13-induced phosphorylation of STAT6. Furthermore, pretreatment with LPA (1 microM, 6 h) attenuated IL-13-induced eotaxin-1 and SOCS-1 gene expression. These results demonstrate that LPA induces IL-13Ralpha2 expression and release via PLD and JNK/AP-1 signal transduction and that pretreatment with LPA down-regulates IL-13 signaling in HBEpCs. Our data suggest a novel mechanism of regulation of IL-13Ralpha2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.
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Affiliation(s)
- Yutong Zhao
- Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
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Abstract
Neuroinflammation is a host defense mechanism associated with neutralization of an insult and restoration of normal structure and function of brain. Neuroinflammation is a hallmark of all major CNS diseases. The main mediators of neuroinflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidation of AA produces pro-inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso-glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro-inflammatory platelet-activating factor. These pro-inflammatory mediators intensify neuroinflammation. Lipoxin, an oxidized product of AA through 5-lipoxygenase, is involved in the resolution of inflammation and is anti-inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuroinflammation by inhibiting transcription factor NFkappaB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators.
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Affiliation(s)
- Akhlaq A Farooqui
- Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA
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