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Dickinson K, Yee EJ, Vigil I, Schulick RD, Zhu Y. GPCRs: emerging targets for novel T cell immune checkpoint therapy. Cancer Immunol Immunother 2024; 73:253. [PMID: 39358616 PMCID: PMC11447192 DOI: 10.1007/s00262-024-03801-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/24/2024] [Accepted: 08/05/2024] [Indexed: 10/04/2024]
Abstract
Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.
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Affiliation(s)
- Kaitlyn Dickinson
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Elliott J Yee
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Isaac Vigil
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Richard D Schulick
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Yuwen Zhu
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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2
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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Taketomi Y, Higashi T, Kano K, Miki Y, Mochizuki C, Toyoshima S, Okayama Y, Nishito Y, Nakae S, Tanaka S, Tokuoka SM, Oda Y, Shichino S, Ueha S, Matsushima K, Akahoshi N, Ishii S, Chun J, Aoki J, Murakami M. Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts. Immunity 2024; 57:1828-1847.e11. [PMID: 39002541 DOI: 10.1016/j.immuni.2024.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2023] [Revised: 04/04/2024] [Accepted: 06/19/2024] [Indexed: 07/15/2024]
Abstract
Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
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Affiliation(s)
- Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Takayoshi Higashi
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshimi Miki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Chika Mochizuki
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shota Toyoshima
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Yoshimichi Okayama
- Allergy and Immunology Research Project Team, Research Institute of Medical Science, Center for Allergy, and Division of Internal Medicine, Department of Respiratory Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan; Department of Allergy and Internal Medicine, Misato Kenwa Hospital, Saitama 341-8555, Japan; Department of Internal Medicine, Division of Respiratory Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan; Advanced Medical Science Research Center, Gunma Paz University Graduate School of Health Sciences, Takasaki 370-0006, Japan
| | - Yasumasa Nishito
- Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan
| | - Satoshi Tanaka
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Suzumi M Tokuoka
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yoshiya Oda
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
| | - Noriyuki Akahoshi
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Satoshi Ishii
- Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Jerold Chun
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
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Fischer C, Schreiber Y, Nitsch R, Vogt J, Thomas D, Geisslinger G, Tegeder I. Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice. Int J Mol Sci 2024; 25:8177. [PMID: 39125747 PMCID: PMC11312285 DOI: 10.3390/ijms25158177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/12/2024] [Revised: 07/20/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
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Affiliation(s)
- Caroline Fischer
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
| | - Yannick Schreiber
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
| | - Robert Nitsch
- Institute for Translational Neuroscience, Medical Faculty, WWU Münster, 48149 Münster, Germany;
| | - Johannes Vogt
- Department of Molecular and Translational Neurosciences, Institute for Anatomy and Center of Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster for Aging associated Diseases (CECAD), University of Cologne, 50923 Köln, Germany;
| | - Dominique Thomas
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
| | - Gerd Geisslinger
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany;
- Fraunhofer Cluster of Excellence of Immune Mediated Diseases (CIMD), 60596 Frankfurt am Main, Germany
| | - Irmgard Tegeder
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany; (C.F.); (D.T.); (G.G.)
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Zhou Q, Chen Y, Liang Y, Sun Y. The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Metabolites 2024; 14:317. [PMID: 38921452 PMCID: PMC11205356 DOI: 10.3390/metabo14060317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/19/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment.
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Affiliation(s)
- Qiqiang Zhou
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
| | - Yahong Chen
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Ying Liang
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Yongchang Sun
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
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Cho HS, Kwon TW, Kim JH, Lee R, Bae CS, Kim HC, Kim JH, Choi SH, Cho IH, Nah SY. Gintonin Alleviates HCl/Ethanol- and Indomethacin-Induced Gastric Ulcers in Mice. Int J Mol Sci 2023; 24:16721. [PMID: 38069044 PMCID: PMC10705886 DOI: 10.3390/ijms242316721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 12/18/2023] Open
Abstract
Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.
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Affiliation(s)
- Han-Sung Cho
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (H.-S.C.); (J.-H.K.)
| | - Tae Woo Kwon
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Ji-Hun Kim
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (H.-S.C.); (J.-H.K.)
| | - Rami Lee
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (H.-S.C.); (J.-H.K.)
| | - Chun-Sik Bae
- College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea
| | - Jong-Hoon Kim
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-City 54596, Republic of Korea
| | - Sun-Hye Choi
- Department of Animal Health, College of Health and Medical Services, Osan University, Osan-si 18119, Republic of Korea
| | - Ik-Hyun Cho
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Seung-Yeol Nah
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (H.-S.C.); (J.-H.K.)
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Dacheux MA, Norman DD, Tigyi GJ, Lee SC. Emerging roles of lysophosphatidic acid receptor subtype 5 (LPAR5) in inflammatory diseases and cancer. Pharmacol Ther 2023; 245:108414. [PMID: 37061203 DOI: 10.1016/j.pharmthera.2023.108414] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that regulates a variety of cellular functions such as cell proliferation, migration, survival, calcium mobilization, cytoskeletal rearrangements, and neurite retraction. The biological actions of LPA are mediated by at least six G protein-coupled receptors known as LPAR1-6. Given that LPAR1-3 were among the first LPARs identified, the majority of research efforts have focused on understanding their biology. This review provides an in-depth discussion of LPAR5, which has recently emerged as a key player in regulating normal intestinal homeostasis and modulating pathological conditions such as pain, itch, inflammatory diseases, and cancer. We also present a chronological overview of the efforts made to develop compounds that target LPAR5 for use as tool compounds to probe or validate LPAR5 biology and therapeutic agents for the treatment of inflammatory diseases and cancer.
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Affiliation(s)
- Mélanie A Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Derek D Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Gábor J Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN, United States of America.
