|
1
|
Sun G, Wang B, Wu X, Cheng J, Ye J, Wang C, Zhu H, Liu X. How do sphingosine-1-phosphate affect immune cells to resolve inflammation? Front Immunol 2024; 15:1362459. [PMID: 38482014 PMCID: PMC10932966 DOI: 10.3389/fimmu.2024.1362459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/06/2024] [Indexed: 04/17/2024] Open
Abstract
Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.
Collapse
Affiliation(s)
- Gehui Sun
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Bin Wang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaoyu Wu
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiangfeng Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junming Ye
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chunli Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hongquan Zhu
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaofeng Liu
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Emergency, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| |
Collapse
|
|
2
|
Chu KO, Chan TI, Chan KP, Yip YW, Bakthavatsalam M, Wang CC, Pang CP, Brelen ME. Untargeted metabolomic analysis of aqueous humor in diabetic macular edema. Mol Vis 2022; 28:230-244. [PMID: 36284671 PMCID: PMC9514551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 08/17/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The mechanism of diabetic macular edema (DME) was explored by comparing the intraocular metabolite profiles of the aqueous humor of patients with DME to those of diabetic patients without DME using untargeted metabolomic analysis. METHODS Aqueous samples from 18 type 2 diabetic patients with DME and 18 type 2 diabetic patients without DME used as controls were analyzed using liquid chromatography-mass spectrometry (LCMS). The two groups of patients were age and gender matched and had no systemic diseases other than diabetes mellitus (DM). The metabolites were analyzed using orthogonal partial least square discriminant analysis. RESULTS The metabolite profiles in DME patients differed from those in DM controls. This indicates the following metabolic derangements in DME: (a) a higher amount of oxidized fatty acids but a lower amount of endogenous antioxidants (oxidative stress); (b) higher levels of β-glucose and homocysteine but a lower level of sorbitol (hyperglycemia); (c) a higher amount of prostaglandin metabolites (inflammation); (d) higher amounts of acylcarnitines, odd-numbered fatty acids, and 7,8-diaminononanoate (respiration deterioration); (e) a higher amount of neurotransmitter metabolites and homovanillic acid (neuronal damage); (f) a lower amount of extracellular matrix (ECM) constituents (ECM deterioration); and (g) a higher amount of di-amino peptides (microvascular damage). CONCLUSIONS The change in the metabolic profiles in the aqueous humor of DME patients compared to DM controls without DME indicates that DME patients may have less capability to resist various stresses or damaging pathological conditions, such as oxidative stress, mitochondrial insufficiency, inflammation, and ECM deterioration.
Collapse
Affiliation(s)
- Kai On Chu
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong,Department of Obstetrics and Gynaecology, the Chinese University of Hong Kong
| | - Tina InLam Chan
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| | - Kwok Ping Chan
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| | - Yolanda WongYing Yip
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| | - Malini Bakthavatsalam
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, the Chinese University of Hong Kong,Li Ka Shing Institute of Health Science, the Chinese University of Hong Kong,School of Biomedical Sciences, the Chinese University of Hong Kong
| | - Chi Pui Pang
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| | - Marten E. Brelen
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong
| |
Collapse
|
|
3
|
Liang Z, He P, Han Y, Yun CC. Survival of Stem Cells and Progenitors in the Intestine Is Regulated by LPA 5-Dependent Signaling. Cell Mol Gastroenterol Hepatol 2022; 14:129-150. [PMID: 35390517 PMCID: PMC9120264 DOI: 10.1016/j.jcmgh.2022.03.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Regeneration of the epithelium by stem cells in the intestine is supported by intrinsic and extrinsic factors. Lysophosphatidic acid (LPA), a bioactive lipid mediator, regulates many cellular functions, including cell proliferation, survival, and cytokine secretion. Here, we identify LPA5 receptor as a potent regulator of the survival of stem cells and transit-amplifying cells in the intestine. METHODS We have used genetic mouse models of conditional deletion of Lpar5, Lpar5f/f;Rosa-CreERT (Lpar5KO), and intestinal epithelial cell-specific Lpar5f/f;AhCre (Lpar5IECKO) mice. Mice were treated with tamoxifen or β-naphthoflavone to delete Lpar5 expression. Enteroids derived from these mice were used to determine the effect of Lpar5 loss on the apoptosis and proliferation of crypt epithelial cells. RESULTS Conditional loss of Lpar5 induced ablation of the intestinal mucosa, which increased morbidity of Lpar5KO mice. Epithelial regeneration was compromised with increased apoptosis and decreased proliferation of crypt epithelial cells by Lpar5 loss. Interestingly, intestinal epithelial cell-specific Lpar5 loss did not cause similar phenotypic defects in vivo. Lpar5 loss reduced intestinal stem cell marker gene expression and reduced lineage tracing from Lgr5+ ISCs. Lpar5 loss induced CXCL10 expression which exerts cytotoxic effects on intestinal stem cells and progenitors in the intestinal crypts. By co-culturing Lpar5KO enteroids with wild-type or Lpar5KO splenocytes, we demonstrated that lymphocytes protect the intestinal crypts via a LPA5-dependent suppression of CXCL10. CONCLUSIONS LPA5 is essential for the regeneration of intestinal epithelium. Our findings reveal a new finding that LPA5 regulates survival of stem cells and transit-amplifying cells in the intestine.
Collapse
Affiliation(s)
- Zhongxing Liang
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Peijian He
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - 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,Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia,Correspondence Address correspondence to: Chris Yun, PhD, Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA 30324. fax: (404) 727-5767.
| |
Collapse
|
|
4
|
Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
Collapse
Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
| |
Collapse
|
|
5
|
Mass Spectrometry Imaging of Lipids in Human Skin Disease Model Hidradenitis Suppurativa by Laser Desorption Ionization from Silicon Nanopost Arrays. Sci Rep 2019; 9:17508. [PMID: 31767918 PMCID: PMC6877612 DOI: 10.1038/s41598-019-53938-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 10/11/2019] [Indexed: 12/20/2022] Open
Abstract
Neutral lipids have been implicated in a host of potentially debilitating human diseases, such as heart disease, type-2 diabetes, and metabolic syndrome. Matrix-assisted laser desorption ionization (MALDI), the method-of-choice for mass spectrometry imaging (MSI), has led to remarkable success in imaging several lipid classes from biological tissue sections. However, due to ion suppression by phospholipids, MALDI has limited ability to efficiently ionize and image neutral lipids, such as triglycerides (TGs). To help overcome this obstacle, we have utilized silicon nanopost arrays (NAPA), a matrix-free laser desorption ionization (LDI) platform. Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease of the apocrine sweat glands. The ability of NAPA to efficiently ionize lipids is exploited in the analysis of human skin samples from sufferers of HS. Ionization by LDI from NAPA allows for the detection and imaging of a number of neutral lipid species, including TGs comprised of shorter, odd-chain fatty acids, which strongly suggests an increased bacterial load within the host tissue, as well as hexosylceramides (HexCers) and galabiosyl-/lactosylceramides that appear to be correlated with the presence of HS. Our results demonstrate that NAPA-LDI-MSI is capable of imaging and potentially differentiating healthy and diseased human skin tissues based on changes in detected neutral lipid composition.
Collapse
|
|
6
|
Hutami IR, Tanaka E, Izawa T. Crosstalk between Fas and S1P 1 signaling via NF-kB in osteoclasts controls bone destruction in the TMJ due to rheumatoid arthritis. JAPANESE DENTAL SCIENCE REVIEW 2019; 55:12-19. [PMID: 30733840 PMCID: PMC6354287 DOI: 10.1016/j.jdsr.2018.09.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 08/27/2018] [Accepted: 09/18/2018] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis (RA) mainly affects various joints of the body, including the temporomandibular joint (TMJ), and it involves an infiltration of autoantibodies and inflammatory leukocytes into articular tissues and the synovium. Initially, the synovial lining tissue becomes engaged with several kinds of infiltrating cells, including osteoclasts, macrophages, lymphocytes, and plasma cells. Eventually, bone degradation occurs. In order to elucidate the best therapy for RA, a comprehensive study of RA pathogenesis needs to be completed. In this article, we discuss a Fas-deficient condition which develops into RA, with an emphasis on the role of sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling which induces the migration of osteoclast precursor cells. We describe that Fas/S1P1 signaling via NF-κB activation in osteoclasts is a key factor in TMJ-RA severity and we discuss a strategy for blocking nuclear translocation of the p50 NF-κB subunit as a potential therapy for attenuating osteoclastogenesis.
