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1
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Berto Gomes LA, Smith OE, Bollwein H, Kowalewski MP. Dynamic Regulation of HIF1α and Oxygen-Sensing Factors in Cyclic Bovine Corpus Luteum and During LPS Challenge. Animals (Basel) 2025; 15:595. [PMID: 40003076 PMCID: PMC11851762 DOI: 10.3390/ani15040595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Understanding the corpus luteum (CL) and its role in cattle reproduction is crucial, particularly as it is a progesterone source for the establishment and maintenance of pregnancy. Reduced oxygen levels significantly impact these processes. This study investigated the effects of the luteal stage on the spatio-temporal gene expression patterns of HIF1α and oxygen-sensing factors, as well as the impact of lipopolysaccharide (LPS)-induced inflammation on these factors. Endothelial inflammatory responses were also addressed. The samples included CL collected at the early, mid, and late stages, as well as biopsies from mid-luteal stage cows treated either with saline (controls) or LPS. Samples collected in subsequent cycles assessed potential carryover effects. RT-PCR revealed upregulation of HIF1α, PHD1, PHD3, FIH, and VHL encoding genes in the mid-luteal stage. In situ hybridization revealed the compartmentalization of HIF1α and its regulators within the luteal and endothelial cells, suggesting their cell-specific roles. LPS treatment affected PHD1 and PHD3 expression, while increasing endothelial pro-inflammatory factors ICAM1 and NFκB, suggesting vascular inflammation and modulated oxygen sensing. These findings reveal new insights into the spatio-temporal expression of HIF1α-regulating factors in the CL, highlighting their potential role in controlling luteal function, detailing their cellular compartmentalization, and the effects of LPS-mediated inflammatory responses.
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Affiliation(s)
- Luiz Antonio Berto Gomes
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland; (L.A.B.G.); (O.E.S.)
| | - Olivia Eilers Smith
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland; (L.A.B.G.); (O.E.S.)
| | - Heinrich Bollwein
- Clinic of Reproductive Medicine, Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland;
- AgroVet-Strickhof, Vetsuisse Faculty, University of Zurich, CH-8315 Eschikon, Switzerland
| | - Mariusz Pawel Kowalewski
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland; (L.A.B.G.); (O.E.S.)
- Center for Clinical Studies (ZKS), Vetsuisse Faculty, University of Zurich, CH-8057 Zurich, Switzerland
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2
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Maniaci A, Briglia M, Allia F, Montalbano G, Romano GL, Zaouali MA, H’mida D, Gagliano C, Malaguarnera R, Lentini M, Graziano ACE, Giurdanella G. The Role of Pericytes in Inner Ear Disorders: A Comprehensive Review. BIOLOGY 2024; 13:802. [PMID: 39452111 PMCID: PMC11504721 DOI: 10.3390/biology13100802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/02/2024] [Accepted: 10/06/2024] [Indexed: 10/26/2024]
Abstract
Inner ear disorders, including sensorineural hearing loss, Meniere's disease, and vestibular neuritis, are prevalent conditions that significantly impact the quality of life. Despite their high incidence, the underlying pathophysiology of these disorders remains elusive, and current treatment options are often inadequate. Emerging evidence suggests that pericytes, a type of vascular mural cell specialized to maintain the integrity and function of the microvasculature, may play a crucial role in the development and progression of inner ear disorders. The pericytes are present in the microvasculature of both the cochlea and the vestibular system, where they regulate blood flow, maintain the blood-labyrinth barrier, facilitate angiogenesis, and provide trophic support to neurons. Understanding their role in inner ear disorders may provide valuable insights into the pathophysiology of these conditions and lead to the development of novel diagnostic and therapeutic strategies, improving the standard of living. This comprehensive review aims to provide a detailed overview of the role of pericytes in inner ear disorders, highlighting the anatomy and physiology in the microvasculature, and analyzing the mechanisms that contribute to the development of the disorders. Furthermore, we explore the potential pericyte-targeted therapies, including antioxidant, anti-inflammatory, and angiogenic approaches, as well as gene therapy strategies.
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Affiliation(s)
- Antonino Maniaci
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Marilena Briglia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Fabio Allia
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giuseppe Montalbano
- Zebrafish Neuromorphology Laboratory, Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;
| | - Giovanni Luca Romano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Avicenne Street, 5019 Monastir, Tunisia;
| | - Dorra H’mida
- Department of Cytogenetics and Reproductive Biology, Farhat Hached Hospital, 4021 Sousse, Tunisia;
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Roberta Malaguarnera
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Mario Lentini
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
- Department of Surgery, ENT Unit, Asp 7 Ragusa, 97100 Ragusa, Italy
| | - Adriana Carol Eleonora Graziano
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
| | - Giovanni Giurdanella
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (A.M.); (M.B.); (F.A.); (G.L.R.); (C.G.); (R.M.); (G.G.)
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Lee NT, Savvidou I, Selan C, Calvello I, Vuong A, Wright DK, Brkljaca R, Willcox A, Chia JSJ, Wang X, Peter K, Robson SC, Medcalf RL, Nandurkar HH, Sashindranath M. Development of endothelial-targeted CD39 as a therapy for ischemic stroke. J Thromb Haemost 2024; 22:2331-2344. [PMID: 38754782 DOI: 10.1016/j.jtha.2024.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 04/11/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND Ischemic stroke is characterized by a necrotic lesion in the brain surrounded by an area of dying cells termed the penumbra. Salvaging the penumbra either with thrombolysis or mechanical retrieval is the cornerstone of stroke management. At-risk neuronal cells release extracellular adenosine triphosphate, triggering microglial activation and causing a thromboinflammatory response, culminating in endothelial activation and vascular disruption. This is further aggravated by ischemia-reperfusion injury that follows all reperfusion therapies. The ecto-enzyme CD39 regulates extracellular adenosine triphosphate by hydrolyzing it to adenosine, which has antithrombotic and anti-inflammatory properties and reverses ischemia-reperfusion injury. OBJECTIVES The objective off the study was to determine the efficacy of our therapeutic, anti-VCAM-CD39 in ischaemic stroke. METHODS We developed anti-VCAM-CD39 that targets the antithrombotic and anti-inflammatory properties of recombinant CD39 to the activated endothelium of the penumbra by binding to vascular cell adhesion molecule (VCAM)-1. Mice were subjected to 30 minutes of middle cerebral artery occlusion and analyzed at 24 hours. Anti-VCAM-CD39 or control agents (saline, nontargeted CD39, or anti-VCAM-inactive CD39) were given at 3 hours after middle cerebral artery occlusion. RESULTS Anti-VCAM-CD39 treatment reduced neurologic deficit; magnetic resonance imaging confirmed significantly smaller infarcts together with an increase in cerebrovascular perfusion. Anti-VCAM-CD39 also restored blood-brain barrier integrity and reduced microglial activation. Coadministration of anti-VCAM-CD39 with thrombolytics (tissue plasminogen activator [tPA]) further reduced infarct volumes and attenuated blood-brain barrier permeability with no associated increase in intracranial hemorrhage. CONCLUSION Anti-VCAM-CD39, uniquely targeted to endothelial cells, could be a new stroke therapy even when administered 3 hours postischemia and may further synergize with thrombolytic therapy to improve stroke outcomes.