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Chen L, Huang L, Dong B, Gu Y, Cang W, Li C, Sun P, Xiang Y. ADCY7 mRNA Is a Novel Biomarker in HPV Infection and Cervical High-Grade Squamous Lesions or Higher. Biomedicines 2023; 11:biomedicines11030868. [PMID: 36979847 PMCID: PMC10045083 DOI: 10.3390/biomedicines11030868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/27/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 03/18/2023] Open
Abstract
The effect of cervical cancer immunotherapy is limited. Combination therapy will be a new direction for cervical cancer. Thus, it is essential to discover a novel and available predictive biomarker to stratify patients who may benefit from immunotherapy for cervical cancer. In this study, 563 participants were enrolled. Adenylate cyclase 7 (ADCY7) mRNA was detected by real-time quantitative PCR (qPCR) with cervical cytology specimens. The relationship between ADCY7 and cervical intraepithelial neoplasia in grade 2 and higher (CIN2+) was analyzed, and the optimal cut-off values of the relative expression of ADCY7 mRNA to predict CIN2+ were calculated. In addition, the clinical significance of ADCY7 in cervical cancer was determined by the Kaplan–Meier Cox regression based on the TCGA database. The mean ADCY7 mRNA expression increased significantly with cervical lesion development, especially compared with CIN2+ (p < 0.05). Moreover, the expression of ADCY7 increased significantly in high-risk human papillomavirus (HR-HPV) infection but not in HPV-A5/6 species. The area under the receiver operating characteristic curve (AUC) of ADCY7 was 0.897, and an optimal cut-off was 0.435. Furthermore, ADCY7 had the highest OR (OR= 8.589; 95% CI (2.281–22.339)) for detecting CIN 2+, followed by HPV genotyping, TCT, and age (OR = 4.487, OR = 2.071, and OR = 1.345; 95% CI (1.156–10.518), (0.370–8.137), and (0.171–4.694), respectively). Moreover, this study indicated that higher ADCY7 levels could be a suitable predictor for poor prognosis in cervical cancer due to immune cell infiltration. A new auxiliary predictor of CIN2+ in cervical cytology specimens is ADCY7 ≥ 0.435. Furthermore, it may be a promising prognosis predictor and potential immunotherapy target for the combined treatment of cervical cancer and possibly further block HR-HPV persistent infection.
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Affiliation(s)
- Lihua Chen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, China
| | - Lixiang Huang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China
| | - Binhua Dong
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China
- Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou 350001, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou 350001, China
| | - Yu Gu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, China
| | - Wei Cang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, China
| | - Chen Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, China
| | - Pengming Sun
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China
- Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou 350001, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou 350001, China
- Correspondence: (P.S.); (Y.X.); Tel.: +86-591-87558732 (P.S.); +86-01065296068 (Y.X.); Fax: +86-591-87551247 (P.S.); +86-01065296218 (Y.X.)
| | - Yang Xiang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100006, China
- Correspondence: (P.S.); (Y.X.); Tel.: +86-591-87558732 (P.S.); +86-01065296068 (Y.X.); Fax: +86-591-87551247 (P.S.); +86-01065296218 (Y.X.)
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Zhang D, Decker AM, Woodhouse K, Snyder R, Patel P, Harris DL, Tao YX, Li JX, Zhang Y. Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects. Eur J Med Chem 2022; 243:114741. [PMID: 36126387 PMCID: PMC10155261 DOI: 10.1016/j.ejmech.2022.114741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2022] [Revised: 08/26/2022] [Accepted: 09/01/2022] [Indexed: 11/18/2022]
Abstract
Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics.
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Affiliation(s)
- Dehui Zhang
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA
| | - Ann M Decker
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA
| | - Kristen Woodhouse
- Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY, 14203, USA
| | - Rodney Snyder
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA
| | - Purvi Patel
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA
| | - Danni L Harris
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA
| | - Yuan-Xiang Tao
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USA
| | - Jun-Xu Li
- Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, Buffalo, NY, 14203, USA
| | - Yanan Zhang
- Research Triangle Institute, Research Triangle Park, NC, 27709, USA.
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10
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Langedijk J, Araya EI, Barroso AR, Tolenaars D, Nazaré M, Belabed H, Schoene J, Chichorro JG, Oude Elferink R. An LPAR5-antagonist that reduces nociception and increases pruriception. FRONTIERS IN PAIN RESEARCH 2022; 3:963174. [PMID: 35959236 PMCID: PMC9360597 DOI: 10.3389/fpain.2022.963174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/07/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The G-protein coupled receptor LPAR5 plays a prominent role in LPA-mediated pain and itch signaling. In this study we focus on the LPAR5-antagonist compound 3 (cpd3) and its ability to affect pain and itch signaling, both in vitro and in vivo. Methods Nociceptive behavior in wild type mice was induced by formalin, carrageenan or prostaglandin E2 (PGE2) injection in the hind paw, and the effect of oral cpd3 administration was measured. Scratch activity was measured after oral administration of cpd3, in mice overexpressing phospholipase A2 (sPLA2tg), in wild type mice (WT) and in TRPA1-deficient mice (Trpa1 KO). In vitro effects of cpd3 were assessed by measuring intracellular calcium release in HMC-1 and HEK-TRPA1 cells. Results As expected, nociceptive behavior (induced by formalin, carrageenan or PGE2) was reduced after treatment with cpd3. Unexpectedly, cpd3 induced scratch activity in mice. In vitro addition of cpd3 to HEK-TRPA1 cells induced an intracellular calcium wave that could be inhibited by the TRPA1-antagonist A-967079. In Trpa1 KO mice, however, the increase in scratch activity after cpd3 administration was not reduced. Conclusions Cpd3 has in vivo antinociceptive effects but induces scratch activity in mice, probably by activation of multiple pruriceptors, including TRPA1. These results urge screening of antinociceptive candidate drugs for activity with pruriceptors.
