1
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George A, Mariya A, Eappen M, Karthikeyan M, Sreenath R. Serum autotaxin level: a promising diagnostic biomarker in differentiating Graves' disease and thyroiditis. J Pharm Pharmacol 2025; 77:56-63. [PMID: 39027928 DOI: 10.1093/jpp/rgae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/19/2023] [Accepted: 07/06/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Recent studies have suggested that serum autotaxin (ATX) may be a promising diagnostic biomarker in differentiating between Graves' disease (GD) and thyroiditis, as well as serving as a monitoring biomarker for GD. This study will evaluate the use of serum ATX as a diagnostic biomarker in these conditions. METHODS In this prospective interventional study, blood samples were collected from the patients who met both inclusion and exclusion criteria, and serum ATX levels were measured by using the MyBioSource human Autotaxin ELISA kit. RESULTS A total of 32 patients were enrolled, of which 18.8% were newly diagnosed with GD, 21.9% were thyroiditis, and 59.3% were on treatment for GD. Serum autotaxin antigen was significantly higher in GD patients than in thyroiditis (603.3217 ± 444.24 v/s 214.74 ± 55.91, P = <.005). Serum ATX measurement successfully discriminated GD patients from thyroiditis (AUC = 0.952, 95%CI: 0.00-1.00) with an optimal cutoff value of ≥257.20 ng/L (sensitivity = 100 and specificity = 81.71). Monitoring the efficacy of serum ATX was analyzed and showed a significant difference. CONCLUSION The serum ATX was higher in subjects with GD as compared to thyroiditis, and ATX levels were found to be decreased during the treatment period. In conclusion, serum ATX can be used as a diagnostic and monitoring biomarker in GD.
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Affiliation(s)
- Angel George
- Department of Pharmacy Practice, Nirmala College of Pharmacy, Muvattupuzha, Ernakulam, Kerala 686661, India
| | - Anns Mariya
- Department of Pharmacy Practice, Nirmala College of Pharmacy, Muvattupuzha, Ernakulam, Kerala 686661, India
| | - Manu Eappen
- Department of Pharmacy Practice, Nirmala College of Pharmacy, Muvattupuzha, Ernakulam, Kerala 686661, India
| | - Marimuthu Karthikeyan
- Department of Pharmacology, Grace College of Pharmacy, Palakkad, Kerala 678004, India
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2
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Laketa D, Lavrnja I. Extracellular Purine Metabolism-Potential Target in Multiple Sclerosis. Mol Neurobiol 2024; 61:8361-8386. [PMID: 38499905 DOI: 10.1007/s12035-024-04104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/26/2023] [Accepted: 03/07/2024] [Indexed: 03/20/2024]
Abstract
The purinergic signaling system comprises a complex network of extracellular purines and purine-metabolizing ectoenzymes, nucleotide and nucleoside receptors, ATP release channels, and nucleoside transporters. Because of its immunomodulatory function, this system is critically involved in the pathogenesis of multiple sclerosis (MS) and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). MS is a chronic neuroinflammatory demyelinating and neurodegenerative disease with autoimmune etiology and great heterogeneity, mostly affecting young adults and leading to permanent disability. In MS/EAE, alterations were detected in almost all components of the purinergic signaling system in both peripheral immune cells and central nervous system (CNS) glial cells, which play an important role in the pathogenesis of the disease. A decrease in extracellular ATP levels and an increase in its downstream metabolites, particularly adenosine and inosine, were frequently observed at MS, indicating a shift in metabolism toward an anti-inflammatory environment. Accordingly, upregulation of the major ectonucleotidase tandem CD39/CD73 was detected in the blood cells and CNS of relapsing-remitting MS patients. Based on the postulated role of A2A receptors in the transition from acute to chronic neuroinflammation, the association of variants of the adenosine deaminase gene with the severity of MS, and the beneficial effects of inosine treatment in EAE, the adenosinergic system emerged as a promising target in neuroinflammation. More recently, several publications have identified ADP-dependent P2Y12 receptors and the major extracellular ADP producing enzyme nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) as novel potential targets in MS.
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Affiliation(s)
- Danijela Laketa
- Department of General Physiology and Biophysics, Institute for Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Studentski Trg 3, Belgrade, Republic of Serbia.
| | - Irena Lavrnja
- Institute for Biological Research, Sinisa Stankovic" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, Republic of Serbia
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3
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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4
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Laface C, Ricci AD, Vallarelli S, Ostuni C, Rizzo A, Ambrogio F, Centonze M, Schirizzi A, De Leonardis G, D’Alessandro R, Lotesoriere C, Giannelli G. Autotaxin-Lysophosphatidate Axis: Promoter of Cancer Development and Possible Therapeutic Implications. Int J Mol Sci 2024; 25:7737. [PMID: 39062979 PMCID: PMC11277072 DOI: 10.3390/ijms25147737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/30/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Simona Vallarelli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Carmela Ostuni
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Francesca Ambrogio
- Section of Dermatology and Venereology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Giampiero De Leonardis
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
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Karalis T, Poulogiannis G. The Emerging Role of LPA as an Oncometabolite. Cells 2024; 13:629. [PMID: 38607068 PMCID: PMC11011573 DOI: 10.3390/cells13070629] [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: 02/15/2024] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024] Open
Abstract
Lysophosphatidic acid (LPA) is a phospholipid that displays potent signalling activities that are regulated in both an autocrine and paracrine manner. It can be found both extra- and intracellularly, where it interacts with different receptors to activate signalling pathways that regulate a plethora of cellular processes, including mitosis, proliferation and migration. LPA metabolism is complex, and its biosynthesis and catabolism are under tight control to ensure proper LPA levels in the body. In cancer patient specimens, LPA levels are frequently higher compared to those of healthy individuals and often correlate with poor responses and more aggressive disease. Accordingly, LPA, through promoting cancer cell migration and invasion, enhances the metastasis and dissemination of tumour cells. In this review, we summarise the role of LPA in the regulation of critical aspects of tumour biology and further discuss the available pre-clinical and clinical evidence regarding the feasibility and efficacy of targeting LPA metabolism for effective anticancer therapy.
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Affiliation(s)
| | - George Poulogiannis
- Signalling and Cancer Metabolism Laboratory, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;
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6
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Petersen-Cherubini CL, Murphy SP, Xin M, Liu Y, Deffenbaugh JL, Jahan I, Rau CN, Yang Y, Lovett-Racke AE. Autotaxin in encephalitogenic CD4 T cells as a therapeutic target for multiple sclerosis. Eur J Immunol 2024; 54:e2350561. [PMID: 37850588 PMCID: PMC10843518 DOI: 10.1002/eji.202350561] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/19/2023]
Abstract
Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the CNS. A defining characteristic of MS is the ability of autoreactive T lymphocytes to cross the blood-brain barrier and mediate inflammation within the CNS. Previous work from our lab found the gene Enpp2 to be highly upregulated in murine encephalitogenic T cells. Enpp2 encodes for the protein autotaxin, a secreted glycoprotein that catalyzes the production of lysophosphatidic acid and promotes transendothelial migration of T cells from the bloodstream into the lymphatic system. The present study sought to characterize autotaxin expression in T cells during CNS autoimmune disease and determine its potential therapeutic value. Myelin-activated CD4 T cells upregulated expression of autotaxin in vitro, and ex vivo analysis of CNS-infiltrating CD4 T cells showed significantly higher autotaxin expression compared with cells from healthy mice. In addition, inhibiting autotaxin in myelin-specific T cells reduced their encephalitogenicity in adoptive transfer studies and decreased in vitro cell motility. Importantly, using two mouse models of MS, treatment with an autotaxin inhibitor ameliorated EAE severity, decreased the number of CNS infiltrating T and B cells, and suppressed relapses, suggesting autotaxin may be a promising therapeutic target in the treatment of MS.