Collapse
Affiliation(s)
| | | | - Takashi Izawa
- Department of Orthodontics and Dentofacial Orthopedics, Tokushima University, Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 7708504, Japan
| |
Collapse
|
|
7
|
Abou Daher A, El Jalkh T, Eid AA, Fornoni A, Marples B, Zeidan YH. Translational Aspects of Sphingolipid Metabolism in Renal Disorders. Int J Mol Sci 2017; 18:E2528. [PMID: 29186855 PMCID: PMC5751131 DOI: 10.3390/ijms18122528] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 11/16/2017] [Accepted: 11/17/2017] [Indexed: 12/13/2022] Open
Abstract
Sphingolipids, long thought to be passive components of biological membranes with merely a structural role, have proved throughout the past decade to be major players in the pathogenesis of many human diseases. The study and characterization of several genetic disorders like Fabry's and Tay Sachs, where sphingolipid metabolism is disrupted, leading to a systemic array of clinical symptoms, have indeed helped elucidate and appreciate the importance of sphingolipids and their metabolites as active signaling molecules. In addition to being involved in dynamic cellular processes like apoptosis, senescence and differentiation, sphingolipids are implicated in critical physiological functions such as immune responses and pathophysiological conditions like inflammation and insulin resistance. Interestingly, the kidneys are among the most sensitive organ systems to sphingolipid alterations, rendering these molecules and the enzymes involved in their metabolism, promising therapeutic targets for numerous nephropathic complications that stand behind podocyte injury and renal failure.
Collapse
Affiliation(s)
- Alaa Abou Daher
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
| | - Tatiana El Jalkh
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
| | - Alessia Fornoni
- Department of Medicine, Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miami, FL 33136, USA.
| | - Brian Marples
- Department of Radiation Oncology, Miller School of Medicine/Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA.
| | - Youssef H Zeidan
- Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon.
- Department of Radiation Oncology, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon.
| |
Collapse
|
|
8
|
Bao Y, Guo Y, Zhang C, Fan F, Yang W. Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer. Int J Mol Sci 2017; 18:ijms18102109. [PMID: 28991193 PMCID: PMC5666791 DOI: 10.3390/ijms18102109] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 09/23/2017] [Accepted: 09/30/2017] [Indexed: 12/15/2022] Open
Abstract
Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.
Collapse
Affiliation(s)
- Yonghua Bao
- Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Yongchen Guo
- Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
| | - Chenglan Zhang
- Department of Nursing, Health Professional College of Heilongjiang Province, Beian 164000, China.
| | - Fenghua Fan
- Department of Nursing, Health Professional College of Heilongjiang Province, Beian 164000, China.
| | - Wancai Yang
- Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
- Department of Pathology, University of Illinois at Chicago, Chicago 60612, IL, USA.
| |
Collapse
|
|
9
|
FTY720 Attenuates Angiotensin II-Induced Podocyte Damage via Inhibiting Inflammatory Cytokines. Mediators Inflamm 2017; 2017:3701385. [PMID: 28270699 PMCID: PMC5320072 DOI: 10.1155/2017/3701385] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/08/2016] [Accepted: 12/26/2016] [Indexed: 12/29/2022] Open
Abstract
FTY720, a new chemical substance derived from the ascomycete Isaria sinclairii, is used for treating multiple sclerosis, renal cancer, and asthma. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite and exists in red blood cells. FTY720 is a synthetic S1P analog which can block S1P evoking physiological effects. Recently studies show that S1P was participating in activated inflammation cells induced renal injury. The objective of this study was to assess the protective effect of FTY720 on kidney damage and the potential mechanism of FTY720 which alleviate podocyte injury in chronic kidney disease. In this study, we selected 40 patients with IgA nephropathy and examined their clinical characteristics. Ang II-infusion rat renal injury model was established to evaluate the glomeruli and tubulointerstitial lesion. The result showed that the concentration of S1P in serum and urine was positively correlated with IgA nephropathy patients' renal injury. FTY720 could reduce renal histological lesions induced by Ang II-infusion in rats. Moreover, FTY720 decreased S1P synthesis in Ang II-infusion rats via downregulation of inflammatory cytokines including TNF-α and IL-6. In addition, FTY720 alleviated exogenous S1P-induced podocyte damage. In conclusion, FTY720 is able to attenuate S1P-induced podocyte damage via reducing inflammatory cytokines.
Collapse
|
|
10
|
Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential. Mediators Inflamm 2016; 2016:8606878. [PMID: 26966342 PMCID: PMC4761394 DOI: 10.1155/2016/8606878] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 01/03/2016] [Indexed: 12/26/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters such as spinster homolog 2 (Spns2). S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1-5, through a process coined as "inside-out signaling." The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod) is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing.
Collapse
|
|
11
|
Fuerst E, Foster HR, Ward JPT, Corrigan CJ, Cousins DJ, Woszczek G. Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells. Allergy 2014; 69:1531-9. [PMID: 25041788 PMCID: PMC4329332 DOI: 10.1111/all.12489] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2014] [Indexed: 01/10/2023]
Abstract
Background Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments. Results S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma.
Collapse
Affiliation(s)
- E. Fuerst
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
| | - H. R. Foster
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
| | - J. P. T. Ward
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
| | - C. J. Corrigan
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
| | - D. J. Cousins
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
- Department of Infection, Immunity and Inflammation; University of Leicester; Leicester UK
| | - G. Woszczek
- Division of Asthma, Allergy and Lung Biology; King's College London; London UK
- MRC & Asthma UK Centre in Allergic Mechanisms of Asthma; London UK
| |
Collapse
|
|
12
|
The spleen responds to intestinal manipulation but does not participate in the inflammatory response in a mouse model of postoperative ileus. PLoS One 2014; 9:e102211. [PMID: 25010202 PMCID: PMC4092106 DOI: 10.1371/journal.pone.0102211] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Accepted: 06/16/2014] [Indexed: 12/21/2022] Open
Abstract
Background Postoperative ileus is characterized by a transient impairment of the gastrointestinal motility after abdominal surgery. The intestinal inflammation, triggered by handling of the intestine, is the main factor responsible for the prolonged dysmotility of the gastrointestinal tract. Secondary lymphoid organs of the intestine were identified as essential components in the dissemination of inflammation to the entire gastrointestinal tract also called field effect. The involvement of the spleen, however, remains unclear. Aim In this study, we investigated whether the spleen responds to manipulation of the intestine and participates in the intestinal inflammation underlying postoperative ileus. Methods Mice underwent Laparotomy (L) or Laparotomy followed by Intestinal Manipulation (IM). Twenty-four hours later, intestinal and colonic inflammation was assessed by QPCR and measurement of the intestinal transit was performed. Analysis of homeostatic chemokines in the spleen was performed by QPCR and splenic cell populations analysed by Flow Cytometry. Blockade of the egress of cells from the spleen was performed by administration of the Sphingosine-1-phosphate receptor 1 (S1P1) agonist CYM-5442 10 h after L/IM. Results A significant decrease in splenic weight and cellularity was observed in IM mice 24 h post-surgery, a phenomenon associated with a decreased splenic expression level of the homeostatic chemokine CCL19. Splenic denervation restored the expression of CCL19 and partially prevented the reduction of splenocytes in IM mice. Treatment with CYM-5442 prevented the egress of splenocytes but did not ameliorate the intestinal inflammation underlying postoperative ileus. Conclusions Intestinal manipulation results in two distinct phenomena: local intestinal inflammation and a decrease in splenic cellularity. The splenic response relies on an alteration of cell trafficking in the spleen and is partially regulated by the splenic nerve. The spleen however does not participate in the intestinal inflammation during POI.