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Affiliation(s)
- Natasha Ting Lee
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia; Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia; Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia
| | - Ioanna Savvidou
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Carly Selan
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Ilaria Calvello
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Amy Vuong
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - David K Wright
- Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Robert Brkljaca
- Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia
| | - Abbey Willcox
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Joanne S J Chia
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Xiaowei Wang
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia; Molecular Imaging and Theranostics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Simon C Robson
- Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert L Medcalf
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Harshal H Nandurkar
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
| | - Maithili Sashindranath
- Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia.
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4
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Bertolini M, Gherardini J, Chéret J, Alam M, Sulk M, Botchkareva NV, Biro T, Funk W, Grieshaber F, Paus R. Mechanical epilation exerts complex biological effects on human hair follicles and perifollicular skin: An ex vivo study approach. Int J Cosmet Sci 2024; 46:175-198. [PMID: 37923568 DOI: 10.1111/ics.12923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/04/2023] [Accepted: 10/12/2023] [Indexed: 11/07/2023]
Abstract
OBJECTIVE Electrical epilation of unwanted hair is a widely used hair removal method, but it is largely unknown how this affects the biology of human hair follicles (HF) and perifollicular skin. Here, we have begun to explore how mechanical epilation changes selected key biological read-out parameters ex vivo within and around the pilosebaceous unit. METHODS Human full-thickness scalp skin samples were epilated ex vivo using an electro-mechanical device, organ-cultured for up to 6 days in serum-free, supplemented medium, and assessed at different time points by quantitative (immuno-)histomorphometry for selected relevant read-out parameters in epilated and sham-epilated control samples. RESULTS Epilation removed most of the hair shafts, often together with fragments of the outer and inner root sheath and hair matrix. This was associated with persistent focal thinning of the HF basal membrane, decreased melanin content of the residual HF epithelium, and increased HF keratinocyte apoptosis, including in the bulge, yet without affecting the number of cytokeratin 15+ HF epithelial stem cells. Sebocyte apoptosis in the peripheral zone was increased, albeit without visibly altering sebum production. Epilation transiently perturbed HF immune privilege, and increased the expression of ICAM-1 in the bulge and bulb mesenchyme, and the number of perifollicular MHC class II+ cells as well as mast cells around the distal epithelium and promoted mast cell degranulation around the suprabulbar and bulbar area. Moreover, compared to controls, several key players of neurogenic skin inflammation, itch, and/or thermosensation (TRPV1, TRPA1, NGF, and NKR1) were differentially expressed in post-epilation skin. CONCLUSION These data generated in denervated, organ-cultured human scalp skin demonstrate that epilation-induced mechanical HF trauma elicits surprisingly complex biological responses. These may contribute to the delayed re-growth of thinner and lighter hair shafts post-epilation and temporary post-epilation discomfort. Our findings also provide pointers regarding the development of topically applicable agents that minimize undesirable sequelae of epilation.
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Affiliation(s)
- Marta Bertolini
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
| | - Jennifer Gherardini
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jérémy Chéret
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Majid Alam
- Department of Dermatology and Venereology, Qatar Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Mathias Sulk
- Department of Dermatology, University of Münster, Münster, Germany
| | - Natalia V Botchkareva
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Tamas Biro
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
| | - Wolfgang Funk
- Clinic for Plastic, Aesthetic and Reconstructive Surgery, Dr. Dr. med. Funk, Munich, Germany
| | | | - Ralf Paus
- Monasterium Laboratory Skin and Hair Research Solutions GmbH, Münster, Germany
- Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- CUTANEON - Skin & Hair Innovations, Hamburg, Germany
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5
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Scott C, Neira Agonh D, White H, Sultana S, Lehmann C. Intravital Microscopy of Lipopolysaccharide-Induced Inflammatory Changes in Different Organ Systems-A Scoping Review. Int J Mol Sci 2023; 24:16345. [PMID: 38003533 PMCID: PMC10671110 DOI: 10.3390/ijms242216345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/02/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Intravital microscopy (IVM) is a powerful imaging tool that captures biological processes in real-time. IVM facilitates the observation of complex cellular interactions in vivo, where ex vivo and in vitro experiments lack the physiological environment. IVM has been used in a multitude of studies under healthy and pathological conditions in different organ systems. IVM has become essential in the characterization of the immune response through visualization of leukocyte-endothelial interactions and subsequent changes within the microcirculation. Lipopolysaccharide (LPS), a common inflammatory trigger, has been used to induce inflammatory changes in various studies utilizing IVM. In this review, we provide an overview of IVM imaging of LPS-induced inflammation in different models, such as the brain, intestines, bladder, and lungs.
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Affiliation(s)
- Cassidy Scott
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H1X5, Canada;
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H1X5, Canada; (H.W.); (S.S.)
| | - Daniel Neira Agonh
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H1X5, Canada;
| | - Hannah White
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H1X5, Canada; (H.W.); (S.S.)
| | - Saki Sultana
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H1X5, Canada; (H.W.); (S.S.)
| | - Christian Lehmann
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H1X5, Canada;
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H1X5, Canada; (H.W.); (S.S.)
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H1X5, Canada;
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6
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Nair AL, Groenendijk L, Overdevest R, Fowke TM, Annida R, Mocellin O, de Vries HE, Wevers NR. Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions. Front Mol Neurosci 2023; 16:1250123. [PMID: 37818458 PMCID: PMC10561300 DOI: 10.3389/fnmol.2023.1250123] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/06/2023] [Indexed: 10/12/2023] Open
Abstract
The blood-brain barrier (BBB) is a highly selective barrier that ensures a homeostatic environment for the central nervous system (CNS). BBB dysfunction, inflammation, and immune cell infiltration are hallmarks of many CNS disorders, including multiple sclerosis and stroke. Physiologically relevant human in vitro models of the BBB are essential to improve our understanding of its function in health and disease, identify novel drug targets, and assess potential new therapies. We present a BBB-on-a-chip model comprising human brain microvascular endothelial cells (HBMECs) cultured in a microfluidic platform that allows parallel culture of 40 chips. In each chip, a perfused HBMEC vessel was grown against an extracellular matrix gel in a membrane-free manner. BBBs-on-chips were exposed to varying concentrations of pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) to mimic inflammation. The effect of the inflammatory conditions was studied by assessing the BBBs-on-chips' barrier function, cell morphology, and expression of cell adhesion molecules. Primary human T cells were perfused through the lumen of the BBBs-on-chips to study T cell adhesion, extravasation, and migration. Under inflammatory conditions, the BBBs-on-chips showed decreased trans-endothelial electrical resistance (TEER), increased permeability to sodium fluorescein, and aberrant cell morphology in a concentration-dependent manner. Moreover, we observed increased expression of cell adhesion molecules and concomitant monocyte adhesion. T cells extravasated from the inflamed blood vessels and migrated towards a C-X-C Motif Chemokine Ligand 12 (CXCL12) gradient. T cell adhesion was significantly reduced and a trend towards decreased migration was observed in presence of Natalizumab, an antibody drug that blocks very late antigen-4 (VLA-4) and is used in the treatment of multiple sclerosis. In conclusion, we demonstrate a high-throughput microfluidic model of the human BBB that can be used to model neuroinflammation and assess anti-inflammatory and barrier-restoring interventions to fight neurological disorders.