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Affiliation(s)
- Cora L. Petersen-Cherubini
- The Ohio State University – Neuroscience Graduate Program
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Shawn P. Murphy
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Matthew Xin
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Yue Liu
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Joshua L. Deffenbaugh
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Ishrat Jahan
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Christina N. Rau
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
| | - Yuhong Yang
- The Ohio State University – Wexner Medical Center – Department of Neurology
| | - Amy E. Lovett-Racke
- The Ohio State University – Wexner Medical Center – Department of Microbial Infection and Immunity
- The Ohio State University – Wexner Medical Center – Department of Neuroscience
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7
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Başpınar A, Özkan D, Tokgöz S, Özkardeş AB, Kaya İO. Diagnostic value of serum autotaxin level in colorectal cancer. Biomark Med 2023; 17:787-798. [PMID: 38095984 DOI: 10.2217/bmm-2023-0496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/18/2024] Open
Abstract
Background: Autotaxin (ATX) is a nucleotide enzyme linked to cell growth, differentiation and migration. This study investigated serum levels of ATX in colorectal cancer (CRC). Methods: The study involved stage I-III CRC diagnosed between December 2020 and 2021, excluding those with neoadjuvant or adjuvant therapy, or metastasis. Healthy volunteers were controls. Serum ATX levels were measured by ELISA and compared. Results: This study included 129 patients (91 in the patient group and 38 in the control group). The optimal cutoff value of ATX for CRC was 169.98 ng/ml, and sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 91.2% (95% CI: 89.4-96.2), 78.9% (95% CI: 62.7-90.4), 4.33 and 0.11, respectively. Conclusion: The serum ATX level is a useful biomarker for CRC.
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Affiliation(s)
- Abdurrahman Başpınar
- Department of General Surgery, Ankara Training and Research Hospital, University of Health Science, Ankara, 06230, Turkey
| | - Didem Özkan
- Department of Microbiology, Etlik City Hospital, University of Health Science, Ankara, 06170, Turkey
| | - Serhat Tokgöz
- Department of General Surgery, Etlik City Hospital, University of Health Science, Ankara, 06170, Turkey
| | - Alper Bilal Özkardeş
- Department of General Surgery, Ankara Hospital, Lokman Hekim University, Ankara, 06510, Turkey
| | - İsmail Oskay Kaya
- Department of General Surgery, Etlik City Hospital, University of Health Science, Ankara, 06170, Turkey
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8
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Torres RM, Turner JA, D’Antonio M, Pelanda R, Kremer KN. Regulation of CD8 T-cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid. Immunol Rev 2023; 317:203-222. [PMID: 37096808 PMCID: PMC10523933 DOI: 10.1111/imr.13208] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/26/2023] [Revised: 04/07/2023] [Accepted: 04/08/2023] [Indexed: 04/26/2023]
Abstract
Lysophosphatidic acid (LPA) is an endogenous bioactive lipid that is produced extracellularly and signals to cells via cognate LPA receptors, which are G-protein coupled receptors (GPCRs). Mature lymphocytes in mice and humans express three LPA receptors, LPA2 , LPA5, and LPA6 , and work from our group has determined that LPA5 signaling by T lymphocytes inhibits specific antigen-receptor signaling pathways that ultimately impair lymphocyte activation, proliferation, and function. In this review, we discuss previous and ongoing work characterizing the ability of an LPA-LPA5 axis to serve as a peripheral immunological tolerance mechanism that restrains adaptive immunity but is subverted during settings of chronic inflammation. Specifically, LPA-LPA5 signaling is found to regulate effector cytotoxic CD8 T cells by (at least) two mechanisms: (i) regulating the actin-microtubule cytoskeleton in a manner that impairs immunological synapse formation between an effector CD8 T cell and antigen-specific target cell, thus directly impairing cytotoxic activity, and (ii) shifting T-cell metabolism to depend on fatty-acid oxidation for mitochondrial respiration and reducing metabolic efficiency. The in vivo outcome of LPA5 inhibitory activity impairs CD8 T-cell killing and tumor immunity in mouse models providing impetus to consider LPA5 antagonism for the treatment of malignancies and chronic infections.
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Affiliation(s)
- Raul M. Torres
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora Colorado, 80045
| | - Jacqueline A. Turner
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora Colorado, 80045
| | - Marc D’Antonio
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora Colorado, 80045
| | - Roberta Pelanda
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora Colorado, 80045
| | - Kimberly N. Kremer
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora Colorado, 80045
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9
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Yaginuma S, Omi J, Uwamizu A, Aoki J. Emerging roles of lysophosphatidylserine as an immune modulator. Immunol Rev 2023; 317:20-29. [PMID: 37036835 DOI: 10.1111/imr.13204] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/14/2023] [Revised: 03/07/2023] [Accepted: 03/18/2023] [Indexed: 04/11/2023]
Abstract
In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed that lysophospholipids (LPL) derived from membrane glycerophospholipids are such environmental factors. They are produced by the action of various phospholipases and modulate immune responses positively or negatively via G-protein-coupled receptor-type receptors. These include lysophosphatidic acid, lysophosphatidylserine (LysoPS), and lysophosphatidylinositol. Here, we summarize what is known about the synthetic pathways, receptors, and immunomodulatory functions of these LPLs. Particular focus is given to LysoPS, which have recently been identified, and recent findings on their immunomodulatory actions are presented.
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Affiliation(s)
- Shun Yaginuma
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Jumpei Omi
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Akiharu Uwamizu
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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10
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Wang Q, Yesitayi G, Liu B, Siti D, Ainiwan M, Aizitiaili A, Ma X. Targeting metabolism in aortic aneurysm and dissection: from basic research to clinical applications. Int J Biol Sci 2023; 19:3869-3891. [PMID: 37564200 PMCID: PMC10411465 DOI: 10.7150/ijbs.85467] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/20/2023] [Accepted: 07/17/2023] [Indexed: 08/12/2023] Open
Abstract
Aortic aneurysm and dissection (AAD) are a group of insidious and lethal cardiovascular diseases that characterized by seriously threatening the life and health of people, but lack effective nonsurgical interventions. Alterations in metabolites are increasingly recognized as universal features of AAD because metabolic abnormalities have been identified not only in arterial tissue but also in blood and vascular cells from both patients and animal models with this disease. Over the past few decades, studies have further supported this notion by linking AAD to various types of metabolites such as those derived from gut microbiota or involved in TCA cycle or lipid metabolism. Many of these altered metabolites may contribute to the pathogenesis of AAD. This review aims to illustrate the close association between body metabolism and the occurrence and development of AAD, as well as summarize the significance of metabolites correlated with the pathological process of AAD. This provides valuable insight for developing new therapeutic agents for AAD. Therefore, we present a brief overview of metabolism in AAD biology, including signaling pathways involved in these processes and current clinical studies targeting AAD metabolisms. It is necessary to understand the metabolic mechanisms underlying AAD to provides significant knowledge for AAD diagnosis and new therapeutics for treatment.
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Affiliation(s)
- Qi Wang
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
| | - Gulinazi Yesitayi
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
| | - Bingyan Liu
- Environment Research Institute, Shandong University, Qingdao 266237, China
| | - Dilixiati Siti
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
| | - Mierxiati Ainiwan
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
| | - Aliya Aizitiaili
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
| | - Xiang Ma
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Medical University, Urumqi, China
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Gomez-Larrauri A, Gangoiti P, Camacho L, Presa N, Martin C, Gomez-Muñoz A. Phosphatidic Acid Stimulates Lung Cancer Cell Migration through Interaction with the LPA1 Receptor and Subsequent Activation of MAP Kinases and STAT3. Biomedicines 2023; 11:1804. [PMID: 37509443 PMCID: PMC10376810 DOI: 10.3390/biomedicines11071804] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/30/2023] Open
Abstract
Phosphatidic acid (PA) is a key bioactive glycerophospholipid that is implicated in the regulation of vital cell functions such as cell growth, differentiation, and migration, and is involved in a variety of pathologic processes. However, the molecular mechanisms by which PA exerts its pathophysiological actions are incompletely understood. In the present work, we demonstrate that PA stimulates the migration of the human non-small cell lung cancer (NSCLC) A549 adenocarcinoma cells, as determined by the transwell migration assay. PA induced the rapid phosphorylation of mitogen-activated protein kinases (MAPKs) ERK1-2, p38, and JNK, and the pretreatment of cells with selective inhibitors of these kinases blocked the PA-stimulated migration of cancer cells. In addition, the chemotactic effect of PA was inhibited by preincubating the cells with pertussis toxin (PTX), a Gi protein inhibitor, suggesting the implication of a Gi protein-coupled receptor in this action. Noteworthy, a blockade of LPA receptor 1 (LPA1) with the specific LPA1 antagonist AM966, or with the selective LPA1 inhibitors Ki1645 or VPC32193, abolished PA-stimulated cell migration. Moreover, PA stimulated the phosphorylation of the transcription factor STAT3 downstream of JAK2, and inhibitors of either JAK2 or STAT3 blocked PA-stimulated cell migration. It can be concluded that PA stimulates lung adenocarcinoma cell migration through an interaction with the LPA1 receptor and subsequent activation of the MAPKs ERK1-2, p38, and JNK, and that the JAK2/STAT3 pathway is also important in this process. These findings suggest that targeting PA formation and/or the LPA1 receptor may provide new strategies to reduce malignancy in lung cancer.