Collapse
|
|
13
|
Hu J, Oda SK, Shotts K, Donovan EE, Strauch P, Pujanauski LM, Victorino F, Al-Shami A, Fujiwara Y, Tigyi G, Oravecz T, Pelanda R, Torres RM. Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response. THE JOURNAL OF IMMUNOLOGY 2014; 193:85-95. [PMID: 24890721 DOI: 10.4049/jimmunol.1300429] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Lysophospholipids have emerged as biologically important chemoattractants capable of directing lymphocyte development, trafficking, and localization. Lysophosphatidic acid (LPA) is a major lysophospholipid found systemically, and its levels are elevated in certain pathological settings, such as cancer and infections. In this study, we demonstrate that BCR signal transduction by mature murine B cells is inhibited upon LPA engagement of the LPA5 (GPR92) receptor via a Gα12/13-Arhgef1 pathway. The inhibition of BCR signaling by LPA5 manifests by impaired intracellular calcium store release and most likely by interfering with inositol 1,4,5-triphosphate receptor activity. We further show that LPA5 also limits Ag-specific induction of CD69 and CD86 expression and that LPA5-deficient B cells display enhanced Ab responses. Thus, these data show that LPA5 negatively regulates BCR signaling, B cell activation, and immune response. Our findings extend the influence of lysophospholipids on immune function and suggest that alterations in LPA levels likely influence adaptive humoral immunity.
Collapse
Affiliation(s)
- Jiancheng Hu
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Shannon K Oda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Kristin Shotts
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Erin E Donovan
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Pamela Strauch
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Lindsey M Pujanauski
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Francisco Victorino
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Amin Al-Shami
- Lexicon Pharmaceuticals, Inc, The Woodlands, TX, 77381 USA.,Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Yuko Fujiwara
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Gabor Tigyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Tamas Oravecz
- Lexicon Pharmaceuticals, Inc, The Woodlands, TX, 77381 USA
| | - Roberta Pelanda
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| | - Raul M Torres
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA
| |
Collapse
|
|
14
|
Yuan S, Wu R, Latek D, Trzaskowski B, Filipek S. Lipid receptor S1P₁ activation scheme concluded from microsecond all-atom molecular dynamics simulations. PLoS Comput Biol 2013; 9:e1003261. [PMID: 24098103 PMCID: PMC3789783 DOI: 10.1371/journal.pcbi.1003261] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 08/22/2013] [Indexed: 01/21/2023] Open
Abstract
Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator which activates G protein–coupled sphingosine 1-phosphate receptors and thus evokes a variety of cell and tissue responses including lymphocyte trafficking, endothelial development, integrity, and maturation. We performed five all-atom 700 ns molecular dynamics simulations of the sphingosine 1-phosphate receptor 1 (S1P1) based on recently released crystal structure of that receptor with an antagonist. We found that the initial movements of amino acid residues occurred in the area of highly conserved W2696.48 in TM6 which is close to the ligand binding location. Those residues located in the central part of the receptor and adjacent to kinks of TM helices comprise of a transmission switch. Side chains movements of those residues were coupled to the movements of water molecules inside the receptor which helped in the gradual opening of intracellular part of the receptor. The most stable parts of the protein were helices TM1 and TM2, while the largest movement was observed for TM7, possibly due to the short intracellular part starting with a helix kink at P7.50, which might be the first helix to move at the intracellular side. We show for the first time the detailed view of the concerted action of the transmission switch and Trp (W6.48) rotamer toggle switch leading to redirection of water molecules flow in the central part of the receptor. That event is a prerequisite for subsequent changes in intracellular part of the receptor involving water influx and opening of the receptor structure. The activation of G-protein-coupled receptors (GPCRs) depends on small differences in agonist and antagonist structures resulting in specific forces they impose on the helical bundle of the receptor. Having the crystal structures of GPCRs in different stages of activation it is possible to investigate the successive conformational changes leading to full activation. The long molecular dynamics simulations can fill the gap spanning between those structures and provide an overview of the activation processes. The water molecules are recognized to be crucial in the activation process which link shifting of ligand in the binding site, the actions of molecular switches and finally the movements of fragments of TM helices. Here, we present five 700 ns MD simulations of lipid S1P1 receptor, either in Apo form, or bound to antagonist ML056 or natural agonist S1P. The Apo and antagonist-bound receptor structures exhibited similar behavior, with their TM bundles nearly intact, while in the case of the agonist-bound receptor we observed movements of intracellular ends of some of TM helices.
Collapse
Affiliation(s)
- Shuguang Yuan
- International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
- Laboratory of Physical Chemistry of Polymers and Membranes, École Polytechnique Fédérale de Lausanne, SB ISIC LCPPM, Lausanne, Switzerland
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
- * E-mail: (SY); (SF)
| | - Rongliang Wu
- International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
| | - Dorota Latek
- International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland
| | | | - Slawomir Filipek
- Faculty of Chemistry, University of Warsaw, Warsaw, Poland
- * E-mail: (SY); (SF)
| |
Collapse
|
|
15
|
Rey M, Hess P, Clozel M, Delahaye S, Gatfield J, Nayler O, Steiner B. Desensitization by progressive up-titration prevents first-dose effects on the heart: guinea pig study with ponesimod, a selective S1P1 receptor modulator. PLoS One 2013; 8:e74285. [PMID: 24069292 PMCID: PMC3771878 DOI: 10.1371/journal.pone.0074285] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 07/30/2013] [Indexed: 11/30/2022] Open
Abstract
Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV) conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate) but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.
Collapse
Affiliation(s)
- Markus Rey
- Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Patrick Hess
- Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
| | | | | | - John Gatfield
- Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
- * E-mail:
| | - Oliver Nayler
- Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
| | - Beat Steiner
- Actelion Pharmaceuticals Ltd., Allschwil, Switzerland
| |
Collapse
|
|
16
|
Bot M, Van Veldhoven PP, de Jager SCA, Johnson J, Nijstad N, Van Santbrink PJ, Westra MM, Van Der Hoeven G, Gijbels MJ, Müller-Tidow C, Varga G, Tietge UJF, Kuiper J, Van Berkel TJC, Nofer JR, Bot I, Biessen EAL. Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice. PLoS One 2013; 8:e63360. [PMID: 23700419 PMCID: PMC3659045 DOI: 10.1371/journal.pone.0063360] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 03/31/2013] [Indexed: 11/19/2022] Open
Abstract
AIMS Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets relevant to atherosclerosis. METHODS AND RESULTS LDL receptor deficient mice that were transplanted with Sgpl1(-/-) bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/-) chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response. CONCLUSIONS Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.
Collapse
Affiliation(s)
- Martine Bot
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | | | - Saskia C. A. de Jager
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Jason Johnson
- Bristol Heart Institute, Bristol Royal Infirmary, Bristol, England
| | - Niels Nijstad
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter J. Van Santbrink
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Marijke M. Westra
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | | | - Marion J. Gijbels
- Experimental Vascular Pathology Group, Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Carsten Müller-Tidow
- Department of Medicine, Hematology and Oncology, University Hospital Münster, Münster, Germany
| | - Georg Varga
- Institute of Experimental Dermatology, University of Münster, Münster, Germany
| | - Uwe J. F. Tietge
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Johan Kuiper
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Theo J. C. Van Berkel
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Jerzy-Roch Nofer
- Center for Laboratory Medicine, University Hospital Münster, Münster, Germany
- Department of Internal Medicine, Endocrinology, and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy
| | - Ilze Bot
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Erik A. L. Biessen
- Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Experimental Vascular Pathology Group, Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
| |
Collapse
|
|
17
|
Leblanc F, Zhang D, Liu X, Loughran TP. Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. Future Oncol 2013; 8:787-801. [PMID: 22830400 DOI: 10.2217/fon.12.75] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis. It is believed that LGL leukemia begins as an antigen-driven immune response with subsequent constitutive activation of cytotoxic T lymphocytes or natural killer cells through PDGF and IL-15 contributing to their survival. Consequently, this leads to a dysregulation of apoptosis and dysfunction of the activation-induced cell death pathway. Treatment of LGL leukemia is based on a low-dose immunosuppressive regimen using methotrexate or cyclophosphamide. However, no standard of therapy has been established, as large prospective trials have not been conducted. In addition, some patients are refractory to treatment. The lack of a curative therapy for LGL leukemia means that new treatment options are needed. Insight into the various dysregulated signaling pathways in LGL leukemia may provide novel therapeutic treatment modalities.