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Affiliation(s)
- Jacqueline Langedijk
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
| | - Erika Ivanna Araya
- Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Brazil
| | - Amanda Ribeiro Barroso
- Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Brazil
| | - Dagmar Tolenaars
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
| | - Marc Nazaré
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Hassane Belabed
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Jens Schoene
- Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | | | - Ronald Oude Elferink
- Amsterdam University Medical Centers (UMC), Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AG&M), Amsterdam, Netherlands
- *Correspondence: Ronald Oude Elferink
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11
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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] [Academic Contribution 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.
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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.
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12
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Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth. Cells 2022; 11:cells11030349. [PMID: 35159157 PMCID: PMC8834237 DOI: 10.3390/cells11030349] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/18/2021] [Revised: 01/08/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
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13
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Biringer RG. Endocannabinoid signaling pathways: beyond CB1R and CB2R. J Cell Commun Signal 2021; 15:335-360. [PMID: 33978927 PMCID: PMC8222499 DOI: 10.1007/s12079-021-00622-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/29/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
The search for cannabinoid receptors other than CB1R and CB2R has been ongoing for over a decade. A number of orphan receptors have been proposed as potential cannabinoid receptors primarily based on phylogenic arguments and reactivity towards known endocannabinoids and phytocannabinoids. Seven putative cannabinoid receptors are described and discussed, and evidence for and against their inclusion in this category are presented.
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Affiliation(s)
- Roger Gregory Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
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14
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Lysophospholipids in Lung Inflammatory Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:373-391. [PMID: 33788203 DOI: 10.1007/978-3-030-63046-1_20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Academic Contribution Register] [Indexed: 01/21/2023]
Abstract
The lysophospholipids (LPLs) belong to a group of bioactive lipids that play pivotal roles in several physiological and pathological processes. LPLs are derivatives of phospholipids and consist of a single hydrophobic fatty acid chain, a hydrophilic head, and a phosphate group with or without a large molecule attached. Among the LPLs, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are the simplest, and have been shown to be involved in lung inflammatory symptoms and diseases such as acute lung injury, asthma, and chronic obstructive pulmonary diseases. G protein-coupled receptors (GPCRs) mediate LPA and S1P signaling. In this chapter, we will discuss on the role of LPA, S1P, their metabolizing enzymes, inhibitors or agonists of their receptors, and their GPCR-mediated signaling in lung inflammatory symptoms and diseases, focusing specially on acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease.
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15
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Lee D, Kim YH, Kim JH. The Role of Lysophosphatidic Acid in Adult Stem Cells. Int J Stem Cells 2020; 13:182-191. [PMID: 32587135 PMCID: PMC7378901 DOI: 10.15283/ijsc20035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/04/2020] [Revised: 04/24/2020] [Accepted: 05/21/2020] [Indexed: 01/06/2023] Open
Abstract
Stem cells are undifferentiated multipotent precursor cells that are capable both of perpetuating themselves as stem cells (self-renewal) and of undergoing differentiation into one or more specialized types of cells. And these stem cells have been reported to reside within distinct anatomic locations termed “niches”. The long-term goals of stem cell biology range from an understanding of cell-lineage determination and tissue organization to cellular therapeutics for degenerative diseases. Stem cells maintain tissue function throughout an organism’s lifespan by replacing differentiated cells. To perform this function, stem cells provide a unique combination of multilineage developmental potential and the capacity to undergo self-renewing divisions. The loss of self-renewal capacity in stem cells underlies certain degenerative diseases and the aging process. This self-renewal regulation must balance the regenerative needs of tissues that persist throughout life. Recent evidence suggests lysophosphatidic acid (LPA) signaling pathway plays an important role in the regulation of a variety of stem cells. In this review, we summarize the evidence linking between LPA and stem cell regulation. The LPA-induced signaling pathway regulates the proliferation and survival of stem cells and progenitors, and thus are likely to play a role in the maintenance of stem cell population in the body. This lipid mediator regulatory system can be a novel potential therapeutics for stem cell maintenance.
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Affiliation(s)
- Dongjun Lee
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Yun Hak Kim
- Department of Anatomy, Pusan National University School of Medicine, Yangsan, Korea.,Department of Biomedical Informatics, Pusan National University School of Medicine, Yangsan, Korea
| | - Jae Ho Kim
- Department of Physiology, Pusan National University School of Medicine, Yangsan, Korea
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16
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Gaire BP, Lee CH, Kim W, Sapkota A, Lee DY, Choi JW. Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages. Cells 2020; 9:cells9081753. [PMID: 32707926 PMCID: PMC7465035 DOI: 10.3390/cells9081753] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2020] [Revised: 07/09/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022] Open
Abstract
The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1β maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.
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Affiliation(s)
- Bhakta Prasad Gaire
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea; (B.P.G.); (C.-H.L.); (W.K.); (A.S.)
| | - Chi-Ho Lee
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea; (B.P.G.); (C.-H.L.); (W.K.); (A.S.)
| | - Wondong Kim
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea; (B.P.G.); (C.-H.L.); (W.K.); (A.S.)
| | - Arjun Sapkota
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea; (B.P.G.); (C.-H.L.); (W.K.); (A.S.)
| | - Do Yup Lee
- Department of Agricultural Biotechnology, Center for Food and Bioconvergence, Research Institute for Agricultural and Life Sciences, Seoul National University, Seoul 08826, Korea;
| | - Ji Woong Choi
- College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea; (B.P.G.); (C.-H.L.); (W.K.); (A.S.)