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Affiliation(s)
- Ana Gomez-Larrauri
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
- Respiratory Department, Cruces University Hospital, 48903 Barakaldo, Bizkaia, Spain
| | - Patricia Gangoiti
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
| | - Laura Camacho
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
| | - Natalia Presa
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
| | - Cesar Martin
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
- Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), 48940 Leioa, Bizkaia, Spain
| | - Antonio Gomez-Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48980 Bilbao, Bizkaia, Spain
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12
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Tsuchida Y, Shoda H, Sawada T, Fujio K. Role of autotaxin in systemic lupus erythematosus. Front Med (Lausanne) 2023; 10:1166343. [PMID: 37122329 PMCID: PMC10130763 DOI: 10.3389/fmed.2023.1166343] [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: 02/15/2023] [Accepted: 03/15/2023] [Indexed: 05/02/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes. SLE is a heterogenous disease, and the pattern of organ involvement and response to treatment differs significantly among patients. Novel biological markers are necessary to assess the extent of organ involvement and predict treatment response in SLE. Lysophosphatidic acid is a lysophospholipid involved in various biological processes, and autotaxin (ATX), which catalyzes the production of lysophosphatidic acid in the extracellular space, has gained attention in various diseases as a potential biomarker. The concentration of ATX is increased in the serum and urine of patients with SLE and lupus nephritis. Recent evidence suggests that ATX produced by plasmacytoid dendritic cells may play an important role in the immune system and pathogenesis of SLE. Furthermore, the production of ATX is associated with type I interferons, a key cytokine in SLE pathogenesis, and ATX may be a potential biomarker and key molecule in SLE.
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Affiliation(s)
- Yumi Tsuchida
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- *Correspondence: Yumi Tsuchida,
| | - Hirofumi Shoda
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuji Sawada
- Department of Rheumatology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Keishi Fujio
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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13
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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14
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Dacheux MA, Lee SC, Shin Y, Norman DD, Lin KH, E S, Yue J, Benyó Z, Tigyi GJ. Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells. Cancers (Basel) 2022; 14:cancers14061586. [PMID: 35326737 PMCID: PMC8946623 DOI: 10.3390/cancers14061586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/26/2022] [Revised: 03/07/2022] [Accepted: 03/17/2022] [Indexed: 01/27/2023] Open
Abstract
Although metastases are the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasizes to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knock out the ATX gene in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/loxP system (Sftpc-CreERT2/Enpp2fl/fl) to generate conditional knockout (KO) mice in which ATX is specifically deleted in ATII cells (i.e., Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allowed us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% (unpaired t-test, p = 0.028) compared to Sftpc-WT control mice, suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p < 0.0001) and TNFα (unpaired t-test, p = 0.0003), which could favor the increase in infiltrating CD8+ T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis.
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Affiliation(s)
- Mélanie A. Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Yoojin Shin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Derek D. Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Kuan-Hung Lin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Shuyu E
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (S.E.); (J.Y.)
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (S.E.); (J.Y.)
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, H-1428 Budapest, Hungary;
| | - Gábor J. Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
- Correspondence: ; Tel.: +1-901-448-4793
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15
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Murakami K, Tamada T, Saigusa D, Miyauchi E, Nara M, Ichinose M, Kurano M, Yatomi Y, Sugiura H. Urine autotaxin levels reflect the disease activity of sarcoidosis. Sci Rep 2022; 12:4372. [PMID: 35288647 PMCID: PMC8921313 DOI: 10.1038/s41598-022-08388-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/26/2021] [Accepted: 03/04/2022] [Indexed: 12/17/2022] Open
Abstract
Since the clinical outcome of patients with sarcoidosis is still unpredictable, a good prognostic biomarker is necessary. Autotaxin (ATX) and phosphatidylserine-specific phospholipase A1 (PS-PLA1) function as main enzymes to produce lysophospholipids (LPLs), and these enzymes are attracting attention as useful biomarkers for several chronic inflammatory diseases. Here, we investigated the relationships between LPLs-producing enzymes and the disease activity of sarcoidosis. In total, 157 patients with sarcoidosis (active state, 51%) were consecutively enrolled. Using plasma or urine specimens, we measured the values of LPLs-producing enzymes. Urine ATX (U-ATX) levels were significantly lower in the active state compared to those in the inactive state, while the plasma ATX (P-ATX) and PS-PLA1 levels showed no significant difference between these two states. Concerning the comparison with existing clinical biomarkers for sarcoidosis, U-ATX showed a weak negative correlation to ACE, P-ATX a weak positive correlation to both ACE and sIL-2R, and PS-PLA1 a weak positive one to sIL-2R. Notably, only the U-ATX levels inversely fluctuated depending on the status of disease activity whether OCS had been used or not. These findings suggest that U-ATX is likely to be a novel and useful molecule for assessing the disease activity of sarcoidosis.
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CXCL12-stimulated lymphocytes produce secondary stimulants that affect the surrounding cell chemotaxis. Biochem Biophys Rep 2021; 28:101128. [PMID: 34527817 PMCID: PMC8430269 DOI: 10.1016/j.bbrep.2021.101128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/14/2021] [Revised: 09/02/2021] [Accepted: 09/02/2021] [Indexed: 11/23/2022] Open
Abstract
Chemotactic factors locally secreted from tissues regulate leukocyte migration via cell membrane receptors that induce intracellular signals. It has been suggested that neutrophils stimulated by bacterial peptides secrete a secondary stimulant that enhances the chemotactic cell migration of the surrounding cells. This paracrine mechanism contributes to chemokine-dependent neutrophil migration, however, it has not yet been extensively studied in lymphocytes. In this study, we provide evidence that lymphocytes stimulated by the chemokine, CXCL12, affect the CXCR4-independent chemotactic response of the surrounding cells. We found that CXCR4-expressing lymphocytes or the conditioned medium from CXCL12-stimulated cells promoted CXCR4-deficient cell chemotaxis. In contrast, the conditioned medium from CXCL12-stimulated cells suppressed CCR7 ligand-dependent directionality and the cell migration speed of CXCR4-deficient cells. These results suggest that paracrine factors from CXCL12-stimulated cells navigate surrounding cells to CXCL12 by controlling the responsiveness to CCR7 ligand chemokines and CXCL12.
CXCL12-stimulated lymphocytes affect the CXCR4-independent chemotactic response of the surrounding cells. The conditioned medium from CXCL12-stimulated cells promoted CXCR4-deficient cell chemotaxis, whereas it suppresses CCR7 ligand-dependent directionality and the cell migration speed. The CXCL12/CXCR4 axis causes the production of a signal-relay molecule that contributes to chemokine-dependent lymphocyte migration.
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Aiello S, Casiraghi F. Lysophosphatidic Acid: Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies? Cells 2021; 10:cells10061390. [PMID: 34200030 PMCID: PMC8229068 DOI: 10.3390/cells10061390] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions—motility, invasion and migration capabilities as well as resistance to apoptotic death—has been recognized by numerous studies over the last two decades. Notably, evidence has recently been accumulating that shows that LPA also contributes to the development of the tumor microenvironment (TME). Indeed, LPA plays a crucial role in inducing angiogenesis and lymphangiogenesis, triggering cellular glycolytic shift and stimulating intratumoral fibrosis. In addition, LPA helps tumoral cells to escape immune surveillance. Treatments that counter the TME components, in order to deprive cancer cells of their crucial support, have been emerging among the promising new anticancer therapies. This review aims to summarize the latest knowledge on how LPA influences both tumor cell functions and the TME by regulating the activity of its different elements, highlighting why and how LPA is worth considering as a molecular target for new anticancer therapies.