Collapse
Affiliation(s)
- Francis Leblanc
- Penn State Hershey Cancer Institute, Experimental Therapeutics, Room 4427, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, USA
| | | | | | | |
Collapse
|
|
18
|
Zhang Y, Chen YCM, Krummel MF, Rosen SD. Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2012; 189:3914-24. [PMID: 22962684 PMCID: PMC3509168 DOI: 10.4049/jimmunol.1201604] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Blood-borne lymphocytes home to lymph nodes by interacting with and crossing high endothelial venules (HEVs). The transendothelial migration (TEM) step is poorly understood. Autotaxin (ATX) is an ectoenzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid and a close relative of sphingosine 1-phosphate. HEVs produce and secrete ATX into the blood. A prior study implicated ATX in the overall homing process, but the step in which it functions and its mechanism of action have not been defined. In this article, we show that HA130, an inhibitor of the enzymatic activity of ATX, slows T cell migration across lymph node HEVs in vivo. Ex vivo, ATX plus LPC or LPA itself induces the polarization of mouse naive T cells and stimulates their motility on an ICAM-1 substratum. Under physiologic shear conditions in a flow chamber, LPA or ATX/LPC strongly enhances TEM of integrin-arrested T cells across an endothelial monolayer. HA130 blunts the TEM-promoting activity of ATX, paralleling its in vivo effects. T cells possess Mn(+2)-activatable receptors for ATX, which are localized at the leading edge of polarized cells. ATX must bind to these receptors to elicit a maximal TEM response, providing a mechanism to focus the action of LPA onto arrested lymphocytes in flowing blood. Our results indicate that LPA produced via ATX facilitates T cell entry into lymph nodes by stimulating TEM, substantiating an additional step in the homing cascade. This entry role for LPA complements the efflux function of sphingosine 1-phosphate.
Collapse
Affiliation(s)
- Yafeng Zhang
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA
| | | | | | | |
Collapse
|
|
19
|
Kays JS, Li C, Nicol GD. Expression of sphingosine 1-phosphate receptors in the rat dorsal root ganglia and defined single isolated sensory neurons. Physiol Genomics 2012; 44:889-901. [PMID: 22805346 PMCID: PMC3472456 DOI: 10.1152/physiolgenomics.00053.2012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Accepted: 07/13/2012] [Indexed: 12/13/2022] Open
Abstract
Previously, we demonstrated that sphingosine 1-phosphate (S1P) increased the excitability of small-diameter sensory neurons, in part, through activation of S1P receptor 1 (S1PR(1)), suggesting that other S1PRs can modulate neuronal excitability. Therefore, studies were undertaken to establish the expression profiles of S1PRs in the intact dorsal root ganglion (DRG) and in defined single isolated sensory neurons. To determine mRNA expression of S1PRs in the DRG, SYBR green quantitative PCR (qPCR) was used. To determine the expression of S1PR mRNAs in single neurons of defined diameters, a preamplification protocol utilizing Taqman primer and probes was used to enhance the sensitivity of detection. The preamplification protocol also permitted detection of mRNA for two hallmark neuronal receptor/ion channels, TRPV1 and P(2)X(3). Expression profiles of S1PR mRNA isolated from lung and brain were used as positive control tissues. In the intact DRG, the order of expression of S1PRs was S1PR(3)>>R(1)≈R(2)>R(5)≈R(4). In the single neurons, the expression of S1PRs was quite variable with some neurons expressing all five subtypes, whereas some expressing only one subtype. In contrast to the DRG, S1PR(1) was the highest expressing subtype in 10 of the 18 small-, medium-, and large-diameter sensory neurons. S1PR(1) was the second highest expressor in -50% of those remaining neurons. Overall, in the single neurons, the order of expression was S1PR(1)>>R(3)≈R(5)>R(4)>R(2). The results obtained from the single defined neurons are consistent with our previous findings wherein S1PR(1) plays a prominent but not exclusive role in the enhancement of neuronal excitability.
Collapse
Affiliation(s)
- J. S. Kays
- Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, Indiana; and
| | - Chao Li
- Medical Neuroscience Program, School of Medicine, Indiana University, Indianapolis, Indiana
| | - G. D. Nicol
- Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, Indiana; and
| |
Collapse
|
|
20
|
Li C, Chi XX, Xie W, Strong JA, Zhang JM, Nicol GD. Sphingosine 1-phosphate receptor 2 antagonist JTE-013 increases the excitability of sensory neurons independently of the receptor. J Neurophysiol 2012; 108:1473-83. [PMID: 22673325 DOI: 10.1152/jn.00825.2011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Previously we demonstrated that sphingosine 1-phosphate receptor 1 (S1PR(1)) played a prominent, but not exclusive, role in enhancing the excitability of small-diameter sensory neurons, suggesting that other S1PRs can modulate neuronal excitability. To examine the potential role of S1PR(2) in regulating neuronal excitability we used the established selective antagonist of S1PR(2), JTE-013. Here we report that exposure to JTE-013 alone produced a significant increase in excitability in a time- and concentration-dependent manner in 70-80% of recorded neurons. Internal perfusion of sensory neurons with guanosine 5'-O-(2-thiodiphosphate) (GDP-β-S) via the recording pipette inhibited the sensitization produced by JTE-013 as well as prostaglandin E(2). Pretreatment with pertussis toxin or the selective S1PR(1) antagonist W146 blocked the sensitization produced by JTE-013. These results indicate that JTE-013 might act as an agonist at other G protein-coupled receptors. In neurons that were sensitized by JTE-013, single-cell RT-PCR studies demonstrated that these neurons did not express the mRNA for S1PR(2). In behavioral studies, injection of JTE-013 into the rat's hindpaw produced a significant increase in the mechanical sensitivity in the ipsilateral, but not contralateral, paw. Injection of JTE-013 did not affect the withdrawal latency to thermal stimulation. Thus JTE-013 augments neuronal excitability independently of S1PR(2) by unknown mechanisms that may involve activation of other G protein-coupled receptors such as S1PR(1). Clearly, further studies are warranted to establish the causal nature of this increased sensitivity, and future studies of neuronal function using JTE-013 should be interpreted with caution.
Collapse
Affiliation(s)
- Chao Li
- Medical Neuroscience Program, School of Medicine, Indiana University, Indianapolis, IN, USA
| | | | | | | | | | | |
Collapse
|
|
21
|
Guerrero M, Urbano M, Zhao J, Crisp M, Chase P, Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E. Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P₄-R) agonists. Bioorg Med Chem Lett 2011; 22:537-42. [PMID: 22119461 DOI: 10.1016/j.bmcl.2011.10.096] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 10/24/2011] [Accepted: 10/26/2011] [Indexed: 10/15/2022]
Abstract
High affinity and selective small molecule agonists of the S1P(4) receptor (S1P(4)-R) may have significant therapeutic utility in diverse disease areas including autoimmune diseases, viral infections and thrombocytopenia. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 3-(2-(2,4-dichlorophenoxy)ethoxy)-6-methyl-2-nitropyridine as a moderately potent and selective S1P(4)-R hit agonist. Design, synthesis and systematic structure-activity relationships study of the HTS-derived hit led to the development of novel potent S1P(4)-R agonists exquisitely selective over the remaining S1P(1-3,5)-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R.