- Correspondence: ; Tel.: +82-32-820-4955
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17
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Regulation of Tumor Immunity by Lysophosphatidic Acid. Cancers (Basel) 2020; 12:cancers12051202. [PMID: 32397679 PMCID: PMC7281403 DOI: 10.3390/cancers12051202] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/24/2020] [Revised: 05/08/2020] [Accepted: 05/09/2020] [Indexed: 12/16/2022] Open
Abstract
The tumor microenvironment (TME) may be best conceptualized as an ecosystem comprised of cancer cells interacting with a multitude of stromal components such as the extracellular matrix (ECM), blood and lymphatic networks, fibroblasts, adipocytes, and cells of the immune system. At the center of this crosstalk between cancer cells and their TME is the bioactive lipid lysophosphatidic acid (LPA). High levels of LPA and the enzyme generating it, termed autotaxin (ATX), are present in many cancers. It is also well documented that LPA drives tumor progression by promoting angiogenesis, proliferation, survival, invasion and metastasis. One of the hallmarks of cancer is the ability to modulate and escape immune detection and eradication. Despite the profound role of LPA in regulating immune functions and inflammation, its role in the context of tumor immunity has not received much attention until recently where emerging studies highlight that this signaling axis may be a means that cancer cells adopt to evade immune detection and eradication. The present review aims to look at the immunomodulatory actions of LPA in baseline immunity to provide a broad understanding of the subject with a special emphasis on LPA and cancer immunity, highlighting the latest progress in this area of research.
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18
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Zhou Y, Little PJ, Ta HT, Xu S, Kamato D. Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease. Pharmacol Ther 2019; 204:107404. [DOI: 10.1016/j.pharmthera.2019.107404] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/21/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
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19
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Plastira I, Joshi L, Bernhart E, Schoene J, Specker E, Nazare M, Sattler W. Small-Molecule Lysophosphatidic Acid Receptor 5 (LPAR5) Antagonists: Versatile Pharmacological Tools to Regulate Inflammatory Signaling in BV-2 Microglia Cells. Front Cell Neurosci 2019; 13:531. [PMID: 31849616 PMCID: PMC6897279 DOI: 10.3389/fncel.2019.00531] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/17/2019] [Accepted: 11/15/2019] [Indexed: 12/30/2022] Open
Abstract
Lysophosphatidic acid (LPA) species in the extracellular environment induce downstream signaling via six different G protein-coupled receptors (LPAR1–6). These signaling cascades are essential for normal brain development and function of the nervous system. However, in response to acute or chronic central nervous system (CNS) damage, LPA levels increase and aberrant signaling events can counteract brain function. Under neuro-inflammatory conditions signaling along the LPA/LPAR5 axis induces a potentially neurotoxic microglia phenotype indicating the need for new pharmacological intervention strategies. Therefore, we compared the effects of two novel small-molecule LPAR5 antagonists on LPA-induced polarization parameters of the BV-2 microglia cell line. AS2717638 is a selective piperidine-based LPAR5 antagonist (IC50 0.038 μM) while compound 3 is a diphenylpyrazole derivative with an IC50 concentration of 0.7 μM in BV-2 cells. Both antagonists compromised cell viability, however, at concentrations above their IC50 concentrations. Both inhibitors blunted LPA-induced phosphorylation of STAT1 and STAT3, p65, and c-Jun and consequently reduced the secretion of pro-inflammatory cyto-/chemokines (IL-6, TNFα, IL-1β, CXCL10, CXCL2, and CCL5) at non-toxic concentrations. Both compounds modulated the expression of intracellular (COX-2 and Arg1) and plasma membrane-located (CD40, CD86, and CD206) polarization markers yet only AS2717638 attenuated the neurotoxic potential of LPA-activated BV-2 cell-conditioned medium towards CATH.a neurons. Our findings from the present in vitro study suggest that the two LPAR5 antagonists represent valuable pharmacological tools to interfere with LPA-induced pro-inflammatory signaling cascades in microglia.
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Affiliation(s)
- Ioanna Plastira
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Lisha Joshi
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Eva Bernhart
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Jens Schoene
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Edgar Specker
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Marc Nazare
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.,Berlin Institute of Health (BIH), Charite & MDC, Berlin, Germany
| | - Wolfgang Sattler
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.,Center for Explorative Lipidomics, BioTechMed-Graz, Graz, Austria
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Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain Behav Immun 2019; 80:146-162. [PMID: 30853569 DOI: 10.1016/j.bbi.2019.03.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/30/2018] [Revised: 03/02/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022] Open
Abstract
Gintonin (GT), a ginseng-derived lysophosphatidic acid receptor ligand, regulates various cellular effects and represses inflammation. However, little is known about the potential value of GT regarding inflammation in the neurodegenerative diseases, such as Huntington's disease (HD). In this study, we investigated whether GT could ameliorate the neurological impairment and striatal toxicity in cellular or animal model of HD. Pre-, co-, and onset-treatment with GT (25, 50, or 100 mg/kg/day, p.o.) alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid (3-NPA). Pretreatment with GT also attenuated mitochondrial dysfunction i.e. succinate dehydrogenase and MitoSOX activities, apoptosis, microglial activation, and mRNA expression of inflammatory mediators i.e. IL-1β, IL-6, TNF-α, COX-2, and iNOS in the striatum after 3-NPA-intoxication. Its action mechanism was associated with lysophosphatidic acid receptors (LPARs) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activations and the inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. These beneficial effects of GT were neutralized by pre-inhibiting LPARs with Ki16425 (a LPAR1/3 antagonist). Interestingly, GT reduced cell death and mutant huntingtin (HTT) aggregates in STHdh cells. It also mitigated neurological impairment in mice with adeno-associated viral (AAV) vector serotype DJ-mediated overexpression of N171-82Q-mutant HTT in the striatum. Taken together, our findings firstly suggested that GT has beneficial effects with a wide therapeutic time-window in 3-NPA-induced striatal toxicity by antioxidant and anti-inflammatory activities through LPA. In addition, GT exerts neuroprotective effects in STHdh cells and AAV vector-infected model of HD. Thus GT might be an innovative therapeutic candidate to treat HD-like syndromes.
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21
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Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11070958. [PMID: 31323936 PMCID: PMC6678549 DOI: 10.3390/cancers11070958] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/10/2019] [Revised: 07/04/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.