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Affiliation(s)
- Arya Lekshmi Nair
- MIMETAS BV, Oegstgeest, Netherlands
- Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience – Neuroinfection and Neuroinflammation, Amsterdam, Netherlands
| | | | | | | | | | | | - Helga E. de Vries
- Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience – Neuroinfection and Neuroinflammation, Amsterdam, Netherlands
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7
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Guo P, Huang J, Zhu B, Huang AC, Jiang L, Fang J, Moses MA. A rationally designed ICAM1 antibody drug conjugate eradicates late-stage and refractory triple-negative breast tumors in vivo. SCIENCE ADVANCES 2023; 9:eabq7866. [PMID: 37146146 PMCID: PMC10162665 DOI: 10.1126/sciadv.abq7866] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Triple-negative breast cancer (TNBC) remains the most lethal form of breast cancer, and effective targeted therapeutics are in urgent need to improve the poor prognosis of TNBC patients. Here, we report the development of a rationally designed antibody drug conjugate (ADC) for the treatment of late-stage and refractory TNBC. We determined that intercellular adhesion molecule-1 (ICAM1), a cell surface receptor overexpressed in TNBC, efficiently facilitates receptor-mediated antibody internalization. We next constructed a panel of four ICAM1 ADCs using different chemical linkers and warheads and compared their in vitro and in vivo efficacies against multiple human TNBC cell lines and a series of standard, late-stage, and refractory TNBC in vivo models. An ICAM1 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker was identified as the optimal ADC formulation owing to its outstanding efficacy and safety, representing an effective ADC candidate for TNBC therapy.
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Affiliation(s)
- Peng Guo
- Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jing Huang
- Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Bing Zhu
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | | | - Lingxiao Jiang
- School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jianmin Fang
- School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Marsha A Moses
- Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
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8
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Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, Scarfó I, Leick MB, Grauwet K, Berger TR, Stewart K, Anekal PV, Jan M, Joung J, Schmidts A, Ouspenskaia T, Law T, Regev A, Getz G, Maus MV. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature 2022; 604:563-570. [PMID: 35418687 DOI: 10.1038/s41586-022-04585-5] [Citation(s) in RCA: 218] [Impact Index Per Article: 72.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/25/2022] [Indexed: 12/12/2022]
Abstract
Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1-6, but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy7,8. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.
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Affiliation(s)
- Rebecca C Larson
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Michael C Kann
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Stefanie R Bailey
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Nicholas J Haradhvala
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA
| | | | - Amanda A Bouffard
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Irene Scarfó
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Mark B Leick
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Korneel Grauwet
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Trisha R Berger
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Kai Stewart
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Max Jan
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Julia Joung
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA, USA.,Department of Biological Engineering, MIT, Cambridge, MA, USA.,McGovern Institute for Brain Research at MIT, Cambridge, MA, USA.,Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
| | - Andrea Schmidts
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | | | - Travis Law
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Biology and Koch Institute of Integrative Cancer Research, MIT, Cambridge, MA, USA.,Genentech, South San Francisco, CA, USA
| | - Gad Getz
- Harvard Medical School, Boston, MA, USA.,Cancer Center, Massachusetts General Hospital, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA. .,Cancer Center, Massachusetts General Hospital, Boston, MA, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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9
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Yang CC, Hsiao LD, Shih YF, Chang CI, Yang CM. Induction of Heme Oxygenase-1 by 15d-Prostaglandin J2 Mediated via a ROS-Dependent Sp1 and AP-1 Cascade Suppresses Lipopolysaccharide-Triggered Interleukin-6 Expression in Mouse Brain Microvascular Endothelial Cells. Antioxidants (Basel) 2022; 11:antiox11040719. [PMID: 35453404 PMCID: PMC9024691 DOI: 10.3390/antiox11040719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/30/2022] [Accepted: 04/04/2022] [Indexed: 12/18/2022] Open
Abstract
Heme oxygenase-1 (HO-1) has been shown to exert antioxidant, anti-inflammatory, and anti-apoptotic effects in various types of cells. Therefore, the induction of HO-1 is an excellent rationale for the development of protective drugs. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) can modulate the expression of antioxidant defense proteins and be beneficial for neuroinflammation. Brain endothelial cells play an important role in the pathophysiology of brain disorders. Whether 15d-PGJ2 can induce HO-1 expression and protect against the inflammatory responses in mouse brain microvascular endothelial (bEnd.3) cells remains unclear. Here, we reveal that 15d-PGJ2 stimulated HO-1 protein and mRNA expression in a time- and concentration-dependent manner in bEnd.3 cells, which was attenuated by diphenyleneiodonium chloride (DPI) and MitoTempo. Thus, activation of NADPH oxidase (NOX)- and mitochondria-derived reactive oxygen species (ROS) mediated 15d-PGJ2-induced HO-1 expression. ROS generation could cause phosphorylation of protein kinase C (PKC)δ, leading to HO-1 expression, which was suppressed by Rottlerin (selective inhibitor PKCδ), DPI, and MitoTempo. We further demonstrated that phosphorylation of c-Jun N-terminal kinase (JNK)1/2 participated in 15d-PGJ2-upregulated HO-1 expression, which was blocked by SP600125 or Rottlerin. Moreover, 15d-PGJ2-induced HO-1 expression was mediated through the activation of c-Jun (a subunit of activator protein 1 (AP-1)) and specificity protein 1 (Sp1), leading to their interaction with the HO-1 promoter, revealed by chromatin immunoprecipitation assay, which was attenuated by SP600125, Mithramycin A, or Tanshinone II A. We further verified the anti-inflammatory effect of HO-1 expression. Our results showed that 15d-PGJ2-induced HO-1 could mitigate the lipopolysaccharide-triggered interleukin-6 expression and secretion, as measured by an ELISA assay kit. These results suggest that 15d-PGJ2-induced HO-1 expression is mediated through the activation of NOX- and mitochondria-derived ROS-dependent PKCδ/JNK1/2/Sp1 and the AP-1 signaling pathway and protects against inflammatory responses in bEnd.3 cells.
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Affiliation(s)
- Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan 33302, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 33302, Taiwan
| | - Li-Der Hsiao
- Department of Pharmacology, College of Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan; (L.-D.H.); (Y.-F.S.); (C.-I.C.)
| | - Ya-Fang Shih
- Department of Pharmacology, College of Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan; (L.-D.H.); (Y.-F.S.); (C.-I.C.)
| | - Ching-I Chang
- Department of Pharmacology, College of Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan; (L.-D.H.); (Y.-F.S.); (C.-I.C.)
| | - Chuen-Mao Yang
- Department of Pharmacology, College of Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan; (L.-D.H.); (Y.-F.S.); (C.-I.C.)
- Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Wufeng, Taichung 41354, Taiwan
- Correspondence: ; Tel.: +886-4-22053366 (ext. 2229)
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10
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The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells. Cells 2021; 10:cells10123515. [PMID: 34944023 PMCID: PMC8700543 DOI: 10.3390/cells10123515] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022] Open
Abstract
The lysine methyltransferase Smyd1 with its characteristic catalytic SET-domain is highly enriched in the embryonic heart and skeletal muscles, participating in cardiomyogenesis, sarcomere assembly and chromatin remodeling. Recently, significant Smyd1 levels were discovered in endothelial cells (ECs) that responded to inflammatory cytokines. Based on these biochemical properties, we hypothesized that Smyd1 is involved in inflammation-triggered signaling in ECs and therefore, investigated its role within the LPS-induced signaling cascade. Human endothelial cells (HUVECs and EA.hy926 cells) responded to LPS stimulation with higher intrinsic Smyd1 expression. By transfection with expression vectors containing gene inserts encoding either intact Smyd1, a catalytically inactive Smyd1-mutant or Smyd1-specific siRNAs, we show that Smyd1 contributes to LPS-triggered expression and secretion of IL-6 in EA.hy926 cells. Further molecular analysis revealed this process to be based on two signaling pathways: Smyd1 increased the activity of NF-κB and promoted the trimethylation of lysine-4 of histone-3 (H3K4me3) within the IL-6 promoter, as shown by ChIP-RT-qPCR combined with IL-6-promoter-driven luciferase reporter gene assays. In summary, our experimental analysis revealed that LPS-binding to ECs leads to the up-regulation of Smyd1 expression to transduce the signal for IL-6 up-regulation via activation of the established NF-κB pathway as well as via epigenetic trimethylation of H3K4.
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11
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Yu JS, Daw J, Portillo JAC, Subauste CS. CD40 Expressed in Endothelial Cells Promotes Upregulation of ICAM-1 But Not Pro-Inflammatory Cytokines, NOS2 and P2X7 in the Diabetic Retina. Invest Ophthalmol Vis Sci 2021; 62:22. [PMID: 34546322 PMCID: PMC8458989 DOI: 10.1167/iovs.62.12.22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose CD40 is an upstream inducer of inflammation in the diabetic retina. CD40 is upregulated in retinal endothelial cells in diabetes. The purpose of this study was to determine whether expression of CD40 in endothelial cells is sufficient to promote inflammatory responses in the retina of diabetic mice. Methods Transgenic mice with CD40 expression restricted to endothelial cells (Trg-CD40 EC), transgenic control mice (Trg-Ctr), B6, and CD40−/− mice were made diabetic using streptozotocin. Leukostasis was assessed using FITC-conjugated ConA. Pro-inflammatory molecule expression was examined by real-time PCR, immunohistochemistry, ELISA, or flow cytometry. Release of ATP was assessed by ATP bioluminescence. Results Diabetic B6 and Trg-CD40 EC mice exhibited increased retinal mRNA levels of ICAM-1, higher ICAM-1 expression in endothelial cells, and increased leukostasis. These responses were not detected in diabetic mice that lacked CD40 (CD40−/− and Trg-Ctr). Diabetic B6 but not Trg-CD40 EC mice upregulated TNF-α, IL-1β, and NOS2 mRNA levels. CD40 stimulation in retinal endothelial cells upregulated ICAM-1 but not TNF-α, IL-1β, or NOS2. CD40 ligation did not trigger ATP release by retinal endothelial cells or pro-inflammatory cytokine production in bystander myeloid cells. In contrast to diabetic B6 mice, diabetic Trg-CD40 EC mice did not upregulate P2X7 mRNA levels in the retina. Conclusions Endothelial cell CD40 promotes ICAM-1 upregulation and leukostasis. In contrast, endothelial cell CD40 does not lead to pro-inflammatory cytokine and NOS2 upregulation likely because it does not activate purinergic-mediated pro-inflammatory molecule expression by myeloid cells or induce expression of these pro-inflammatory molecules in endothelial cells.
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Affiliation(s)
- Jin-Sang Yu
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Jad Daw
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Jose-Andres C Portillo
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Carlos S Subauste
- Division of Infectious Diseases and HIV Medicine, Dept. of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States
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12
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Singh H, Singh A, Khan AA, Gupta V. Immune mediating molecules and pathogenesis of COVID-19-associated neurological disease. Microb Pathog 2021; 158:105023. [PMID: 34090983 PMCID: PMC8177310 DOI: 10.1016/j.micpath.2021.105023] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/30/2021] [Accepted: 05/30/2021] [Indexed: 01/08/2023]
Abstract
Background Long period of SARS-CoV-2 infection has been associated with psychiatric and cognitive disorders in adolescents and children. SARS-CoV-2 remains dormant in the CNS leading to neurological complications. The wide expression of ACE2 in the brain raises concern for its involvement in SARS-CoV-2 infection. Though, the mechanistic insights about blood-brain barriers (BBB) crossing by SARS-CoV-2 and further brain infection are still not clear. Moreover, the mechanism behind dormant SARS-CoV-2 infections leading to chronic neurological disorders needs to be unveiled. There is an urgent need to find out the risk factor involved in COVID-19-associated neurological disease. Therefore, the role of immune-associated genes in the pathogenesis of COVID-19 associated neurological diseases is presented which could contribute to finding associated genetic risk factors. Method The search utilizing multiple databases, specifically, EMBASE, PubMed (Medline), and Google Scholar was performed. Moreover, the literature survey on the involvement of COVID-19, neuropathogenesis, and its consequences was done. Description Persistent inflammatory stimuli may promote the progression of neurodegenerative diseases. An increased expression level of cytokine, chemokine, and decreased expression level of immune cells has been associated with the COVID-19 patient. Cytokine storm was observed in severe COVID-19 patients. The nature of SARS-CoV-2 infection can be neuroinflammatory. Genes of immune response could be associated with neurodegenerative diseases. Conclusion The present review will provide a useful framework and help in understanding COVID-19-associated neuropathogenesis. Experimental studies on immune-associated genes in COVID-19 patients with neurological manifestations could be helpful to establish its neuropathogenesis.