Collapse
Affiliation(s)
- Miguel Guerrero
- Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Goetzl EJ, Schwartz JB, Huang MC. Defective T cell chemotaxis to sphingosine 1-phosphate and chemokine CCL21 in idiopathic T lymphocytopenia. J Clin Immunol 2011; 31:744-51. [PMID: 21671128 DOI: 10.1007/s10875-011-9554-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 05/27/2011] [Indexed: 01/23/2023]
Abstract
T cell chemotaxis to sphingosine 1-phosphate (S1P) and the chemokines CCL21 and CCL5 was studied in ten adults with T lymphocytopenia, other immunological abnormalities (nine of ten), and frequent bacterial infections (seven of ten). Mean chemotactic responses to S1P of CD4 T cells from CD4 T lymphocytopenic patients and of CD8 T cells from CD8 T lymphocytopenic patients were significantly lower than those of healthy matched controls. Chemotaxis to CCL21 was lower than that of controls for CD4 T cells of three CD4 T lymphocytopenic patients and for CD8 T cells of three CD8 T lymphocytopenic patients, but none of the T cells of patients had diminished chemotaxis to CCL5. Defective T cell chemotactic responses to S1P and some chemokines may lead to subset-selective abnormal T cell trafficking and chronic T cell lymphocytopenia.
Collapse
Affiliation(s)
- Edward J Goetzl
- Department of Medicine, University of California, Geriatric Research Center, San Francisco, CA 94112, USA.
| | | | | |
Collapse
|
|
23
|
Awad AS, Rouse MD, Khutsishvili K, Huang L, Bolton WK, Lynch KR, Okusa MD. Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int 2011; 79:1090-8. [PMID: 21289599 DOI: 10.1038/ki.2010.544] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sphingosine 1-phosphate (S1P), a pleiotropic lipid mediator, binds to five related G-protein-coupled receptors to exert its effects. As S1P1 receptor (S1P1R) activation blocks kidney inflammation in acute renal injury, we tested whether activation of S1P1Rs ameliorates renal injury in early-stage diabetic nephropathy (DN) in rats. Urinary albumin excretion increased in vehicle-treated diabetic rats (single injection of streptozotocin), compared with controls, and was associated with tubule injury and increased urinary tumor necrosis factor-α (TNF-α) at 9 weeks. These effects were significantly reduced by FTY720, a non-selective, or SEW2871, a selective S1P1R agonist. Interestingly, only FTY720 was associated with reduced total lymphocyte levels. Albuminuria was reduced by SEW2871 in both Rag-1 (T- and B-cell deficient) and wild-type diabetic mice after 6 weeks, suggesting that the effect was independent of lymphocytes. Another receptor, S1P3R, did not contribute to the FTY720-mediated protection, as albuminuria was also reduced in diabetic S1P3R knockout mice. Further, both agonists restored WT-1 staining along with podocin and nephrin mRNA expression, suggesting podocyte protection. This was corroborated in vitro, as SEW2871 reduced TNF-α and vascular endothelial growth factor mRNA expression in immortalized podocytes grown in media containing high glucose. Whether targeting kidney S1P1Rs will be a useful therapeutic measure in DN will need direct testing.
Collapse
Affiliation(s)
- Alaa S Awad
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Iwasaki T, Tsunemi S, Kitano S, Kanda C, Sekiguchi M, Kitano M, Sano H. Role of sphingosine 1-phosphate signaling for the pathogenesis of autoimmune diseases. Inflamm Regen 2011. [DOI: 10.2492/inflammregen.31.175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
|
|
25
|
Sefcik LS, Aronin CEP, Awojoodu AO, Shin SJ, Mac Gabhann F, MacDonald TL, Wamhoff BR, Lynch KR, Peirce SM, Botchwey EA. Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth. Tissue Eng Part A 2010; 17:617-29. [PMID: 20874260 DOI: 10.1089/ten.tea.2010.0404] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Proper spatial and temporal regulation of microvascular remodeling is critical to the formation of functional vascular networks, spanning the various arterial, venous, capillary, and collateral vessel systems. Recently, our group has demonstrated that sustained release of sphingosine 1-phosphate (S1P) from biodegradable polymers promotes microvascular network growth and arteriolar expansion. In this study, we employed S1P receptor-specific compounds to activate and antagonize different combinations of S1P receptors to elucidate those receptors most critical for promotion of pharmacologically induced microvascular network growth. We show that S1P(1) and S1P(3) receptors act synergistically to enhance functional network formation via increased functional length density, arteriolar diameter expansion, and increased vascular branching in the dorsal skinfold window chamber model. FTY720, a potent activator of S1P(1) and S1P(3), promoted a 107% and 153% increase in length density 3 and 7 days after implantation, respectively. It also increased arteriolar diameters by 60% and 85% 3 and 7 days after implantation. FTY720-stimulated branching in venules significantly more than unloaded poly(D, L-lactic-co-glycolic acid). When implanted on the mouse spinotrapezius muscle, FTY720 stimulated an arteriogenic response characterized by increased tortuosity and collateralization of branching microvascular networks. Our results demonstrate the effectiveness of S1P(1) and S1P(3) receptor-selective agonists (such as FTY720) in promoting microvascular growth for tissue engineering applications.
Collapse
Affiliation(s)
- Lauren S Sefcik
- Department of Chemical and Biomolecular Engineering, Lafayette College, Easton, Pennsylvania, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Regulation of phosphatidic Acid metabolism by sphingolipids in the central nervous system. J Lipids 2010; 2011:342576. [PMID: 21490799 PMCID: PMC3068476 DOI: 10.1155/2011/342576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 10/14/2010] [Indexed: 12/12/2022] Open
Abstract
This paper explores the way ceramide, sphingosine, ceramide 1-phosphate, and sphingosine 1-phosphate modulate the generation of second lipid messengers from phosphatidic acid in two experimental models of the central nervous system: in vertebrate rod outer segments prepared from dark-adapted retinas as well as in rod outer segments prepared from light-adapted retinas and in rat cerebral cortex synaptosomes under physiological aging conditions. Particular attention is paid to lipid phosphate phosphatase, diacylglycerol lipase, and monoacylglycerol lipase. Based on the findings reported in this paper, it can be concluded that proteins related to phototransduction phenomena are involved in the effects derived from sphingosine 1-phosphate/sphingosine or ceramide 1-phosphate/ceramide and that age-related changes occur in the metabolism of phosphatidic acid from cerebral cortex synaptosomes in the presence of either sphingosine 1-phosphate/sphingosine or ceramide 1-phosphate/ceramide. The present paper demonstrates, in two different models of central nervous system, how sphingolipids influence phosphatidic acid metabolism under different physiological conditions such as light and aging.
Collapse
|
|
27
|
Chi XX, Nicol GD. The sphingosine 1-phosphate receptor, S1PR₁, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. J Neurophysiol 2010; 104:2741-8. [PMID: 20844107 DOI: 10.1152/jn.00709.2010] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) through its interaction with a family of G protein-coupled receptors (S1PR) is proving to have a significant impact on the activation of a variety of cell types, most notably those cells mediating the inflammatory response. Previously, we showed that S1P enhanced the excitability of small diameter sensory neurons, and mRNA for S1PR(1-4) was expressed in sensory neurons. These initial findings did not determine which S1PR subtype(s) mediated the increased excitability. Here, we report that exposure to the selective S1PR(1) agonist, SEW2871, produced a significant increase in excitability of some, but not all, sensory neurons. To further examine the role of S1PR(1), neurons were treated with siRNA targeted to S1PR(1). siRNA reduced S1PR(1) protein expression by 75% and blocked the sensitization produced by SEW2871, although some neurons remained responsive to subsequent exposure to S1P. Treatment with scramble siRNA did not alter S1PR(1) expression. Recordings from siRNA- and scramble-treated neurons suggested three distinct populations based on their sensitivities to SEW2871 and S1P. Approximately 50% of the neurons exhibited a significant increase in excitability after exposure to SEW2871 and subsequent S1P produced no additional increase; ∼25% were not affected by SEW2871 but S1P significantly increased excitability; and ∼25% of the neurons were not sensitized by either SEW2871 or S1P. RT-PCR measurements obtained from single neurons showed that 50% of the small diameter neurons expressed the mRNA for S1PR(1). These results indicate that S1PR(1) plays a prominent, although not exclusive, role in mediating the enhancement of excitability produced by S1P.