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Blanchard L, Girard JP. High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis 2021; 24:719-753. [PMID: 33956259 PMCID: PMC8487881 DOI: 10.1007/s10456-021-09792-8] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/29/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022]
Abstract
High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders (bacterial and viral infections) and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79+ tumor-associated HEVs (TA-HEVs) are frequently found in human tumors in CD3+ T cell-rich areas or CD20+ B-cell rich tertiary lymphoid structures (TLSs). TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.
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Affiliation(s)
- Lucas Blanchard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
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Zhang X, Li M, Yin N, Zhang J. The Expression Regulation and Biological Function of Autotaxin. Cells 2021; 10:cells10040939. [PMID: 33921676 PMCID: PMC8073485 DOI: 10.3390/cells10040939] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2021] [Revised: 04/15/2021] [Accepted: 04/15/2021] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein and functions as a key enzyme to produce extracellular lysophosphatidic acid (LPA). LPA interacts with at least six G protein-coupled receptors, LPAR1-6, on the cell membrane to activate various signal transduction pathways through distinct G proteins, such as Gi/0, G12/13, Gq/11, and Gs. The ATX-LPA axis plays an important role in physiological and pathological processes, including embryogenesis, obesity, and inflammation. ATX is one of the top 40 most unregulated genes in metastatic cancer, and the ATX-LPA axis is involved in the development of different types of cancers, such as colorectal cancer, ovarian cancer, breast cancer, and glioblastoma. ATX expression is under multifaceted controls at the transcription, post-transcription, and secretion levels. ATX and LPA in the tumor microenvironment not only promote cell proliferation, migration, and survival, but also increase the expression of inflammation-related circuits, which results in poor outcomes for patients with cancer. Currently, ATX is regarded as a potential cancer therapeutic target, and an increasing number of ATX inhibitors have been developed. In this review, we focus on the mechanism of ATX expression regulation and the functions of ATX in cancer development.
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Affiliation(s)
| | | | | | - Junjie Zhang
- Correspondence: ; Tel.: +86-10-58802137; Fax: +86-10-58807720
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20
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Phosphatidic Acid Stimulates Myoblast Proliferation through Interaction with LPA1 and LPA2 Receptors. Int J Mol Sci 2021; 22:ijms22031452. [PMID: 33535610 PMCID: PMC7867176 DOI: 10.3390/ijms22031452] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 12/31/2022] Open
Abstract
Phosphatidic acid (PA) is a bioactive phospholipid capable of regulating key biological functions, including neutrophil respiratory burst, chemotaxis, or cell growth and differentiation. However, the mechanisms whereby PA exerts these actions are not completely understood. In this work, we show that PA stimulates myoblast proliferation, as determined by measuring the incorporation of [3H]thymidine into DNA and by staining the cells with crystal violet. PA induced the rapid phosphorylation of Akt and ERK1/2, and pretreatment of the cells with specific small interferin RNA (siRNA) to silence the genes encoding these kinases, or with selective pharmacologic inhibitors, blocked PA-stimulated myoblast proliferation. The mitogenic effects of PA were abolished by the preincubation of the myoblasts with pertussis toxin, a Gi protein inhibitor, suggesting the implication of Gi protein-coupled receptors in this action. Although some of the effects of PA have been associated with its possible conversion to lysoPA (LPA), treatment of the myoblasts with PA for up to 60 min did not produce any significant amount of LPA in these cells. Of interest, pharmacological blockade of the LPA receptors 1 and 2, or specific siRNA to silence the genes encoding these receptors, abolished PA-stimulated myoblast proliferation. Moreover, PA was able to compete with LPA for binding to LPA receptors, suggesting that PA can act as a ligand of LPA receptors. It can be concluded that PA stimulates myoblast proliferation through interaction with LPA1 and LPA2 receptors and the subsequent activation of the PI3K/Akt and MEK/ERK1-2 pathways, independently of LPA formation.
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Miao Y, Zhao Y, Han L, Ma X, Deng J, Yang J, Lü S, Shao F, Kong W, Wang W, Xu Q, Wang X, Feng J. NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment. Cell Mol Life Sci 2021; 78:1709-1727. [PMID: 32734582 PMCID: PMC11073013 DOI: 10.1007/s00018-020-03607-7] [Citation(s) in RCA: 15] [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: 02/22/2020] [Revised: 07/09/2020] [Accepted: 07/22/2020] [Indexed: 01/08/2023]
Abstract
Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.
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Affiliation(s)
- Yutong Miao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Yang Zhao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China
| | - Lulu Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Xiaolong Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Jiacheng Deng
- Cardiovascular Division, BHF Center for Vascular Regeneration, King's College London, London, UK
| | - Juan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Silin Lü
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Fangyu Shao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Wengong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China
| | - Qingbo Xu
- Cardiovascular Division, BHF Center for Vascular Regeneration, King's College London, London, UK
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
| | - Juan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
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22
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Lipids in the tumor microenvironment: From cancer progression to treatment. Prog Lipid Res 2020; 80:101055. [PMID: 32791170 DOI: 10.1016/j.plipres.2020.101055] [Citation(s) in RCA: 217] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/15/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022]
Abstract
Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.
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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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Eckert N, Permanyer M, Yu K, Werth K, Förster R. Chemokines and other mediators in the development and functional organization of lymph nodes. Immunol Rev 2020; 289:62-83. [PMID: 30977201 DOI: 10.1111/imr.12746] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/06/2018] [Accepted: 01/22/2019] [Indexed: 12/28/2022]
Abstract
Secondary lymphoid organs like lymph nodes (LNs) are the main inductive sites for adaptive immune responses. Lymphocytes are constantly entering LNs, scanning the environment for their cognate antigen and get replenished by incoming cells after a certain period of time. As only a minor percentage of lymphocytes recognizes cognate antigen, this mechanism of permanent recirculation ensures fast and effective immune responses when necessary. Thus, homing, positioning, and activation as well as egress require precise regulation within LNs. In this review we discuss the mediators, including chemokines, cytokines, growth factors, and others that are involved in the formation of the LN anlage and subsequent functional organization of LNs. We highlight very recent findings in the fields of LN development, steady-state migration in LNs, and the intranodal processes during an adaptive immune response.
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Affiliation(s)
- Nadine Eckert
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Marc Permanyer
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Kai Yu
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Kathrin Werth
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Reinhold Förster
- Institute of Immunology, Hannover Medical School, Hannover, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11070958. [PMID: 31323936 PMCID: PMC6678549 DOI: 10.3390/cancers11070958] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/10/2019] [Revised: 07/04/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.
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26
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Hisano Y, Kono M, Cartier A, Engelbrecht E, Kano K, Kawakami K, Xiong Y, Piao W, Galvani S, Yanagida K, Kuo A, Ono Y, Ishida S, Aoki J, Proia RL, Bromberg JS, Inoue A, Hla T. Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes. J Exp Med 2019; 216:1582-1598. [PMID: 31147448 PMCID: PMC6605750 DOI: 10.1084/jem.20181895] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/04/2018] [Revised: 03/29/2019] [Accepted: 05/06/2019] [Indexed: 12/16/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) activate G protein-coupled receptors (GPCRs) to regulate biological processes. Using a genome-wide CRISPR/dCas9-based GPCR signaling screen, LPAR1 was identified as an inducer of S1PR1/β-arrestin coupling while suppressing Gαi signaling. S1pr1 and Lpar1-positive lymphatic endothelial cells (LECs) of lymph nodes exhibit constitutive S1PR1/β-arrestin signaling, which was suppressed by LPAR1 antagonism. Pharmacological inhibition or genetic loss of function of Lpar1 reduced the frequency of punctate junctions at sinus-lining LECs. Ligand activation of transfected LPAR1 in endothelial cells remodeled junctions from continuous to punctate structures and increased transendothelial permeability. In addition, LPAR1 antagonism in mice increased lymph node retention of adoptively transferred lymphocytes. These data suggest that cross-talk between LPAR1 and S1PR1 promotes the porous junctional architecture of sinus-lining LECs, which enables efficient lymphocyte trafficking. Heterotypic inter-GPCR coupling may regulate complex cellular phenotypes in physiological milieu containing many GPCR ligands.