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Affiliation(s)
- HariOm Singh
- Department of Molecular Biology, ICMR-National AIDS Research Institute, Pune, India.
| | - Amita Singh
- District Women Hospital, Prayagraj, UP, 211003, India
| | - Abdul Arif Khan
- Department of Microbiology, ICMR-National AIDS Research Institute, Pune, India
| | - Vivek Gupta
- Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, 282001, India
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13
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Rahman HS, Tan BL, Othman HH, Chartrand MS, Pathak Y, Mohan S, Abdullah R, Alitheen NB. An Overview of In Vitro, In Vivo, and Computational Techniques for Cancer-Associated Angiogenesis Studies. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8857428. [PMID: 33381591 PMCID: PMC7748901 DOI: 10.1155/2020/8857428] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/09/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022]
Abstract
Angiogenesis is a crucial area in scientific research because it involves many important physiological and pathological processes. Indeed, angiogenesis is critical for normal physiological processes, including wound healing and embryonic development, as well as being a component of many disorders, such as rheumatoid arthritis, obesity, and diabetic retinopathies. Investigations of angiogenic mechanisms require assays that can activate the critical steps of angiogenesis as well as provide a tool for assessing the efficacy of therapeutic agents. Thus, angiogenesis assays are key tools for studying the mechanisms of angiogenesis and identifying the potential therapeutic strategies to modulate neovascularization. However, the regulation of angiogenesis is highly complex and not fully understood. Difficulties in assessing the regulators of angiogenic response have necessitated the development of an alternative approach. In this paper, we review the standard models for the study of tumor angiogenesis on the macroscopic scale that include in vitro, in vivo, and computational models. We also highlight the differences in several modeling approaches and describe key advances in understanding the computational models that contributed to the knowledge base of the field.
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Affiliation(s)
- Heshu Sulaiman Rahman
- Department of Physiology, College of Medicine, University of Sulaimani, 46001 Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, College of Health Sciences, Komar University of Science and Technology, Chaq Chaq Qularaesee, 46001 Sulaymaniyah, Iraq
| | - Bee Ling Tan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Hemn Hassan Othman
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, 46001 Sulaymaniyah, Iraq
| | | | - Yashwant Pathak
- College of Pharmacy, University of South Florida, Tampa, USA and Adjunct Professor at Faculty of Pharmacy, University of Airlangga, Surabaya, Indonesia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan, Saudi Arabia
| | - Rasedee Abdullah
- Department of Veterinary Laboratory Diagnosis, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Noorjahan Banu Alitheen
- Department of Cell and Molecular Biology, Faculty of Biotechnology and Bio-Molecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
- Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
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14
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Kunjiappan S, Pavadai P, Vellaichamy S, Ram Kumar Pandian S, Ravishankar V, Palanisamy P, Govindaraj S, Srinivasan G, Premanand A, Sankaranarayanan M, Theivendren P. Surface receptor‐mediated targeted drug delivery systems for enhanced cancer treatment: A state‐of‐the‐art review. Drug Dev Res 2020; 82:309-340. [DOI: 10.1002/ddr.21758] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Selvaraj Kunjiappan
- Department of Biotechnology Kalasalingam Academy of Research and Education Krishnankoil Tamilnadu India
| | - Parasuraman Pavadai
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy M.S. Ramaiah University of Applied Sciences Bengaluru Karnataka India
| | - Sivakumar Vellaichamy
- Department of Pharmaceutics Arulmigu Kalasalingam College of Pharmacy Krishnankoil Tamilnadu India
| | | | | | - Ponnusamy Palanisamy
- School of Mechanical Engineering Vellore Institute of Technology Vellore Tamilnadu India
| | - Saravanan Govindaraj
- Department of Pharmaceutical Chemistry MNR College of Pharmacy Sangareddy Telangana India
| | - Gowshiki Srinivasan
- Department of Biotechnology Kalasalingam Academy of Research and Education Krishnankoil Tamilnadu India
| | - Adhvitha Premanand
- Department of Biotechnology Kalasalingam Academy of Research and Education Krishnankoil Tamilnadu India
| | | | - Panneerselvam Theivendren
- Department of Pharmaceutical Chemistry Swamy Vivekananda College of Pharmacy Elayampalayam, Namakkal Tamilnadu India
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15
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Goncharov NV, Popova PI, Avdonin PP, Kudryavtsev IV, Serebryakova MK, Korf EA, Avdonin PV. Markers of Endothelial Cells in Normal and Pathological Conditions. BIOCHEMISTRY MOSCOW SUPPLEMENT SERIES A-MEMBRANE AND CELL BIOLOGY 2020; 14:167-183. [PMID: 33072245 PMCID: PMC7553370 DOI: 10.1134/s1990747819030140] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/28/2019] [Accepted: 04/02/2019] [Indexed: 01/22/2023]
Abstract
Endothelial cells (ECs) line the blood vessels and lymphatic vessels, as well as heart chambers, forming the border between the tissues, on the one hand, and blood or lymph, on the other. Such a strategic position of the endothelium determines its most important functional role in the regulation of vascular tone, hemostasis, and inflammatory processes. The damaged endothelium can be both a cause and a consequence of many diseases. The state of the endothelium is indicated by the phenotype of these cells, represented mainly by (trans)membrane markers (surface antigens). This review defines endothelial markers, provides a list of them, and considers the mechanisms of their expression and the role of the endothelium in certain pathological conditions.
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Affiliation(s)
- N V Goncharov
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia.,Research Institute of Hygiene, Occupational Pathology and Human Ecology, 188663 p.o. Kuz'molovskii, Leningrad oblast Russia
| | - P I Popova
- City Polyclinic no. 19, 142238 St. Petersburg, Russia
| | - P P Avdonin
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - I V Kudryavtsev
- Institute of Experimental Medicine, 197376 St. Petersburg, Russia.,Far-East Federal University, 690091 Vladivostok, Russia
| | - M K Serebryakova
- Institute of Experimental Medicine, 197376 St. Petersburg, Russia
| | - E A Korf
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia
| | - P V Avdonin
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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16
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Ito S, Oishi M, Ogata S, Uemura T, Couraud PO, Masuda T, Ohtsuki S. Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro. Pharmaceutics 2020; 12:pharmaceutics12060579. [PMID: 32585920 PMCID: PMC7356521 DOI: 10.3390/pharmaceutics12060579] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 12/19/2022] Open
Abstract
Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood–brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells. Of these, 34 cell-surface proteins were selectively internalized into human brain microvascular endothelial cells, but not into human umbilical vein endothelial cells (HUVECs), a model of human peripheral microvascular endothelial cells. Two cell-surface proteins, intercellular adhesion molecule-1 (ICAM1) and podocalyxin (PODXL), were identified as BBB-localized endocytic cell-surface proteins in humans, using open mRNA and protein databases. Immunohistochemical evaluation confirmed PODXL expression in the plasma membrane of hCMEC/D3 cells and revealed that anti-PODXL antibody-labeled cell-surface PODXL internalized into hCMEC/D3 cells. Immunohistochemistry further revealed that PODXL is localized at the luminal side of human brain microvessels, supporting its potential suitability for translational applications. In conclusion, our findings highlight novel endocytic cell-surface proteins capable of internalizing into human brain microvascular endothelial cells. ICAM1 or PODXL targeted antibody or ligand-labeled biopharmaceuticals and nanocarriers may provide effective targeted delivery to the brain across the BBB for the treatment of central nervous system (CNS) diseases.