Collapse
Affiliation(s)
- Xian Xuan Chi
- Department of Pharmacology and Toxicology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
| | | |
Collapse
|
|
28
|
Morris AJ, Panchatcharam M, Cheng HY, Federico L, Fulkerson Z, Selim S, Miriyala S, Escalante-Alcalde D, Smyth SS. Regulation of blood and vascular cell function by bioactive lysophospholipids. J Thromb Haemost 2009; 7 Suppl 1:38-43. [PMID: 19630765 PMCID: PMC2801156 DOI: 10.1111/j.1538-7836.2009.03405.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Lysophosphatidic acid (LPA), its sphingolipid homolog sphingosine 1-phosphate (S1P) and several other related molecules constitute a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, inflammation, immunomodulation, apoptosis and development. LPA and S1P are present in physiologically relevant concentrations in the circulation. In isolated cell culture systems or animal models, these lipids exert a range of effects that suggest that S1P and LPA could play important roles in maintaining normal vascular homeostasis and in vascular injury responses. LPA and S1P act on a series of G protein-coupled receptors, and LPA may also be an endogenous regulator of PPARgamma activity. In this review, we discuss potential roles for lysolipid signaling in the vasculature and mechanisms by which these bioactive lipids could contribute to cardiovascular disease.
Collapse
Affiliation(s)
- A J Morris
- The Gill Heart Institute, Division of Cardiovascular Medicine, Lexington, KY, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Goldsmith M, Avni D, Levy-Rimler G, Mashiach R, Ernst O, Levi M, Webb B, Meijler MM, Gray NS, Rosen H, Zor T. A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-alpha and induces interleukin-10 production in activated macrophages. Immunology 2009; 127:103-15. [PMID: 18793216 DOI: 10.1111/j.1365-2567.2008.02928.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Tight regulation of the production of the key pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is essential for the prevention of chronic inflammatory diseases. In vivo administration of a synthetic phospholipid, named hereafter phospho-ceramide analogue-1 (PCERA-1), was previously found to suppress lipopolysaccharide (LPS)-induced TNF-alpha blood levels. We therefore investigated the in vitro anti-inflammatory effects of PCERA-1. Here, we show that extracellular PCERA-1 potently suppresses production of the pro-inflammatory cytokine TNF-alpha in RAW264.7 macrophages, and in addition, independently and reciprocally regulates the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Specificity is demonstrated by the inability of the phospholipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) to perform these activities. Similar TNF-alpha suppression and IL-10 induction by PCERA-1 were observed in macrophages when activated by Toll-like receptor 4 (TLR4), TLR2 and TLR7 agonists. Regulation of cytokine production is demonstrated at the mRNA and protein levels. Finally, we show that, while PCERA-1 does not block activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinases by LPS, it elevates the intracellular cAMP level. In conclusion, the anti-inflammatory activity of PCERA-1 seems to be mediated by a cell membrane receptor, upstream of cAMP production, and eventually TNF-alpha suppression and IL-10 induction. Thus, identification of the PCERA-1 receptor may provide new pharmacological means to block inflammation.
Collapse
Affiliation(s)
- Meir Goldsmith
- Department of Molecular and Structural Biochemistry, Life Sciences Institute, Tel-Aviv University, Tel-Aviv, Israel
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Abstract
Lysophosphatidic acid (LPA) can affect the growth, migration, and activation of many different cell types. Research in this field has recently accelerated due to the molecular cloning of LPA receptors as well as advances in our understanding of LPA metabolism. A major pathway for LPA generation is the hydrolysis of lysophosphatidylcholine by the enzyme autotaxin (ATX). Although most research to-date has been conducted in other disciplines (e.g., neurobiology and cardiovascular diseases), emerging data point to an important role for LPA and ATX in regulating immune responses. Here we review current understanding of LPA and ATX in immunity with an emphasis on migration and activation of lymphocytes and dendritic cells. New gene-targeted and transgenic mice, receptor-specific antibodies, and pathway antagonists should rapidly enhance our understanding of this versatile lysolipid in immune responses in the near future.
Collapse
Affiliation(s)
- Steve N Georas
- Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, NY 14610, USA.
| |
Collapse
|
|
31
|
Miron VE, Hall JA, Kennedy TE, Soliven B, Antel JP. Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:1143-52. [PMID: 18772343 DOI: 10.2353/ajpath.2008.080478] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Fingolimod is a sphingosine-1-phosphate (S1P) analogue that has been used in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis. Fingolimod readily accesses the central nervous system, raising the issue of its direct effects on neural cells. We assessed the effects of active fingolimod on dissociated cultures of mature, myelin-producing oligodendrocytes (OLGs) derived from adult human brain. Human OLGs express S1P receptor transcripts in relative abundance of S1P5>S1P3>S1P1, with undetectable levels of S1P4. Low doses of fingolimod (100 pmol/L to 1 nmol/L) induced initial membrane elaboration (2 days), subsequent retraction (4 days), and recurrence of extension with prolonged treatment (8 days). Higher doses (10 nmol/L to 1 mumol/L) caused the opposite modulation of membrane dynamics. Retraction was rescued by co-treatment with the S1P3/S1P5 pathway antagonist, suramin, and was associated with RhoA-mediated cytoskeletal signaling. Membrane elaboration was mimicked using the S1P1 agonist SEW2871. Fingolimod rescued human OLGs from serum and glucose deprivation-induced apoptosis, which was reversed with suramin co-treatment and mimicked using an S1P5 agonist. High doses of fingolimod induced an initial down-regulation of S1P5 mRNA levels relative to control (4 hours), subsequent up-regulation (2 days), and recurrent down-regulation (8 days). S1P1 mRNA levels were inversely regulated compared with S1P5. These results indicate that fingolimod modulates maturity- and species-specific OLG membrane dynamics and survival responses that are directly relevant for myelin integrity.
Collapse
Affiliation(s)
- Veronique E Miron
- Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | | | | | | | | |
Collapse
|
|
32
|
Ryan JJ, Spiegel S. The role of sphingosine-1-phosphate and its receptors in asthma. ACTA ACUST UNITED AC 2008; 21:89-96. [PMID: 18389100 DOI: 10.1358/dnp.2008.21.2.1188195] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that plays important roles in allergic responses, including asthma and anaphylaxis, the incidence of which is rising worldwide especially in industrialized urban populations. In this review, we will discuss how S1P is formed and released, and how it acts at many cellular levels, including mast cells, the airway epithelium, airway smooth muscle and many immune cells. Since the actions of S1P on all of these cells could exacerbate allergic responses, the proteins that synthesize, release and respond to S1P offer plausible targets for a new generation of antiinflammatory therapeutics.
Collapse
Affiliation(s)
- John J Ryan
- Department of Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA
| | | |
Collapse
|
|
33
|
Smyth SS, Cheng HY, Miriyala S, Panchatcharam M, Morris AJ. Roles of lysophosphatidic acid in cardiovascular physiology and disease. Biochim Biophys Acta Mol Cell Biol Lipids 2008; 1781:563-70. [PMID: 18586114 DOI: 10.1016/j.bbalip.2008.05.008] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2008] [Revised: 05/27/2008] [Accepted: 05/30/2008] [Indexed: 02/07/2023]
Abstract
The bioactive lipid mediator lysophosphatidic acid (LPA) exerts a range of effects on the cardiovasculature that suggest a role in a variety of critical cardiovascular functions and clinically important cardiovascular diseases. LPA is an activator of platelets from a majority of human donors identifying a possible role as a regulator of acute thrombosis and platelet function in atherogenesis and vascular injury responses. Of particular interest in this context, LPA is an effective phenotypic modulator of vascular smooth muscle cells promoting the de-differentiation, proliferation and migration of these cells that are required for the development of intimal hyperplasia. Exogenous administration of LPA results in acute and systemic changes in blood pressure in different animal species, suggesting a role for LPA in both normal blood pressure regulation and hypertension. Advances in our understanding of the molecular machinery responsible for the synthesis, actions and inactivation of LPA now promise to provide the tools required to define the role of LPA in cardiovascular physiology and disease. In this review we discuss aspects of LPA signaling in the cardiovasculature focusing on recent advances and attempting to highlight presently unresolved issues and promising avenues for further investigation.