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Affiliation(s)
- Yu Hisano
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Mari Kono
- Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Andreane Cartier
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Eric Engelbrecht
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Kuniyuki Kano
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Kouki Kawakami
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yanbao Xiong
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Wenji Piao
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Sylvain Galvani
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Keisuke Yanagida
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Andrew Kuo
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
| | - Yuki Ono
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Satoru Ishida
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Junken Aoki
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Richard L Proia
- Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Jonathan S Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Asuka Inoue
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA
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Mathew D, Kremer KN, Strauch P, Tigyi G, Pelanda R, Torres RM. LPA 5 Is an Inhibitory Receptor That Suppresses CD8 T-Cell Cytotoxic Function via Disruption of Early TCR Signaling. Front Immunol 2019; 10:1159. [PMID: 31231367 PMCID: PMC6558414 DOI: 10.3389/fimmu.2019.01159] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/04/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022] Open
Abstract
Persistent T cell antigen receptor (TCR) signaling by CD8 T cells is a feature of cancer and chronic infections and results in the sustained expression of, and signaling by, inhibitory receptors, which ultimately impair cytotoxic activity via poorly characterized mechanisms. We have previously determined that the LPA5 GPCR expressed by CD8 T cells, upon engaging the lysophosphatidic acid (LPA) bioactive serum lipid, functions as an inhibitory receptor able to negatively regulate TCR signaling. Notably, the levels of LPA and autotaxin (ATX), the phospholipase D enzyme that produces LPA, are often increased in chronic inflammatory disorders such as chronic infections, autoimmune diseases, obesity, and cancer. In this report, we demonstrate that LPA engagement selectively by LPA5 on human and mouse CD8 T cells leads to the inhibition of several early TCR signaling events including intracellular calcium mobilization and ERK activation. We further show that, as a consequence of LPA5 suppression of TCR signaling, the exocytosis of perforin-containing granules is significantly impaired and reflected by repressed in vitro and in vivo CD8 T cell cytolytic activity. Thus, these data not only document LPA5 as a novel inhibitory receptor but also determine the molecular and biochemical mechanisms by which a naturally occurring serum lipid that is elevated under settings of chronic inflammation signals to suppress CD8 T cell killing activity in both human and murine cells. As diverse tumors have repeatedly been shown to aberrantly produce LPA that acts in an autocrine manner to promote tumorigenesis, our findings further implicate LPA in activating a novel inhibitory receptor whose signaling may be therapeutically silenced to promote CD8 T cell immunity.
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Affiliation(s)
- Divij Mathew
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Kimberly N. Kremer
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Pamela Strauch
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Gabor Tigyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Raul M. Torres
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States,*Correspondence: Raul M. Torres
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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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29
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Autotaxin-Lysophosphatidic Acid Axis Blockade Improves Inflammation by Regulating Th17 Cell Differentiation in DSS-Induced Chronic Colitis Mice. Inflammation 2019; 42:1530-1541. [DOI: 10.1007/s10753-019-01015-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
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30
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Law SH, Chan ML, Marathe GK, Parveen F, Chen CH, Ke LY. An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases. Int J Mol Sci 2019; 20:ijms20051149. [PMID: 30845751 PMCID: PMC6429061 DOI: 10.3390/ijms20051149] [Citation(s) in RCA: 465] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/06/2019] [Revised: 02/27/2019] [Accepted: 02/28/2019] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A2 (PLA2). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA2 increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A1 activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.
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Affiliation(s)
- Shi-Hui Law
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Mei-Lin Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Division of Thoracic Surgery, Department of Surgery, MacKay Memorial Hospital, MacKay Medical College, Taipei 10449, Taiwan.
| | - Gopal K Marathe
- Department of Studies in Biochemistry, Manasagangothri, University of Mysore, Mysore-570006, India.
| | - Farzana Parveen
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Chu-Huang Chen
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA.
| | - Liang-Yin Ke
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
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Lin S, Haque A, Raeman R, Guo L, He P, Denning TL, El-Rayes B, Moolenaar WH, Yun CC. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. FASEB J 2019; 33:3623-3635. [PMID: 30481488 PMCID: PMC6404565 DOI: 10.1096/fj.201801415rr] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/09/2018] [Accepted: 10/22/2018] [Indexed: 12/13/2022]
Abstract
Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1-/- and μMT mice, suggesting B cells as a major ATX-producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.-Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El-Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon.
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Affiliation(s)
- Songbai Lin
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Abedul Haque
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Reben Raeman
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Leilei Guo
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Peijian He
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
| | - Timothy L. Denning
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; and
| | - Wouter H. Moolenaar
- Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - C. Chris Yun
- Atlanta Veterans Administration Medical Center, Decatur, Georgia, USA
- Division of Digestive Diseases, Emory University, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; and
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32
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Kim NH, Sadra A, Park HY, Oh SM, Chun J, Yoon JK, Huh SO. HeLa E-Box Binding Protein, HEB, Inhibits Promoter Activity of the Lysophosphatidic Acid Receptor Gene Lpar1 in Neocortical Neuroblast Cells. Mol Cells 2019; 42:123-134. [PMID: 30622227 PMCID: PMC6399008 DOI: 10.14348/molcells.2018.0399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2018] [Revised: 12/04/2018] [Accepted: 12/07/2018] [Indexed: 01/20/2023] Open
Abstract
Lysophosphatidic acid (LPA) is an endogenous lysophospholipid with signaling properties outside of the cell and it signals through specific G protein-coupled receptors, known as LPA1-6. For one of its receptors, LPA1 (gene name Lpar1), details on the cis-acting elements for transcriptional control have not been defined. Using 5'RACE analysis, we report the identification of an alternative transcription start site of mouse Lpar1 and characterize approximately 3,500 bp of non-coding flanking sequence 5' of mouse Lpar1 gene for promoter activity. Transient transfection of cells derived from mouse neocortical neuroblasts with constructs from the 5' regions of mouse Lpar1 gene revealed the region between -248 to +225 serving as the basal promoter for Lpar1. This region also lacks a TATA box. For the region between -761 to -248, a negative regulatory element affected the basal expression of Lpar1. This region has three E-box sequences and mutagenesis of these E-boxes, followed by transient expression, demonstrated that two of the E-boxes act as negative modulators of Lpar1. One of these E-box sequences bound the HeLa E-box binding protein (HEB), and modulation of HEB levels in the transfected cells regulated the transcription of the reporter gene. Based on our data, we propose that HEB may be required for a proper regulation of Lpar1 expression in the embryonic neocortical neuroblast cells and to affect its function in both normal brain development and disease settings.
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Affiliation(s)
- Nam-Ho Kim
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 24252,
Korea
| | - Ali Sadra
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 24252,
Korea
| | - Hee-Young Park
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 24252,
Korea
| | - Sung-Min Oh
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 24252,
Korea
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, CA 92037,
USA
| | - Jeong Kyo Yoon
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Asan 31538,
Korea
| | - Sung-Oh Huh
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon 24252,
Korea
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33
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Ninou I, Kaffe E, Müller S, Budd DC, Stevenson CS, Ullmer C, Aidinis V. Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis. Pulm Pharmacol Ther 2018; 52:32-40. [DOI: 10.1016/j.pupt.2018.08.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/18/2018] [Accepted: 08/16/2018] [Indexed: 02/08/2023]
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Meng G, Tang X, Yang Z, Zhao Y, Curtis JM, McMullen TPW, Brindley DN. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer. FASEB J 2018; 33:1899-1910. [PMID: 30192654 DOI: 10.1096/fj.201801226r] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase-2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti-inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX-LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10-1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL-6, TNF-α, peroxisome proliferator-activated receptor (PPAR)-γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex-induced decreases in ATX and adiponectin secretion, but did not reverse Dex-induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex-treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1-phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti-inflammatory effects of Dex through decreased signaling by the ATX-LPA-inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.-Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer.