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22
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Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
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Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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Ramesh S, Govindarajulu M, Suppiramaniam V, Moore T, Dhanasekaran M. Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease. Int J Mol Sci 2018; 19:ijms19071827. [PMID: 29933579 PMCID: PMC6073975 DOI: 10.3390/ijms19071827] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/01/2018] [Revised: 06/12/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
The brain contains various forms of lipids that are important for maintaining its structural integrity and regulating various signaling cascades. Autotaxin (ATX) is an ecto-nucleotide pyrophosphatase/phosphodiesterase-2 enzyme that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA). LPA is a major bioactive lipid which acts through G protein-coupled receptors (GPCRs) and plays an important role in mediating cellular signaling processes. The majority of synthesized LPA is derived from membrane phospholipids through the action of the secreted enzyme ATX. Both ATX and LPA are highly expressed in the central nervous system. Dysfunctional expression and activity of ATX with associated changes in LPA signaling have recently been implicated in the pathogenesis of Alzheimer’s disease (AD). This review focuses on the current understanding of LPA signaling, with emphasis on the importance of the autotaxin–lysophosphatidic acid (ATX–LPA) pathway and its alterations in AD and a brief note on future therapeutic applications based on ATX–LPA signaling.
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Affiliation(s)
- Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
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Shao Y, Nanayakkara G, Cheng J, Cueto R, Yang WY, Park JY, Wang H, Yang X. Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury. Antioxid Redox Signal 2018; 28:973-986. [PMID: 28325059 PMCID: PMC5849278 DOI: 10.1089/ars.2017.7069] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Significance: We proposed lysophospholipids (LPLs) and LPL-G-protein-coupled receptors (GPCRs) as conditional danger-associated molecular patterns (DAMPs) and conditional DAMP receptors as a paradigm shift to the widely accepted classical DAMP and DAMP receptor model. Recent Advances: The aberrant levels of LPLs and GPCRs activate pro-inflammatory signal transduction pathways, trigger innate immune response, and lead to tissue oxidative and inflammatory injury. Critical Issues: Classical DAMP model specifies only the endogenous metabolites that are released from damaged/dying cells as DAMPs, but fails to identify elevated endogenous metabolites secreted from viable/live cells during pathologies as DAMPs. The current classification of DAMPs also fails to clarify the following concerns: (i) Are molecules, which bind to pattern recognition receptors (PRRs), the only DAMPs contributing to inflammation and tissue injury? (ii) Are all DAMPs acting only via classical PRRs during cellular stress? To answer these questions, we reviewed the molecular characteristics and signaling mechanisms of LPLs, a group of endogenous metabolites and their specific receptors and analyzed the significant progress achieved in characterizing oxidative stress mechanisms of LPL mediated tissue injury. Future Directions: Further LPLs and LPL-GPCRs may serve as potential therapeutic targets for the treatment of pathologies induced by sterile inflammation. Antioxid. Redox Signal. 28, 973-986.
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Affiliation(s)
- Ying Shao
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Gayani Nanayakkara
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Jiali Cheng
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Ramon Cueto
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - William Y Yang
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Joon-Young Park
- Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania
| | - Hong Wang
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Xiaofeng Yang
- Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Abstract
Mast cells are haematopoietic cells that arise from pluripotent precursors of the bone marrow. They play immunomodulatory roles in both health and disease. When appropriately activated, mast cells undergo degranulation, and preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on various inflammatory settings are closely associated with the enzymatic characteristics of tryptase, the main granule compound of mast cells. Tryptase degranulation is often linked with the development of an immune response, allergy, inflammation, and remodelling of tissue architecture. Tryptase also represents an informative diagnostic marker of certain diseases and a prospective target for pharmacotherapy. In this review, we discuss the current knowledge about mast cell tryptase as one of the mast cell secretome proteases. The main points of the reviewed publications are highlighted with our microscopic images of mast cell tryptases visualized using immunohistochemical staining.
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Affiliation(s)
- Dmitri Atiakshin
- Research Institute of Experimental Biology and Medicine, Voronezh N. N. Burdenko State Medical University, Voronezh, Russia
| | - Igor Buchwalow
- Institute for Hematopathology, Fangdieckstr. 75a, 22547, Hamburg, Germany.
| | - Vera Samoilova
- Institute for Hematopathology, Fangdieckstr. 75a, 22547, Hamburg, Germany
| | - Markus Tiemann
- Institute for Hematopathology, Fangdieckstr. 75a, 22547, Hamburg, Germany
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Kritikou E, van Puijvelde GHM, van der Heijden T, van Santbrink PJ, Swart M, Schaftenaar FH, Kröner MJ, Kuiper J, Bot I. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice. Sci Rep 2016; 6:37585. [PMID: 27883026 PMCID: PMC5121611 DOI: 10.1038/srep37585] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/01/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.