Collapse
Affiliation(s)
- Susan S Smyth
- Department of Veterans Affairs Medical Center, Lexington, Kentucky 40511, USA.
| | | | | | | | | |
Collapse
|
|
34
|
Kekkonen RA, Sysi-Aho M, Seppänen-Laakso T, Julkunen I, Vapaatalo H, Orešič M, Korpela R. Effect of probiotic Lactobacillus rhamnosus GG intervention on global serum lipidomic profiles in healthy adults. World J Gastroenterol 2008; 14:3188-94. [PMID: 18506924 PMCID: PMC2712851 DOI: 10.3748/wjg.14.3188] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of three weeks’ intervention with a probiotic Lactobacillus rhamnosus GG (LGG) bacteria on global serum lipidomic profiles and evaluate whether the changes in inflammatory variables (CRP, TNF-α and IL-6) are reflected in the global lipidomic profiles of healthy adults.
METHODS: We performed UPLC/MS-based global lipidomic platform analysis of serum samples (n = 26) in a substudy of a randomised, double-blind, placebo-controlled 3-wk clinical intervention trial investigating the immunomodulatory effects of probiotics in healthy adults.
RESULTS: A total of 407 lipids were identified, corresponding to 13 different lipid classes. Serum samples showed decreases in the levels of lysophosphatidylcholines (LysoGPCho), sphingomyelins (SM) and several glycerophosphatidylcholines (GPCho), while triacylglycerols (TAG) were mainly increased in the probiotic LGG group during the intervention. Among the inflammatory variables, IL-6 was moderately associated by changes in global lipidomic profiles, with the top-ranked lipid associated with IL-6 being the proinflammatory LysoGPCho (20:4). There was a weak association between the lipidomic profiles and the two other inflammatory markers, TNF-α and CRP.
CONCLUSION: This was the first study to investigate the effects of probiotic intervention on global lipidomic profiles in humans. There are indications that probiotic LGG intervention may lead to changes in serum global lipid profiles, as reflected in decreased GPCho, LysoGPCho and SM as well as mainly increased TAG.
Collapse
|
|
35
|
Goetzl EJ, Liao JJ, Huang MC. Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity. Biochim Biophys Acta Mol Cell Biol Lipids 2008; 1781:503-7. [PMID: 18381082 DOI: 10.1016/j.bbalip.2008.03.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2008] [Revised: 02/22/2008] [Accepted: 03/03/2008] [Indexed: 01/20/2023]
Abstract
The lipid mediator sphingosine 1-phosphate (S1P) and its type 1 G protein-coupled receptor (S1P1) affect mammalian immunity through alterations in thymocyte emigration, differentiation of T cell subsets, lymphocyte trafficking in lymphoid organs and other tissues, T cell-dendritic cell and T cell-B cell interactions, and cytokine generation. Recent attention to effects of the S1P-S1P1 axis on non-migration functions of lymphocytes includes delineation of a role in terminal differentiation and survival of Th17 effector cells and adaptive Treg cells of the CD4 T cell constellation, and a greater understanding of interactions of the S1P-S1P1 axis with immune cytokines in lymphocyte survival and activities. This breadth of involvement of the S1P-S1P1 axis in immune responses that often are altered in immunological diseases has provided many opportunities for novel therapeutic interventions. A spectrum of pharmacological and immunochemical agents is available that alter immunity by affecting either tissue and fluid concentrations of S1P or levels of expression and signaling activities of S1P1. Such agents have so far been beneficial in the settings of autoimmunity and rejection of transplanted organs, and are likely to become valuable constituents of combined drug programs.
Collapse
Affiliation(s)
- Edward J Goetzl
- Department of Medicine, University of California Medical Center, San Francisco, CA 94143, USA.
| | | | | |
Collapse
|
|
36
|
Kanda H, Newton R, Klein R, Morita Y, Gunn MD, Rosen SD. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 2008; 9:415-23. [PMID: 18327261 DOI: 10.1038/ni1573] [Citation(s) in RCA: 211] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2007] [Accepted: 02/08/2008] [Indexed: 12/23/2022]
Abstract
The extracellular lysophospholipase D autotaxin (ATX) and its product, lysophosphatidic acid, have diverse functions in development and cancer, but little is known about their functions in the immune system. Here we found that ATX had high expression in the high endothelial venules of lymphoid organs and was secreted. Chemokine-activated lymphocytes expressed receptors with enhanced affinity for ATX, which provides a mechanism for targeting the secreted ATX to lymphocytes undergoing recruitment. Lysophosphatidic acid induced chemokinesis in T cells. Intravenous injection of enzymatically inactive ATX attenuated the homing of T cells to lymphoid tissues, probably through competition with endogenous ATX and exertion of a dominant negative effect. Our results support the idea of a new and general step in the homing cascade in which the ectoenzyme ATX facilitates the entry of lymphocytes into lymphoid organs.
Collapse
Affiliation(s)
- Hidenobu Kanda
- Department of Anatomy, Program in Immunology, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA
| | | | | | | | | | | |
Collapse
|
|
37
|
Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int 2008; 73:1220-30. [PMID: 18322542 DOI: 10.1038/ki.2008.34] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis, vascular maturation, immunity, chemotaxis, and other important biological pathways. Recently, clinical trials have targeted S1P receptors (S1PRs) for autoimmune diseases and transplantation and have generated considerable interest in developing additional, more selective compounds. This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease.
Collapse
|
|
38
|
Grégoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T. The trafficking of natural killer cells. Immunol Rev 2008; 220:169-82. [PMID: 17979846 PMCID: PMC7165697 DOI: 10.1111/j.1600-065x.2007.00563.x] [Citation(s) in RCA: 408] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Natural killer (NK) cells are large granular lymphocytes of the innate immune system that participate in the early control of microbial infections and cancer. NK cells can induce the death of autologous cells undergoing various forms of stress, recognizing and providing non-microbial 'danger' signals to the immune system. NK cells are widely distributed in lymphoid and non-lymphoid organs. NK cell precursors originate from the bone marrow and go through a complex maturation process that leads to the acquisition of their effector functions, to changes in their expression of integrins and chemotactic receptors, and to their redistribution from the bone marrow and lymph nodes to blood, spleen, liver, and lung. Here, we describe the tissue localization of NK cells, using NKp46 as an NK cell marker, and review the current knowledge on the mechanisms that govern their trafficking in humans and in mice.
Collapse
Affiliation(s)
- Claude Grégoire
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Kunisawa J, Kurashima Y, Gohda M, Higuchi M, Ishikawa I, Miura F, Ogahara I, Kiyono H. Sphingosine 1-phosphate regulates peritoneal B-cell trafficking for subsequent intestinal IgA production. Blood 2007; 109:3749-56. [PMID: 17234743 DOI: 10.1182/blood-2006-08-041582] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractSphingosine 1-phosphate (S1P) is known to play a pivotal role in the regulation of lymphocyte emigration from organized lymphoid tissues such as the peripheral lymph nodes and thymus, but its immunologic role in unorganized and diffused tissues remains to be elucidated. Here we show that the trafficking of peritoneal B cells is principally regulated by S1P. All peritoneal B cells including B1a, B1b, and B2 B cells express comparable levels of the type 1 S1P receptor. Thus, treatment with FTY720, an S1P receptor modulator, caused the rapid disappearance of peritoneal B cells by inhibiting both their emigration from parathymic lymph nodes and their recirculation from the blood into the peritoneal cavity without affecting their progenitor populations. These changes did not affect natural plasma antibody production or phosphorylcholine (PC)–specific antibody production in serum after peritoneal immunization with heat-killed Streptococcal pneumoniae (R36A). However, FTY720 dramatically reduced peritoneal B cell-derived natural intestinal secretory IgA production without affecting the expression of J-chain and polyimmunoglobulin receptors. Additionally, FTY720 impaired the generation of PC-specific fecal IgA responses after oral immunization with R36A. These findings point to a pivotal role for S1P in connecting peritoneal B cells with intestinal B-cell immunity.