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Affiliation(s)
- Guanmin Meng
- Signal Transduction Research Group, Department of Biochemistry, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada
| | - Zelei Yang
- Signal Transduction Research Group, Department of Biochemistry, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada
| | - YuanYuan Zhao
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada; and
| | - Jonathan M Curtis
- Department of Agricultural, Food, and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada; and
| | - Todd P W McMullen
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada
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Simmons S, Erfinanda L, Bartz C, Kuebler WM. Novel mechanisms regulating endothelial barrier function in the pulmonary microcirculation. J Physiol 2018; 597:997-1021. [PMID: 30015354 DOI: 10.1113/jp276245] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/31/2018] [Accepted: 05/25/2018] [Indexed: 12/11/2022] Open
Abstract
The pulmonary epithelial and vascular endothelial cell layers provide two sequential physical and immunological barriers that together form a semi-permeable interface and prevent alveolar and interstitial oedema formation. In this review, we focus specifically on the continuous endothelium of the pulmonary microvascular bed that warrants strict control of the exchange of gases, fluid, solutes and circulating cells between the plasma and the interstitial space. The present review provides an overview of emerging molecular mechanisms that permit constant transcellular exchange between the vascular and interstitial compartment, and cause, prevent or reverse lung endothelial barrier failure under experimental conditions, yet with a clinical perspective. Based on recent findings and at times seemingly conflicting results we discuss emerging paradigms of permeability regulation by altered ion transport as well as shifts in the homeostasis of sphingolipids, angiopoietins and prostaglandins.
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Affiliation(s)
- Szandor Simmons
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Lasti Erfinanda
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Bartz
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.,Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.,Departments of Surgery and Physiology, University of Toronto, Toronto, ON, Canada
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36
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Ninou I, Magkrioti C, Aidinis V. Autotaxin in Pathophysiology and Pulmonary Fibrosis. Front Med (Lausanne) 2018; 5:180. [PMID: 29951481 PMCID: PMC6008954 DOI: 10.3389/fmed.2018.00180] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022] Open
Abstract
Lysophospholipid signaling is emerging as a druggable regulator of pathophysiological responses, and especially fibrosis, exemplified by the relative ongoing clinical trials in idiopathic pulmonary fibrosis (IPF) patients. In this review, we focus on ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2), or as more widely known Autotaxin (ATX), a secreted lysophospholipase D (lysoPLD) largely responsible for extracellular lysophosphatidic acid (LPA) production. In turn, LPA is a bioactive phospholipid autacoid, forming locally upon increased ATX levels and acting also locally through its receptors, likely guided by ATX's structural conformation and cell surface associations. Increased ATX activity levels have been detected in many inflammatory and fibroproliferative conditions, while genetic and pharmacologic studies have confirmed a pleiotropic participation of ATX/LPA in different processes and disorders. In pulmonary fibrosis, ATX levels rise in the broncheoalveolar fluid (BALF) and stimulate LPA production. LPA engagement of its receptors activate multiple G-protein mediated signal transduction pathways leading to different responses from pulmonary cells including the production of pro-inflammatory signals from stressed epithelial cells, the modulation of endothelial physiology, the activation of TGF signaling and the stimulation of fibroblast accumulation. Genetic or pharmacologic targeting of the ATX/LPA axis attenuated disease development in animal models, thus providing the proof of principle for therapeutic interventions.
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Affiliation(s)
- Ioanna Ninou
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Christiana Magkrioti
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vassilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
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37
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38
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Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice. Oncotarget 2018; 8:27240-27251. [PMID: 28460477 PMCID: PMC5432331 DOI: 10.18632/oncotarget.15916] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/11/2016] [Accepted: 02/20/2017] [Indexed: 01/05/2023] Open
Abstract
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS.
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Zhou R, Yang Y, Park SY, Nguyen TT, Seo YW, Lee KH, Lee JH, Kim KK, Hur JS, Kim H. The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis. Sci Rep 2017; 7:8136. [PMID: 28811522 PMCID: PMC5557893 DOI: 10.1038/s41598-017-08225-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/12/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023] Open
Abstract
Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed β-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of β-catenin and downregulating β-catenin/LEF and c-jun/AP-1 downstream target genes such as CD44, cyclin-D1 and c-myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN)-mediated AP-1 activity and the activity of the KITENIN 3′-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT² Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo. Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity.
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Affiliation(s)
- Rui Zhou
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea
| | - Yi Yang
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea.,Korean Lichen Research Institute, Sunchon National University, Sunchon, Republic of Korea
| | - So-Yeon Park
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea
| | - Thanh Thi Nguyen
- Korean Lichen Research Institute, Sunchon National University, Sunchon, Republic of Korea.,Faculty of Natural Science and Technology, Tay Nguyen University, Buon Ma Thuot, Vietnam
| | - Young-Woo Seo
- Korea Basic Science Institute, Gwangju Center, Gwangju, Republic of Korea
| | - Kyung Hwa Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jae Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Kyung Keun Kim
- Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Jae-Seoun Hur
- Korean Lichen Research Institute, Sunchon National University, Sunchon, Republic of Korea
| | - Hangun Kim
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon, Republic of Korea.
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Schmitz K, Brunkhorst R, de Bruin N, Mayer CA, Häussler A, Ferreiros N, Schiffmann S, Parnham MJ, Tunaru S, Chun J, Offermanns S, Foerch C, Scholich K, Vogt J, Wicker S, Lötsch J, Geisslinger G, Tegeder I. Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis. Acta Neuropathol Commun 2017; 5:42. [PMID: 28578681 PMCID: PMC5457661 DOI: 10.1186/s40478-017-0446-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2017] [Accepted: 05/21/2017] [Indexed: 01/18/2023] Open
Abstract
Abstract Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2-/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical abstract Graphical summary of lysophosphatidic signaling in multiple sclerosis![]() Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0446-4) contains supplementary material, which is available to authorized users.
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Chen J, Cai Z, Zhang L, Yin Y, Chen X, Chen C, Zhang Y, Zhai S, Long X, Liu X, Wang X. Lis1 Regulates Germinal Center B Cell Antigen Acquisition and Affinity Maturation. THE JOURNAL OF IMMUNOLOGY 2017; 198:4304-4311. [PMID: 28446568 DOI: 10.4049/jimmunol.1700159] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/31/2017] [Accepted: 03/27/2017] [Indexed: 01/07/2023]
Abstract
The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.
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Affiliation(s)
- Jingjing Chen
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Zhenming Cai
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Le Zhang
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Yuye Yin
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Xufeng Chen
- State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chao Chen
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Yang Zhang
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Sulan Zhai
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Xuehui Long
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
| | - Xiaolong Liu
- State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaoming Wang
- Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and
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Meng G, Tang X, Yang Z, Benesch MGK, Marshall A, Murray D, Hemmings DG, Wuest F, McMullen TPW, Brindley DN. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy. FASEB J 2017; 31:4064-4077. [PMID: 28539367 DOI: 10.1096/fj.201700159r] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/21/2017] [Accepted: 04/08/2017] [Indexed: 01/08/2023]
Abstract
We have previously established that adipose tissue adjacent to breast tumors becomes inflamed by tumor-derived cytokines. This stimulates autotaxin (ATX) secretion from adipocytes, whereas breast cancer cells produce insignificant ATX. Lysophosphatidate produced by ATX promotes inflammatory cytokine secretion in a vicious inflammatory cycle, which increases tumor growth and metastasis and decreases response to chemotherapy. We hypothesized that damage to adipose tissue during radiotherapy for breast cancer should promote lysophosphatidic acid (LPA) signaling and further inflammatory signaling, which could potentially protect cancer cells from subsequent fractions of radiation therapy. To test this hypothesis, we exposed rat and human adipose tissue to radiation doses (0.25-5 Gy) that were expected during radiotherapy. This exposure increased mRNA levels for ATX, cyclooxygenase-2, IL-1β, IL-6, IL-10, TNF-α, and LPA1 and LPA2 receptors by 1.8- to 5.1-fold after 4 to 48 h. There were also 1.5- to 2.5-fold increases in the secretion of ATX and 14 inflammatory mediators after irradiating at 1 Gy. Inhibition of the radiation-induced activation of NF-κB, cyclooxygenase-2, poly (ADP-ribose) polymerase-1, or ataxia telangiectasia and Rad3-related protein blocked inflammatory responses to γ-radiation. Consequently, collateral damage to adipose tissue during radiotherapy could establish a comprehensive wound-healing response that involves increased signaling by LPA, cyclooxygenase-2, and other inflammatory mediators that could decrease the efficacy of further radiotherapy or chemotherapy.-Meng, G., Tang, X., Yang, Z., Benesch, M. G. K., Marshall, A., Murray, D., Hemmings, D. G., Wuest, F., McMullen, T. P. W., Brindley, D. N. Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy.