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Affiliation(s)
- Shingo Ito
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.I.); (T.M.)
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;
- Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.O.); (T.U.)
| | - Mariko Oishi
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;
| | - Seiryo Ogata
- Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.O.); (T.U.)
| | - Tatsuki Uemura
- Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.O.); (T.U.)
| | - Pierre-Olivier Couraud
- Institut Cochin, Universite de Paris, Inserm U1016, CNRS UMR8104, 22 rue Méchain, 75014 Paris, France;
| | - Takeshi Masuda
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.I.); (T.M.)
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;
- Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.O.); (T.U.)
| | - Sumio Ohtsuki
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.I.); (T.M.)
- Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan;
- Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (S.O.); (T.U.)
- Correspondence: ; Tel.: +81-96-371-4323
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17
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Ge S, Jiang X, Paul D, Song L, Wang X, Pachter JS. Human ES-derived MSCs correct TNF-α-mediated alterations in a blood-brain barrier model. Fluids Barriers CNS 2019; 16:18. [PMID: 31256757 PMCID: PMC6600885 DOI: 10.1186/s12987-019-0138-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 05/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background Immune cell trafficking into the CNS is considered to contribute to pathogenesis in MS and its animal model, EAE. Disruption of the blood–brain barrier (BBB) is a hallmark of these pathologies and a potential target of therapeutics. Human embryonic stem cell-derived mesenchymal stem/stromal cells (hES-MSCs) have shown superior therapeutic efficacy, compared to bone marrow-derived MSCs, in reducing clinical symptoms and neuropathology of EAE. However, it has not yet been reported whether hES-MSCs inhibit and/or repair the BBB damage associated with neuroinflammation that accompanies EAE. Methods BMECs were cultured on Transwell inserts as a BBB model for all the experiments. Disruption of BBB models was induced by TNF-α, a pro-inflammatory cytokine that is a hallmark of acute and chronic neuroinflammation. Results Results indicated that hES-MSCs reversed the TNF-α-induced changes in tight junction proteins, permeability, transendothelial electrical resistance, and expression of adhesion molecules, especially when these cells were placed in direct contact with BMEC. Conclusions hES-MSCs and/or products derived from them could potentially serve as novel therapeutics to repair BBB disturbances in MS. Electronic supplementary material The online version of this article (10.1186/s12987-019-0138-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shujun Ge
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.
| | - Xi Jiang
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.,Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Debayon Paul
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
| | - Li Song
- ImStem Biotechnology, Inc., 400 Farmington Ave., Farmington, CT, 06030, USA
| | - Xiaofang Wang
- ImStem Biotechnology, Inc., 400 Farmington Ave., Farmington, CT, 06030, USA
| | - Joel S Pachter
- Blood-Brain Barrier Laboratory, Dept. of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
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18
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Gram A, Grazul-Bilska AT, Boos A, Rahman NA, Kowalewski MP. Lipopolysaccharide disrupts gap junctional intercellular communication in an immortalized ovine luteal endothelial cell line. Toxicol In Vitro 2019; 60:437-449. [PMID: 31154062 DOI: 10.1016/j.tiv.2019.05.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/13/2019] [Accepted: 05/27/2019] [Indexed: 10/26/2022]
Abstract
Gram-negative bacteria, in particular Escherichia coli with its cell wall lipopolysaccharide (LPS), often cause metritis and mastitis in domestic animals. Ovarian LPS accumulation may initiate local inflammatory reactions mediated through cell surface Toll-like receptors (TLRs). This may disrupt ovarian functionality leading to infertility. Possible adverse effects of LPS on luteal activity are not yet well explored. We hypothesized that LPS could lead to alterations in luteal vascular functionality. Therefore, we established an in vitro cell line model (OLENDO) by immortalizing microvascular endothelial cells isolated from ovine corpus luteum (CL) with a potent Simian Virus 40 T-antigen (SV40-Tag). OLENDO exhibit endothelial cell characteristics, like low-density lipoprotein (LDL) uptake, express BSL-I, and VEGFR2, as well as TLR2 and TLR4 receptors. LPS-treatment of OLENDO altered in vitro tube formation, had no effects on cell viability and decreased gap junctional intercellular communication (GJIC). LPS did not impair GJA1/Cx43 protein expression, but altered its cellular localization showing signs of internalization. Taken together, we demonstrated the mechanisms underlying LPS induced impairment of luteal GJIC and immune processes in a novel and well-characterized OLENDO cell line.
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Affiliation(s)
- Aykut Gram
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
| | | | - Alois Boos
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Nafis A Rahman
- Institute of Biomedicine, University of Turku, Turku, Finland; Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland
| | - Mariusz P Kowalewski
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
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Hunter LW, Jayachandran M, Miller VM. Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli. Biol Sex Differ 2019; 10:26. [PMID: 31118073 PMCID: PMC6532199 DOI: 10.1186/s13293-019-0241-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 05/13/2019] [Indexed: 01/06/2023] Open
Abstract
Background There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated by inflammatory and thrombotic factors have the potential to disrupt endothelial cells of the brain microvasculature. Therefore, experiments were designed to identify sex differences in the phenotype of MV released from cultured human brain microvascular endothelial cells (HBMEC) in response to inflammatory and thrombotic stimuli. Methods Cultured HBMEC derived from 20- to 30-year-old male and female donors were treated for 20 h with medium supplemented with tumor necrosis factor alpha (TNFα; 20 ng/ml), thrombin (THR; 2 U/ml), or vehicle (i.e., control). MV were isolated from the conditioned media by high-speed centrifugation and quantified by digital flow cytometry by labeling with fluorophore-conjugated primary antibodies against PECAM-1, integrin αvβ3, ICAM-1, E-selectin, or MCAM. In addition, temporal uptake of labeled MV into control HBMEC was examined by confocal microscopy. Results Under control conditions, male HBMEC released fewer MV expressing each antigen, except for PECAM-1, than female cells (P < 0.05). Neither TNFα nor THR reduced cell viability. However, TNFα induced apoptosis in female and male cells, whereas THR increased apoptosis marginally only in male cells. TNFα increased expression of all antigens tested on MV in male cells, but only increased expression of integrin αvβ3, ICAM-1, and E-selectin on MV from female cells. THR increased expression of PECAM-1, ICAM-1, and MCAM-1 on MV from male but not female cells. MV were internalized and localized to lysosomes within 90 min after their application to HBMEC. Conclusions There are sex differences in expression of cell adhesion molecules on MV released from HBMEC under control conditions and upon activation by TNFα or THR. MV taken up by unstimulated HBMEC may impact the integrity of the brain microvasculature and account, in part, for sex differences in vascular pathologies in the brain.