Collapse
MESH Headings
- Animals
- Antibodies, Antiphospholipid/biosynthesis
- Antibodies, Antiphospholipid/immunology
- Antibodies, Bacterial/biosynthesis
- Antibodies, Bacterial/immunology
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- Bacterial Vaccines/immunology
- Bacterial Vaccines/pharmacology
- Cell Movement/drug effects
- Female
- Fingolimod Hydrochloride
- Immunoglobulin A/immunology
- Immunoglobulin A/metabolism
- Immunoglobulin J-Chains/biosynthesis
- Immunoglobulin J-Chains/immunology
- Immunosuppressive Agents/pharmacology
- Intestine, Small/immunology
- Intestine, Small/metabolism
- Lymphoid Tissue/immunology
- Lymphoid Tissue/metabolism
- Lysophospholipids/pharmacology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred ICR
- Mice, SCID
- Peritoneal Cavity
- Propylene Glycols/pharmacology
- Receptors, Lysosphingolipid/agonists
- Receptors, Lysosphingolipid/biosynthesis
- Receptors, Lysosphingolipid/immunology
- Sphingosine/analogs & derivatives
- Sphingosine/pharmacology
- Streptococcus pneumoniae/immunology
- Vaccination
Collapse
Affiliation(s)
- Jun Kunisawa
- Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Jiang X, Han X. Characterization and direct quantitation of sphingoid base-1-phosphates from lipid extracts: a shotgun lipidomics approach. J Lipid Res 2006; 47:1865-73. [PMID: 16682747 PMCID: PMC2141545 DOI: 10.1194/jlr.d600012-jlr200] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Here, we have extended shotgun lipidomics for the characterization and quantitation of sphingosine-1-phosphate (S1P) and dihydrosphingosine-1-phosphate (DHS1P) in crude lipid extracts in the presence of ammonium hydroxide by using precursor ion scanning of m/z 79.0 (corresponding to [PO(3)](-)) in the negative-ion mode. It is demonstrated that a broad linear dynamic range for the quantitation of both S1P and DHS1P and a detection limit at low amol/mul concentration are achieved using this approach. The developed method for the quantitation of sphingoid base-1-phosphates is generally simpler and more efficient than other previously published methods. Multiple factors influencing the quantitation of sphingoid base-1-phosphates, including ion suppression, extraction efficiency, and potential overlapping with other molecular species, were examined extensively and/or are discussed. Mass levels of S1P and DHS1P in multiple biological samples, including human plasma, mouse plasma, and mouse brain tissues (e.g., cortex, cerebellum, spinal cord, and brain stem), were determined by the developed methodology. Accordingly, this technique, as a new addition to shotgun lipidomics technology, will be extremely useful for understanding the pathways of sphingolipid metabolism and for exploring the important roles of sphingoid base-1-phosphates in a wide range of physiological and pathological studies.
Collapse
Affiliation(s)
| | - Xianlin Han
- To whom correspondence should be addressed. e-mail:
| |
Collapse
|
|
41
|
Islam SA, Thomas SY, Hess C, Medoff BD, Means TK, Brander C, Lilly CM, Tager AM, Luster AD. The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans. Blood 2005; 107:444-53. [PMID: 16179368 PMCID: PMC1490027 DOI: 10.1182/blood-2005-06-2362] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We have recently shown that the leukotriene B(4) (LTB(4))-BLT1 pathway is important in early effector T-cell recruitment in mouse models of inflammation. Here we characterize the phenotype and function of human peripheral blood BLT1(+) T cells in health and illustrate their involvement in asthma and acute infection. In healthy individuals, BLT1(+) T cells are a rare peripheral blood T-cell population enriched for the activation markers CD38 and HLA-DR. Compared with BLT1(-) T cells, a larger proportion of peripheral blood BLT1(+) T cells express the effector cytokines IFNgamma and IL-4 and inflammatory chemokine receptors, CCR1, CCR2, CCR6, and CXCR1. Consequently, in healthy individuals peripheral blood BLT1(+) T cells are a rare antigen-primed T-cell subset with unique phenotypic, migratory, and functional properties. BLT1 expression on T cells is tightly regulated by inflammation and only transiently expressed after naive T-cell activation by dendritic cells. Although rare in the peripheral blood of healthy individuals, BLT1(+) T cells are markedly increased in frequency in the peripheral blood in response to acute Epstein-Barr virus (EBV) infection and moderately increased in the airways of asymptomatic allergic asthmatics. Our studies provide novel insights into the LTB(4)-BLT1 lipid chemoattractant pathway in human T-cell responses, and how it may link innate and adaptive immunity.
Collapse
MESH Headings
- ADP-ribosyl Cyclase 1/immunology
- ADP-ribosyl Cyclase 1/metabolism
- Acute Disease
- Asthma/immunology
- Bronchoalveolar Lavage Fluid/cytology
- Case-Control Studies
- Cells, Cultured
- Epstein-Barr Virus Infections/immunology
- Epstein-Barr Virus Infections/metabolism
- HLA-DR Antigens/immunology
- HLA-DR Antigens/metabolism
- Herpesvirus 4, Human/isolation & purification
- Humans
- Inflammation
- Interferon-gamma/metabolism
- Interleukin-4/metabolism
- Leukotriene B4/metabolism
- Lymphocyte Activation
- Protein Serine-Threonine Kinases/metabolism
- Receptors, CCR2
- Receptors, CCR6
- Receptors, Chemokine/metabolism
- Receptors, Interleukin-8A/metabolism
- Receptors, Leukotriene B4/genetics
- Receptors, Leukotriene B4/immunology
- Receptors, Leukotriene B4/metabolism
- Receptors, Purinergic P2/genetics
- Receptors, Purinergic P2/immunology
- Receptors, Purinergic P2/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
Collapse
Affiliation(s)
- Sabina A Islam
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Fieger CB, Huang MC, Van Brocklyn JR, Goetzl EJ. Type 1 sphingosine 1-phosphate G protein-coupled receptor signaling of lymphocyte functions requires sulfation of its extracellular amino-terminal tyrosines. FASEB J 2005; 19:1926-8. [PMID: 16148028 PMCID: PMC1557661 DOI: 10.1096/fj.05-4476fje] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The type 1 sphingosine 1-phosphate (S1P) G protein-coupled receptor (S1P1) transduces signals from S1P that mediate thymocyte emigration, T cell transmigration of lymph nodes, and T cell chemotaxis in tissues. Alterations in expression of functional S1P1 receptors by lymphocytes are the major mechanisms controlling their responses to S1P and were thought to be solely a consequence of the balance between surface down-regulation and insertion. However, results now show that lack of sulfation of tyrosines 19 and 22 of the extracellular N terminus of S1P1 diminishes high-affinity S1P binding and decreases S1P signaling of T cell migration and other functions. Non-sulfatable mutant (Y19,22F)S1P1 endows T cells with lower-affinity binding of [32P]S1P than wild-type S1P1 and transduces lesser effects of S1P on chemotaxis, chemokine-elicited chemotaxis, and T cell receptor-mediated proliferation and cytokine generation. Inhibition of S1P1 tyrosine sulfation or sulfatase removal of S1P1 sulfate in mouse CD4 T cells suppresses immune functional effects of S1P. Tyrosine sulfation of S1P1 may be a major controller of S1P effects on T cell traffic.
Collapse
Affiliation(s)
| | - Mei-Chuan Huang
- Medicine and Microbiology-Immunology, University of California, San Francisco, California; and
| | | | - Edward J. Goetzl
- Medicine and Microbiology-Immunology, University of California, San Francisco, California; and
- Corresponding author: Edward J. Goetzl, University of California, Room UB8B, UC Box 0711, 533 Parnassus at 4th Ave., San Francisco, CA, 94143-0711. E-mail:
| |
Collapse
|