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Affiliation(s)
- Eva Kritikou
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | | | | | | | - Maarten Swart
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | | | - Mara J Kröner
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | - Johan Kuiper
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
| | - Ilze Bot
- Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands
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Plastira I, Bernhart E, Goeritzer M, Reicher H, Kumble VB, Kogelnik N, Wintersperger A, Hammer A, Schlager S, Jandl K, Heinemann A, Kratky D, Malle E, Sattler W. 1-Oleyl-lysophosphatidic acid (LPA) promotes polarization of BV-2 and primary murine microglia towards an M1-like phenotype. J Neuroinflammation 2016; 13:205. [PMID: 27565558 PMCID: PMC5002165 DOI: 10.1186/s12974-016-0701-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/21/2016] [Accepted: 08/20/2016] [Indexed: 01/09/2023] Open
Abstract
Background Microglia, the immunocompetent cells of the CNS, rapidly respond to brain injury and disease by altering their morphology and phenotype to adopt an activated state. Microglia can exist broadly between two different states, namely the classical (M1) and the alternative (M2) phenotype. The first is characterized by the production of pro-inflammatory cytokines/chemokines and reactive oxygen and/or nitrogen species. In contrast, alternatively activated microglia are typified by an anti-inflammatory phenotype supporting wound healing and debris clearance. The objective of the present study was to determine the outcome of lysophosphatidic acid (LPA)-mediated signaling events on microglia polarization. Methods LPA receptor expression and cyto-/chemokine mRNA levels in BV-2 and primary murine microglia (PMM) were determined by qPCR. M1/M2 marker expression was analyzed by Western blotting, immunofluorescence microscopy, or flow cytometry. Cyto-/chemokine secretion was quantitated by ELISA. Results BV-2 cells express LPA receptor 2 (LPA2), 3, 5, and 6, whereas PMM express LPA1, 2, 4, 5, and 6. We show that LPA treatment of BV-2 and PMM leads to a shift towards a pro-inflammatory M1-like phenotype. LPA treatment increased CD40 and CD86 (M1 markers) and reduced CD206 (M2 marker) expression. LPA increased inducible nitric oxide synthase (iNOS) and COX-2 levels (both M1), while the M2 marker Arginase-1 was suppressed in BV-2 cells. Immunofluorescence studies (iNOS, COX-2, Arginase-1, and RELMα) extended these findings to PMM. Upregulation of M1 markers in BV-2 and PMM was accompanied by increased cyto-/chemokine transcription and secretion (IL-1β, TNFα, IL-6, CCL5, and CXCL2). The pharmacological LPA5 antagonist TCLPA5 blunted most of these pro-inflammatory responses. Conclusions LPA drives BV-2 and PMM towards a pro-inflammatory M1-like phenotype. Suppression by TCLPA5 indicates that the LPA/LPA5 signaling axis could represent a potential pharmacological target to interfere with microglia polarization in disease.
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Affiliation(s)
- Ioanna Plastira
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Eva Bernhart
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Madeleine Goeritzer
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Helga Reicher
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Vishwanath Bhat Kumble
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Nora Kogelnik
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Andrea Wintersperger
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Astrid Hammer
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria
| | - Stefanie Schlager
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Katharina Jandl
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Dagmar Kratky
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Ernst Malle
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria
| | - Wolfgang Sattler
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010, Graz, Austria. .,BioTechMed-Graz, Graz, Austria.
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Knowlden SA, Hillman SE, Chapman TJ, Patil R, Miller DD, Tigyi G, Georas SN. Novel Inhibitory Effect of a Lysophosphatidic Acid 2 Agonist on Allergen-Driven Airway Inflammation. Am J Respir Cell Mol Biol 2016; 54:402-9. [PMID: 26248018 DOI: 10.1165/rcmb.2015-0124oc] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/24/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a pleiotropic lipid signaling molecule associated with asthma pathobiology. LPA elicits its effects by binding to at least six known cell surface G protein-coupled receptors (LPA1-6) that are expressed in the lung in a cell type-specific manner. LPA2 in particular has emerged as an attractive therapeutic target in asthma because it appears to transduce inhibitory or cell-protective signals. We studied a novel and specific small molecule LPA2 agonist (2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid [DBIBB]) in a mouse model of house dust mite-induced allergic airway inflammation. Mice injected with DBIBB developed significantly less airway and lung inflammation compared with vehicle-treated controls. Levels of lung Th2 cytokines were also significantly attenuated by DBIBB. We conclude that pharmacologic activation of LPA2 attenuates Th2-driven allergic airway inflammation in a mouse model of asthma. Targeting LPA receptor signaling holds therapeutic promise in allergic asthma.
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Affiliation(s)
- Sara A Knowlden
- 1 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Sara E Hillman
- 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, New York
| | - Timothy J Chapman
- 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, New York
| | - Renukadevi Patil
- 3 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and.,4 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Duane D Miller
- 4 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Gabor Tigyi
- 3 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and
| | - Steve N Georas
- 1 Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York.,2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, New York
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29
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Abstract
The present review examines the pig as a model for physiological studies in human subjects related to nutrient sensing, appetite regulation, gut barrier function, intestinal microbiota and nutritional neuroscience. The nutrient-sensing mechanisms regarding acids (sour), carbohydrates (sweet), glutamic acid (umami) and fatty acids are conserved between humans and pigs. In contrast, pigs show limited perception of high-intensity sweeteners and NaCl and sense a wider array of amino acids than humans. Differences on bitter taste may reflect the adaptation to ecosystems. In relation to appetite regulation, plasma concentrations of cholecystokinin and glucagon-like peptide-1 are similar in pigs and humans, while peptide YY in pigs is ten to twenty times higher and ghrelin two to five times lower than in humans. Pigs are an excellent model for human studies for vagal nerve function related to the hormonal regulation of food intake. Similarly, the study of gut barrier functions reveals conserved defence mechanisms between the two species particularly in functional permeability. However, human data are scant for some of the defence systems and nutritional programming. The pig model has been valuable for studying the changes in human microbiota following nutritional interventions. In particular, the use of human flora-associated pigs is a useful model for infants, but the long-term stability of the implanted human microbiota in pigs remains to be investigated. The similarity of the pig and human brain anatomy and development is paradigmatic. Brain explorations and therapies described in pig, when compared with available human data, highlight their value in nutritional neuroscience, particularly regarding functional neuroimaging techniques.
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Yu Y, Blokhuis BR, Garssen J, Redegeld FA. Non-IgE mediated mast cell activation. Eur J Pharmacol 2016; 778:33-43. [DOI: 10.1016/j.ejphar.2015.07.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/18/2015] [Revised: 06/15/2015] [Accepted: 07/07/2015] [Indexed: 12/28/2022]
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Kozian DH, von Haeften E, Joho S, Czechtizky W, Anumala UR, Roux P, Dudda A, Evers A, Nazare M. Modulation of Hexadecyl-LPA-Mediated Activation of Mast Cells and Microglia by a Chemical Probe for LPA5. Chembiochem 2016; 17:861-5. [PMID: 26812365 DOI: 10.1002/cbic.201500559] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/21/2015] [Indexed: 11/05/2022]
Abstract
Mast cells and microglia play a critical role in innate immunity and inflammation and can be activated by a wide range of endogenous and exogenous stimuli. Lysophosphatidic acid (LPA) has recently been reported to activate mast cells and microglia. Using the human mast cell line HMC-1 and the mouse microglia cell line BV-2, we show that LPA-mediated activation can be prevented by blockade of the LPA receptor 5 (LPA5) in both cell lines. The identification of new LPA5-specific antagonists as tool compounds to probe and modulate the LPA5/LPA axis in relevant in vitro and in vivo assays should contribute to better understanding of the underlying role of LPAs in the development and progression of (neuro-) inflammatory diseases.