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Affiliation(s)
- Guanmin Meng
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.,Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Zelei Yang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Alison Marshall
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - David Murray
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Denise G Hemmings
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Frank Wuest
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Todd P W McMullen
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;
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43
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Lee JM, Park SJ, Im DS. Calcium Signaling of Lysophosphatidylethanolamine through LPA 1 in Human SH-SY5Y Neuroblastoma Cells. Biomol Ther (Seoul) 2017; 25:194-201. [PMID: 27302965 PMCID: PMC5340545 DOI: 10.4062/biomolther.2016.046] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/25/2016] [Revised: 04/11/2016] [Accepted: 04/22/2016] [Indexed: 02/02/2023] Open
Abstract
Lysophosphatidylethanolamine (LPE), a lyso-type metabolite of phosphatidylethanolamine, has been reported to be an intercellular signaling molecule. LPE mobilizes intracellular Ca2+ through G-protein-coupled receptor (GPCR) in some cells types. However, GPCRs for lysophosphatidic acid (LPA) were not implicated in the LPE-mediated activities in LPA GPCR overexpression systems or in SK-OV3 ovarian cancer cells. In the present study, in human SH-SY5Y neuroblastoma cells, experiments with LPA1 antagonists showed LPE induced intracellular Ca2+ increases in an LPA1 GPCR-dependent manner. Furthermore, LPE increased intracellular Ca2+ through pertussis-sensitive G proteins, edelfosine-sensitive-phospholipase C, 2-APB-sensitive IP3 receptors, Ca2+ release from intracellular Ca2+ stores, and subsequent Ca2+ influx across plasma membranes, and LPA acted on LPA1 and LPA2 receptors to induce Ca2+ response in a 2-APB-sensitive and insensitive manner. These findings suggest novel involvements for LPE and LPA in calcium signaling in human SH-SY5Y neuroblastoma cells.
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Affiliation(s)
- Jung-Min Lee
- Molecular Inflammation Research Center for Aging Intervention (MRCA) and College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Soo-Jin Park
- Molecular Inflammation Research Center for Aging Intervention (MRCA) and College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
| | - Dong-Soon Im
- Molecular Inflammation Research Center for Aging Intervention (MRCA) and College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
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Zschiebsch K, Fischer C, Pickert G, Häussler A, Radeke H, Grösch S, Ferreirós N, Geisslinger G, Werner ER, Tegeder I. Tetrahydrobiopterin Attenuates DSS-evoked Colitis in Mice by Rebalancing Redox and Lipid Signalling. J Crohns Colitis 2016; 10:965-78. [PMID: 26928964 DOI: 10.1093/ecco-jcc/jjw056] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/08/2016] [Accepted: 02/01/2016] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Guanosine triphosphate cyclohydrolase [GCH1] governs the production of the enzyme cofactor tetrahydrobiopterin [BH4] which is essential for biogenic amine synthesis, lipid metabolism via alkylglycerol monooxygenase [AGMO], and redox coupling of nitric oxide synthases [NOSs]. Inflammation-evoked unequal regulation of GCH1 and NOS or AGMO may cause redox stress and lipid imbalances. METHODS The present study assessed potential therapeutic effects of rebalancing these systems with BH4 in experimental colitis in mice. RESULTS Oral treatment with BH4 as a suspension of crushed tablets attenuated colitis, whereas inhibition of its production had opposite effects: aggravated weight loss, epithelial haemorrhages and ulcers, neutrophil infiltrates, production of reactive oxygen species, and unfavourable profile changes of endocannabinoids, ceramides, and lysophosphatidic acids. Conversely, oral BH4 normalised biopterin, reduced in vivo activity of oxidases and peroxidases in the inflamed gut, favoured nitric oxide over hydrogen peroxide, and maintained normal levels of lipid signalling molecules. BH4 favoured thereby resident CD3+CD8+ and regulatory CD3+CD25+ intraepithelial T cells that are important for epithelial integrity. CONCLUSIONS BH4 protected against colitis in mice via two major pathways: [i] by reduction of oxidative stress; and [ii] by re-orchestration of alkyl- and acylglycerolipid signalling via AGMO. Oral treatment with BH4 is a safe approved supplementary therapy for genetic BH4 deficiency and did not excessively increase systemic BH4 levels. Therefore, one may consider repurposing of oral BH4 as an adjunctive treatment for colitis.
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Affiliation(s)
- Katja Zschiebsch
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Caroline Fischer
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Geethanjali Pickert
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Annett Häussler
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Heinfried Radeke
- Department of Experimental Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Sabine Grösch
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Nerea Ferreirós
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Gerd Geisslinger
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
| | - Ernst R Werner
- Division of Biological Chemistry, Medical University of Innsbruck, Austria
| | - Irmgard Tegeder
- Department of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Germany
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Katakai T, Kinashi T. Microenvironmental Control of High-Speed Interstitial T Cell Migration in the Lymph Node. Front Immunol 2016; 7:194. [PMID: 27242799 PMCID: PMC4865483 DOI: 10.3389/fimmu.2016.00194] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/03/2016] [Accepted: 05/02/2016] [Indexed: 12/30/2022] Open
Abstract
T cells are highly concentrated in the lymph node (LN) paracortex, which serves an important role in triggering adoptive immune responses. Live imaging using two-photon laser scanning microscopy revealed vigorous and non-directional T cell migration within this area at average velocity of more than 10 μm/min. Active interstitial T cell movement is considered to be crucial for scanning large numbers of dendritic cells (DCs) to find rare cognate antigens. However, the mechanism by which T cells achieve such high-speed movement in a densely packed, dynamic tissue environment is not fully understood. Several new findings suggest that fibroblastic reticular cells (FRCs) and DCs control T cell movement in a multilateral manner. Chemokines and lysophosphatidic acid produced by FRCs cooperatively promote the migration, while DCs facilitate LFA-1-dependent motility via expression of ICAM-1. Furthermore, the highly dense and confined microenvironment likely plays a key role in anchorage-independent motility. We propose that T cells dynamically switch between two motility modes; anchorage-dependent and -independent manners. Unique tissue microenvironment and characteristic migration modality of T cells cooperatively generate high-speed interstitial movement in the LN.
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Affiliation(s)
- Tomoya Katakai
- Department of Immunology, Graduate School of Medical and Dental Sciences, Niigata University , Niigata , Japan
| | - Tatsuo Kinashi
- Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University , Hirakata , Japan
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46
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G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling. Int J Mol Sci 2016; 17:215. [PMID: 26861299 PMCID: PMC4783947 DOI: 10.3390/ijms17020215] [Citation(s) in RCA: 45] [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: 12/19/2015] [Revised: 01/29/2016] [Accepted: 02/01/2016] [Indexed: 12/13/2022] Open
Abstract
A hallmark of G-protein-coupled receptors (GPCRs) is their ability to recognize and respond to chemically diverse ligands. Lysophospholipids constitute a relatively recent addition to these ligands and carry out their biological functions by activating G-proteins coupled to a large family of cell-surface receptors. This review aims to highlight salient features of cell signaling by one class of these receptors, known as lysophosphatidic acid (LPA) receptors, in the context of phosphatidylinositol 3-kinase (PI3K)-AKT pathway activation. LPA moieties efficiently activate AKT phosphorylation and activation in a multitude of cell types. The interplay between LPA, its receptors, the associated Gαi/o subunits, PI3K and AKT contributes to the regulation of cell survival, migration, proliferation and confers chemotherapy-resistance in certain cancers. However, detailed information on the regulation of PI3K-AKT signals induced by LPA receptors is missing from the literature. Here, some urgent issues for investigation are highlighted.