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Affiliation(s)
- Larry W Hunter
- Department of Surgery, Mayo Clinic, Medical Science Bldg. 4-20, 200 First St. SW, Rochester, MN, 55905, USA
| | - Muthuvel Jayachandran
- Department of Surgery, Mayo Clinic, Medical Science Bldg. 4-20, 200 First St. SW, Rochester, MN, 55905, USA.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA.,Divisions of Hematology Research and Nephrology and Hypertension Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Virginia M Miller
- Department of Surgery, Mayo Clinic, Medical Science Bldg. 4-20, 200 First St. SW, Rochester, MN, 55905, USA. .,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA. .,Women's Health Research Center, Mayo Clinic, Rochester, MN, 55905, USA.
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20
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Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol 2019; 316:C135-C153. [PMID: 30379577 PMCID: PMC6397344 DOI: 10.1152/ajpcell.00136.2018] [Citation(s) in RCA: 546] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 10/29/2018] [Accepted: 10/30/2018] [Indexed: 12/25/2022]
Abstract
As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.
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Affiliation(s)
- Changjun Yang
- Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
| | - Kimberly E Hawkins
- Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
| | - Sylvain Doré
- Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
- Departments of Anesthesiology, Neurology, Psychiatry, Psychology, and Pharmaceutics, McKnight Brain Institute, University of Florida , Gainesville, Florida
| | - Eduardo Candelario-Jalil
- Department of Neuroscience, McKnight Brain Institute, University of Florida , Gainesville, Florida
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21
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Wei H, Lv M, Wen C, Zhang A, Yang K, Zhou H, Wang X. Identification of an intercellular cell adhesion molecule-1 homologue from grass carp: Evidence for its involvement in the immune cell adhesion in teleost. FISH & SHELLFISH IMMUNOLOGY 2018; 81:67-72. [PMID: 29981884 DOI: 10.1016/j.fsi.2018.07.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/04/2018] [Accepted: 07/05/2018] [Indexed: 06/08/2023]
Abstract
Intercellular cell adhesion molecule-1 (ICAM-1) is a single-chain transmembrane glycoprotein which plays key roles in transendothelial migration of leukocytes and interaction between antigen presenting cells and T cells. In teleost, information of cell adhesion-related molecules is still lacking. In this study, we identified a gene from grass carp sharing similar exon and intron organization with human ICAM-1. Cloning and in silico analysis of its homologues in zebrafish and other two cyprinid fishes, respectively demonstrated the existence of the gene in these fishes. Moreover, the molecular features of these genes in fishes were conserved compared with human ICAM-1. In grass carp, the transcripts of this gene were detected with high levels in heart and liver and its mRNA expression in headkidney leukocytes was induced by Il-1β. Overexpression of this molecule in COS-7 cells could increase the adhesion of the cells with grass carp peripheral blood lymphocytes (PBLs), and the adhesion was further enhanced by lipopolysaccharide stimulation on PBLs. Further studies revealed that the mRNA levels of lymphocyte function-associated antigen-1, a ligand for ICAM-1, were much higher in the PBLs adhering to the COS-7 cells with overexpressing this molecule than in the PBLs alone. These results collectively showed that the newly cloned cDNA encodes grass carp intercellular cell adhesion molecule-1 (Icam-1) and it can mediate the adhesion of PBLs. This provides functional evidence for the existence of Icam-1 in teleost and will facilitate investigation on the transendothelial migration of leukocytes in fish species.
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Affiliation(s)
- He Wei
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China; School of Biomedical Sciences, Chengdu Medical College, Chengdu, People's Republic of China
| | - Mengyuan Lv
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Chao Wen
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Anying Zhang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Kun Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Hong Zhou
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Xinyan Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
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22
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Nishinaka A, Inoue Y, Fuma S, Hida Y, Nakamura S, Shimazawa M, Hara H. Pathophysiological Role of VEGF on Retinal Edema and Nonperfused Areas in Mouse Eyes With Retinal Vein Occlusion. ACTA ACUST UNITED AC 2018; 59:4701-4713. [DOI: 10.1167/iovs.18-23994] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Anri Nishinaka
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Yuki Inoue
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Shinichiro Fuma
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Yoshifumi Hida
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Shinsuke Nakamura
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Masamitsu Shimazawa
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
| | - Hideaki Hara
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
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23
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Goncharov NV, Nadeev AD, Jenkins RO, Avdonin PV. Markers and Biomarkers of Endothelium: When Something Is Rotten in the State. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:9759735. [PMID: 29333215 PMCID: PMC5733214 DOI: 10.1155/2017/9759735] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 09/05/2017] [Indexed: 12/14/2022]
Abstract
Endothelium is a community of endothelial cells (ECs), which line the blood and lymphatic vessels, thus forming an interface between the tissues and the blood or lympha. This strategic position of endothelium infers its indispensable functional role in controlling vasoregulation, haemostasis, and inflammation. The state of endothelium is simultaneously the cause and effect of many diseases, and this is coupled with modifications of endothelial phenotype represented by markers and with biochemical profile of blood represented by biomarkers. In this paper, we briefly review data on the functional role of endothelium, give definitions of endothelial markers and biomarkers, touch on the methodological approaches for revealing biomarkers, present an implicit role of endothelium in some toxicological mechanistic studies, and survey the role of reactive oxygen species (ROS) in modulation of endothelial status.
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Affiliation(s)
- Nikolay V. Goncharov
- Research Institute of Hygiene, Occupational Pathology and Human Ecology, Saint Petersburg, Russia
- Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, Saint Petersburg, Russia
| | - Alexander D. Nadeev
- Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, Saint Petersburg, Russia
- Institute of Cell Biophysics RAS, Pushchino, Russia
| | - Richard O. Jenkins
- School of Allied Health Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK
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24
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Qian T, Maguire SE, Canfield SG, Bao X, Olson WR, Shusta EV, Palecek SP. Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells. SCIENCE ADVANCES 2017; 3:e1701679. [PMID: 29134197 PMCID: PMC5677350 DOI: 10.1126/sciadv.1701679] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 10/11/2017] [Indexed: 05/18/2023]
Abstract
The blood-brain barrier (BBB) is composed of specialized endothelial cells that are critical to neurological health. A key tool for understanding human BBB development and its role in neurological disease is a reliable and scalable source of functional brain microvascular endothelial cells (BMECs). Human pluripotent stem cells (hPSCs) can theoretically generate unlimited quantities of any cell lineage in vitro, including BMECs, for disease modeling, drug screening, and cell-based therapies. We demonstrate a facile, chemically defined method to differentiate hPSCs to BMECs in a developmentally relevant progression via small-molecule activation of key signaling pathways. hPSCs are first induced to mesoderm commitment by activating canonical Wnt signaling. Next, these mesoderm precursors progress to endothelial progenitors, and treatment with retinoic acid leads to acquisition of BBB-specific markers and phenotypes. hPSC-derived BMECs generated via this protocol exhibit endothelial properties, including tube formation and low-density lipoprotein uptake, as well as efflux transporter activities characteristic of BMECs. Notably, these cells exhibit high transendothelial electrical resistance above 3000 ohm·cm2. These hPSC-derived BMECs serve as a robust human in vitro BBB model that can be used to study brain disease and inform therapeutic development.