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Affiliation(s)
- Detlef H Kozian
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany.
| | | | - Sabrina Joho
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Werngard Czechtizky
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Upendra R Anumala
- Leibniz-Institut für Molekulare Pharmakologie FMP, Campus Berlin Buch, 13125, Berlin, Germany
| | - Pascale Roux
- Sanofi SA, 1541, avenue Marcel Merieux, 69280, Marcy l'Etoile, France
| | - Angela Dudda
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Andreas Evers
- Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65962, Frankfurt, Germany
| | - Marc Nazare
- Leibniz-Institut für Molekulare Pharmakologie FMP, Campus Berlin Buch, 13125, Berlin, Germany.
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Benesch MGK, Tang X, Venkatraman G, Bekele RT, Brindley DN. Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo. J Biomed Res 2015; 30:272-84. [PMID: 27533936 PMCID: PMC4946318 DOI: 10.7555/jbr.30.20150058] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/11/2015] [Revised: 05/12/2015] [Accepted: 05/20/2015] [Indexed: 12/21/2022] Open
Abstract
Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.
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Affiliation(s)
- Matthew G K Benesch
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Xiaoyun Tang
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Ganesh Venkatraman
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - Raie T Bekele
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada
| | - David N Brindley
- Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
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Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that is present in all tissues examined to date. LPA signals extracellularly via cognate G protein-coupled receptors to mediate cellular processes such as survival, proliferation, differentiation, migration, adhesion and morphology. These LPA-influenced processes impact many aspects of organismal development. In particular, LPA signalling has been shown to affect fertility and reproduction, formation of the nervous system, and development of the vasculature. Here and in the accompanying poster, we review the developmentally related features of LPA signalling.
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Affiliation(s)
- Xiaoyan Sheng
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Yun C Yung
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Allison Chen
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Jerold Chun
- Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
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Llona-Minguez S, Ghassemian A, Helleday T. Lysophosphatidic acid receptor (LPAR) modulators: The current pharmacological toolbox. Prog Lipid Res 2015; 58:51-75. [DOI: 10.1016/j.plipres.2015.01.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2014] [Revised: 01/15/2015] [Accepted: 01/20/2015] [Indexed: 12/17/2022]
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Stoddard NC, Chun J. Promising pharmacological directions in the world of lysophosphatidic Acid signaling. Biomol Ther (Seoul) 2015; 23:1-11. [PMID: 25593637 PMCID: PMC4286743 DOI: 10.4062/biomolther.2014.109] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2014] [Revised: 12/02/2014] [Accepted: 12/02/2014] [Indexed: 12/18/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.
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Affiliation(s)
- Nicole C Stoddard
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037 ; Biomedical Sciences Graduate Program, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
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Yun CC, Kumar A. Diverse roles of LPA signaling in the intestinal epithelium. Exp Cell Res 2014; 333:201-207. [PMID: 25433271 DOI: 10.1016/j.yexcr.2014.11.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2014] [Accepted: 11/05/2014] [Indexed: 12/19/2022]
Abstract
Lysophosphatidic acid (LPA) is a lipid mediator that modulates a wide variety of cellular functions. Elevated LPA signaling has been reported in patients with colorectal cancer or inflammatory bowel diseases, and the tumorigenic role of LPA has been demonstrated in experimental models of colon cancer. However, emerging evidence indicates the importance of LPA signaling in epithelial wound healing and regulation of intestinal electrolyte transport. Here, we briefly review current knowledge of the biological roles of LPA signaling in the intestinal tract.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; Atlanta VA Medical Center, Decatur, GA, USA.
| | - Ajay Kumar
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
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Potentials of the Circulating Pruritogenic Mediator Lysophosphatidic Acid in Development of Allergic Skin Inflammation in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:1593-603. [DOI: 10.1016/j.ajpath.2014.01.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/30/2013] [Revised: 01/05/2014] [Accepted: 01/16/2014] [Indexed: 01/03/2023]
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Knowlden S, Georas SN. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 192:851-7. [PMID: 24443508 DOI: 10.4049/jimmunol.1302831] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Lysophosphatidic acid (LPA) is a pleiotropic lipid molecule with potent effects on cell growth and motility. Major progress has been made in recent years in deciphering the mechanisms of LPA generation and how it acts on target cells. Most research has been conducted in other disciplines, but emerging data indicate that LPA has an important role to play in immunity. A key discovery was that autotaxin (ATX), an enzyme previously implicated in cancer cell motility, generates extracellular LPA from the precursor lysophosphatidylcholine. Steady-state ATX is expressed by only a few tissues, including high endothelial venules in lymph nodes, but inflammatory signals can upregulate ATX expression in different tissues. In this article, we review current thinking about the ATX/LPA axis in lymphocyte homing, as well as in models of allergic airway inflammation and asthma. New insights into the role of LPA in regulating immune responses should be forthcoming in the near future.
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Affiliation(s)
- Sara Knowlden
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
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Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res 2014; 55:1192-214. [PMID: 24643338 DOI: 10.1194/jlr.r046458] [Citation(s) in RCA: 530] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/20/2013] [Indexed: 12/18/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1-6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets.