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Takeda A, Kobayashi D, Aoi K, Sasaki N, Sugiura Y, Igarashi H, Tohya K, Inoue A, Hata E, Akahoshi N, Hayasaka H, Kikuta J, Scandella E, Ludewig B, Ishii S, Aoki J, Suematsu M, Ishii M, Takeda K, Jalkanen S, Miyasaka M, Umemoto E. Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility. eLife 2016; 5:e10561. [PMID: 26830463 PMCID: PMC4755752 DOI: 10.7554/elife.10561] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/21/2015] [Accepted: 12/26/2015] [Indexed: 12/14/2022] Open
Abstract
Lymph nodes (LNs) are highly confined environments with a cell-dense three-dimensional meshwork, in which lymphocyte migration is regulated by intracellular contractile proteins. However, the molecular cues directing intranodal cell migration remain poorly characterized. Here we demonstrate that lysophosphatidic acid (LPA) produced by LN fibroblastic reticular cells (FRCs) acts locally to LPA2 to induce T-cell motility. In vivo, either specific ablation of LPA-producing ectoenzyme autotaxin in FRCs or LPA2 deficiency in T cells markedly decreased intranodal T cell motility, and FRC-derived LPA critically affected the LPA2-dependent T-cell motility. In vitro, LPA activated the small GTPase RhoA in T cells and limited T-cell adhesion to the underlying substrate via LPA2. The LPA-LPA2 axis also enhanced T-cell migration through narrow pores in a three-dimensional environment, in a ROCK-myosin II-dependent manner. These results strongly suggest that FRC-derived LPA serves as a cell-extrinsic factor that optimizes T-cell movement through the densely packed LN reticular network. DOI:http://dx.doi.org/10.7554/eLife.10561.001 Small organs called lymph nodes are found throughout the body and help to filter out harmful particles and cells. Lymph nodes are packed with different types of immune cells, such as the T-cells that play a number of roles in detecting and destroying bacteria, viruses and other disease-causing microbes. Within the lymph node, T-cells crawl along a meshwork made up of cells called fibroblastic reticular cells. The T-cells appear to move in random patterns, but the signals that drive this movement remain ill-defined. Now, Takeda et al. reveal that a lipid called lysophosphatidic acid (LPA), which is produced by the fibroblastic reticular cells, is responsible for regulating how T-cells move around inside the lymph nodes. T-cells are able to detect LPA via certain receptor proteins on their surface. Takeda et al. engineered mice that were either unable to produce a particular LPA receptor on their T-cells, or that produced less LPA than normal. The T-cells of these mice moved around less than T-cells in normal mice. Further experiments revealed that LPA signaling also affects the signaling pathway that alters how well the T-cells stick to nearby surfaces. This suggests that LPA helps to optimize T-cell movement to allow the cells to navigate the small spaces found between the fibroblastic reticular cells. In the future, targeting the processes involved in LPA signaling could help to develop new treatments for disorders of the immune system. DOI:http://dx.doi.org/10.7554/eLife.10561.002
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Affiliation(s)
- Akira Takeda
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Daichi Kobayashi
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Keita Aoi
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoko Sasaki
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuki Sugiura
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.,JST Precursory Research for Embryonic Science and Technology project, Saitama, Japan
| | - Hidemitsu Igarashi
- Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Kazuo Tohya
- Department of Anatomy, Kansai University of Health Sciences, Awaji, Japan
| | - Asuka Inoue
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Erina Hata
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Noriyuki Akahoshi
- Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Haruko Hayasaka
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Junichi Kikuta
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Elke Scandella
- Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Satoshi Ishii
- Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Makoto Suematsu
- Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.,Core Research for Evolutional Science and Technology project, Saitama, Japan
| | - Masaru Ishii
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Takeda
- WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sirpa Jalkanen
- MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Masayuki Miyasaka
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,MediCity Research Laboratory, University of Turku, Turku, Finland
| | - Eiji Umemoto
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
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48
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Federico L, Jeong KJ, Vellano CP, Mills GB. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression. J Lipid Res 2016; 57:25-35. [PMID: 25977291 PMCID: PMC4689343 DOI: 10.1194/jlr.r060020] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/15/2015] [Revised: 05/07/2015] [Indexed: 12/18/2022] Open
Abstract
The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, inflammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers.
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Affiliation(s)
- Lorenzo Federico
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Kang Jin Jeong
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Christopher P Vellano
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
| | - Gordon B Mills
- Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX
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Hata E, Sasaki N, Takeda A, Tohya K, Umemoto E, Akahoshi N, Ishii S, Bando K, Abe T, Kano K, Aoki J, Hayasaka H, Miyasaka M. Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes. Int Immunol 2015; 28:283-92. [PMID: 26714589 PMCID: PMC4885216 DOI: 10.1093/intimm/dxv072] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/19/2015] [Accepted: 11/26/2015] [Indexed: 12/20/2022] Open
Abstract
HEV LPA receptors differentially regulate lymphocyte recirculation Naive lymphocytes continuously migrate from the blood into lymph nodes (LNs) via high endothelial venules (HEVs). To extravasate from the HEVs, lymphocytes undergo multiple adhesion steps, including tethering, rolling, firm adhesion and transmigration. We previously showed that autotaxin (ATX), an enzyme that generates lysophosphatidic acid (LPA), is highly expressed in HEVs, and that the ATX/LPA axis plays an important role in the lymphocyte transmigration across HEVs. However, the detailed mechanism underlying this axis’s involvement in lymphocyte transmigration has remained ill-defined. Here, we show that two LPA receptors, LPA4 and LPA6, are selectively expressed on HEV endothelial cells (ECs) and that LPA4 plays a major role in the lymphocyte transmigration across HEVs in mice. In the absence of LPA4 expression, lymphocytes accumulated heavily within the HEV EC layer, compared to wild-type (WT) mice. This accumulation was also observed in the absence of LPA6 expression, but it was less pronounced. Adoptive transfer experiments using WT lymphocytes revealed that the LPA4 deficiency in ECs specifically compromised the lymphocyte transmigration process, whereas the effect of LPA6 deficiency was not significant. These results indicate that the signals evoked in HEV ECs via the LPA4 and LPA6 differentially regulate lymphocyte extravasation from HEVs in the peripheral LNs.
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Affiliation(s)
- Erina Hata
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naoko Sasaki
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | | | - Kazuo Tohya
- Department of Anatomy, Kansai University of Health Sciences, Kumatori, Osaka 590-0482, Japan
| | - Eiji Umemoto
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Noriyuki Akahoshi
- Department of Immunology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
| | - Satoshi Ishii
- Department of Immunology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan
| | - Kana Bando
- Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan
| | - Takaya Abe
- Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan
| | - Kuniyuki Kano
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Haruko Hayasaka
- Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Department of Life Science, Faculty of Science & Engineering, Kinki University, Higashi-Osaka-shi, Osaka 577-8502, Japan
| | - Masayuki Miyasaka
- Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Suita, Osaka 565-0871, Japan
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50
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Stein JV. T Cell Motility as Modulator of Interactions with Dendritic Cells. Front Immunol 2015; 6:559. [PMID: 26579132 PMCID: PMC4629691 DOI: 10.3389/fimmu.2015.00559] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/10/2015] [Accepted: 10/19/2015] [Indexed: 01/13/2023] Open
Abstract
It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naïve to an activated or tolerant/anergic status. Although many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naïve T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. T cell detachment from DCs providing suboptimal stimulation allows them to search for DCs with higher levels of stimulatory signals, while storing a transient memory of short encounters. In turn, adhesion of weakly reactive T cells to DCs presenting peptides presented on major histocompatibility complex with low affinity is prevented by lipid mediators. Finally, controlled recruitment of CD8(+) T cells to cognate DC-CD4(+) T cell clusters shapes memory T cell formation and the quality of the immune response. Dynamic physiological lymphocyte motility therefore constitutes a mechanism to mitigate low avidity T cell activation and to improve the search for "optimal" DCs, while contributing to peripheral tolerance induction in the absence of inflammation.
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Affiliation(s)
- Jens V Stein
- Theodor Kocher Institute, University of Bern , Bern , Switzerland
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