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Affiliation(s)
- Yun C Yung
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
| | - Nicole C Stoddard
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037 Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037
| | - Jerold Chun
- Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Arriazu R, Durán E, Pozuelo JM, Santamaria L. Expression of lysophosphatidic acid receptor 1 and relation with cell proliferation, apoptosis, and angiogenesis on preneoplastic changes induced by cadmium chloride in the rat ventral prostate. PLoS One 2013; 8:e57742. [PMID: 23451264 PMCID: PMC3579784 DOI: 10.1371/journal.pone.0057742] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/17/2012] [Accepted: 01/24/2013] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Lysophosphatidic acid (LPA) is a phospholipid growth factor involved in cell proliferation, differentiation, migration, inflammation, angiogenesis, wound healing, cancer invasion, and survival. This study was directed to evaluate the immunoexpression of LPA-1, cell proliferation, apoptosis, and angiogenesis markers in preneoplastic lesions induced with cadmium chloride in rat prostate. METHODS The following parameters were calculated in ventral prostate of normal rats and rats that received Cd in drinking water during 24 months: percentages of cells immunoreactive to LPA-1 (LILPA1), PCNA (LIPCNA), MCM7 (LIMCM7), ubiquitin (LIUBI), apoptotic cells (LIAPO), and p53 (LIp53); volume fraction of Bcl-2 (VFBcl-2); and length of microvessels per unit of volume (LVMV/mm3). Data were analyzed using Student's t-test and Pearson correlation test. RESULTS The LILPA1 in dysplastic lesions and normal epithelium of Cd-treated rats was significantly higher than those in the control group. Markers of proliferation were significantly increased in dysplastic lesions, whereas some apoptotic markers were significantly decreased. No significant differences between groups were found in VFBcl-2. Dysplastic lesions showed a significant increase of LIp53. The length of microvessels per unit of volume was elevated in dysplastic acini. Statistically significant correlations were found only between LILPA1 and LIUBI. CONCLUSIONS Our results suggest that LPA-1 might be implicated in dysplastic lesions induced by cadmium chloride development. More studies are needed to confirm its potential contribution to the disease.
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Affiliation(s)
- Riánsares Arriazu
- Histology Laboratory, Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, School of Medicine, CEU-San Pablo University, Madrid, Spain.
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Current progress in non-Edg family LPA receptor research. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1831:33-41. [PMID: 22902318 DOI: 10.1016/j.bbalip.2012.08.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/29/2012] [Revised: 08/01/2012] [Accepted: 08/02/2012] [Indexed: 01/08/2023]
Abstract
Lysophosphatidic acid (LPA) is the simplest phospholipid yet possesses myriad biological functions. Until 2003, the functions of LPA were thought to be elicited exclusively by three subtypes of the endothelial differentiation gene (Edg) family of G protein-coupled receptors - LPA(1), LPA(2), and LPA(3). However, several biological functions of LPA could not be assigned to any of these receptors indicating the existence of one or more additional LPA receptor(s). More recently, the discovery of a second cluster of LPA receptors which includes LPA(4), LPA(5), and LPA(6) has paved the way for new avenues of LPA research. Analyses of these non-Edg family LPA receptors have begun to fill in gaps to understand biological functions of LPA such as platelet aggregation and vascular development that could not be ascribed to classical Edg family LPA receptors and are also unveiling new biological functions. Here we review recent progress in the non-Edg family LPA receptor research, with special emphasis on the pharmacology, signaling, and physiological roles of this family of receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
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Jongsma M, Matas-Rico E, Rzadkowski A, Jalink K, Moolenaar WH. LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor. PLoS One 2011; 6:e29260. [PMID: 22195035 PMCID: PMC3237609 DOI: 10.1371/journal.pone.0029260] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/15/2011] [Accepted: 11/23/2011] [Indexed: 01/08/2023] Open
Abstract
Lysophosphatidic acid (LPA), a lipid mediator enriched in serum, stimulates cell migration, proliferation and other functions in many cell types. LPA acts on six known G protein-coupled receptors, termed LPA1–6, showing both overlapping and distinct signaling properties. Here we show that, unexpectedly, LPA and serum almost completely inhibit the transwell migration of B16 melanoma cells, with alkyl-LPA(18∶1) being 10-fold more potent than acyl-LPA(18∶1). The anti-migratory response to LPA is highly polarized and dependent on protein kinase A (PKA) but not Rho kinase activity; it is associated with a rapid increase in intracellular cAMP levels and PIP3 depletion from the plasma membrane. B16 cells express LPA2, LPA5 and LPA6 receptors. We show that LPA-induced chemorepulsion is mediated specifically by the alkyl-LPA-preferring LPA5 receptor (GPR92), which raises intracellular cAMP via a noncanonical pathway. Our results define LPA5 as an anti-migratory receptor and they implicate the cAMP-PKA pathway, along with reduced PIP3 signaling, as an effector of chemorepulsion in B16 melanoma cells.
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Affiliation(s)
- Maikel Jongsma
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Elisa Matas-Rico
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Adrian Rzadkowski
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Kees Jalink
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wouter H. Moolenaar
- Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- * E-mail:
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Blaho VA, Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev 2011; 111:6299-320. [PMID: 21939239 PMCID: PMC3216694 DOI: 10.1021/cr200273u] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Affiliation(s)
- Victoria A. Blaho
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
| | - Timothy Hla
- Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10065
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Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. Originally, LPA was thought to elicit its biological functions through three subtypes of endothelial differentiation gene (Edg) family G protein-coupled receptors (LPA1, LPA2 and LPA3) until our group identified a fourth subtype, LPA4. The discovery of this receptor, which is structurally distinct from the Edg family LPA receptors, led to the identification of two additional LPA receptors, LPA5 and LPA6, homologous to LPA4. These 'non-Edg family' LPA receptors now provide a new framework for understanding the diverse functions of LPA, including vascular development, platelet activation and hair growth. In this review, we summarize the identification, intracellular signalling and biological functions of this novel cluster of LPA receptors.
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Affiliation(s)
- Keisuke Yanagida
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033
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