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Affiliation(s)
- Tongcheng Qian
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Shaenah E. Maguire
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Scott G. Canfield
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Xiaoping Bao
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - William R. Olson
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Eric V. Shusta
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Sean P. Palecek
- Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
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25
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Involvement of the IL-1 system in experimental autoimmune encephalomyelitis and multiple sclerosis: Breaking the vicious cycle between IL-1β and GM-CSF. Brain Behav Immun 2017; 62:1-8. [PMID: 27432634 DOI: 10.1016/j.bbi.2016.07.146] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/07/2016] [Accepted: 07/14/2016] [Indexed: 02/08/2023] Open
Abstract
Multiple sclerosis (MS) is an autoimmune disease that affects hundreds of thousands of people worldwide. Given the autoimmune nature of the disease, a large part of the research has focused on autoreactive T and B cells. However, research on the involvement of myeloid cells in the pathophysiology of MS has received a strong and renewed attention over the recent years. Despite the multitude of inflammatory mediators involved in innate immunity, only a select group of cytokines are absolutely critical to the development of CNS autoimmunity, among which is interleukin (IL)-1. While the importance of the IL-1 system in experimental autoimmune encephalomyelitis (EAE) and MS has been recognized for about 20years, it is only recently that we have begun to understand that IL-1 plays multifaceted roles in disease initiation, development, amplification and chronicity. Here, we review the recent findings showing an implication of the IL-1 system in EAE and MS, and introduce a model that highlights how IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF) are interacting together to create a vicious feedback cycle of CNS inflammation that ultimately leads to myelin and neuronal damage.
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26
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Son WR, Nam MH, Hong CO, Kim Y, Lee KW. Plantamajoside from Plantago asiatica modulates human umbilical vein endothelial cell dysfunction by glyceraldehyde-induced AGEs via MAPK/NF-κB. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:66. [PMID: 28109289 PMCID: PMC5251346 DOI: 10.1186/s12906-017-1570-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 01/07/2017] [Indexed: 01/25/2023]
Abstract
Background Plantago asiatica has been traditionally used for traditional medicine around East Asia. Plantamajoside (PM), which is isolated from this plant, is known for biological properties including anti-inflammation and antioxidant activity. To demonstrate the biological activity of PM against endothelial dysfunction induced by advanced glycation end-products (AGEs), a cellular inflammatory mechanism system was evaluated in human umbilical vein endothelial cells (HUVECs). Methods We obtained PM through previous research in our laboratory. We formed the AGEs from bovine serum albumin with glyceraldehyde in the dark for seven days. To confirm the modulation of the inflammatory mechanism in endothelial dysfunction, we quantified the various pro-inflammatory cytokines and endothelial dysfunction-related proteins in the HUVECs with Western blotting and with real-time and quantitative real-time polymerase chain reactions. Results Co-treatment with PM and AGEs significantly suppressed inflammatory cytokines and adhesion molecule expression. Moreover, the PM treatment for down-regulated inflammatory signals and blocked monocyte adhesion on the HUVECs. Conclusions Theses results demonstrated that PM, as a potential natural compound, protects AGE-induced endothelial cells against inflammatory cellular dysfunction. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1570-1) contains supplementary material, which is available to authorized users.
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27
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Wu Z, Zhu SZ, Hu YF, Gu Y, Wang SN, Lin ZZ, Xie ZS, Pan SY. Glibenclamide enhances the effects of delayed hypothermia after experimental stroke in rats. Brain Res 2016; 1643:113-22. [PMID: 27134036 DOI: 10.1016/j.brainres.2016.04.067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Revised: 04/24/2016] [Accepted: 04/27/2016] [Indexed: 11/25/2022]
Abstract
In order to evaluate whether glibenclamide can extend the therapeutic window during which induced hypothermia can protect against stroke, we subjected adult male Sprague-Dawley rats to middle cerebral artery occlusion (MCAO). We first verified the protective effects of hypothermia induced at 0, 2, 4 or 6h after MCAO onset, and then we assessed the effects of the combination of glibenclamide and hypothermia at 6, 8 or 10h after MCAO onset. At 24h after MCAO, we assessed brain edema, infarct volume, modified neurological severity score, Evans Blue leakage and expression of Sulfonylurea receptor 1 (SUR1) protein and pro-inflammatory factors. No protective effects were observed when hypothermia was induced too long after MCAO. At 6h after MCAO onset, hypothermia alone failed to decrease cerebral edema and infarct volume, but the combination of glibenclamide and hypothermia decreased both. The combination also improved neurological outcome, ameliorated blood-brain barrier damage and decreased levels of COX-2, TNF-α and IL-1β. These results suggest that glibenclamide enhances and extends the therapeutic effects of delayed hypothermia against ischemia stroke, potentially by ameliorating blood-brain barrier damage and declining levels of pro-inflammatory factors.
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Affiliation(s)
- Zhou Wu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shu-Zhen Zhu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ya-Fang Hu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yong Gu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng-Nan Wang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhen-Zhou Lin
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zuo-Shan Xie
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Su-Yue Pan
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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28
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Blauth K, Owens GP, Bennett JL. The Ins and Outs of B Cells in Multiple Sclerosis. Front Immunol 2015; 6:565. [PMID: 26594215 PMCID: PMC4633507 DOI: 10.3389/fimmu.2015.00565] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 10/23/2015] [Indexed: 12/25/2022] Open
Abstract
B cells play a central role in multiple sclerosis (MS) pathology. B and plasma cells may contribute to disease activity through multiple mechanisms: antigen presentation, cytokine secretion, or antibody production. Molecular analyses of B cell populations in MS patients have revealed significant overlaps between peripheral lymphoid and clonally expanded central nervous system (CNS) B cell populations, indicating that B cell trafficking may play a critical role in driving MS exacerbations. In this review, we will assess our current knowledge of the mechanisms and pathways governing B cell migration into the CNS and examine evidence for and against a compartmentalized B cell response driving progressive MS pathology.
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Affiliation(s)
- Kevin Blauth
- Department of Neurology, University of Colorado Denver , Aurora, CO , USA
| | - Gregory P Owens
- Department of Neurology, University of Colorado Denver , Aurora, CO , USA
| | - Jeffrey L Bennett
- Department of Neurology, University of Colorado Denver , Aurora, CO , USA ; Department of Ophthalmology, University of Colorado Denver , Aurora, CO , USA ; Program in Neuroscience, University of Colorado Denver , Aurora, CO , USA
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29
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Ji R, Meng L, Li Q, Lu Q. TAM receptor deficiency affects adult hippocampal neurogenesis. Metab Brain Dis 2015; 30:633-44. [PMID: 25487541 PMCID: PMC4414696 DOI: 10.1007/s11011-014-9636-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Accepted: 11/17/2014] [Indexed: 10/24/2022]
Abstract
The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus.
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Affiliation(s)
- Rui Ji
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Lingbin Meng
- Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Qiutang Li
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Qingxian Lu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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30
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Multiple Sclerosis and T Lymphocytes: An Entangled Story. J Neuroimmune Pharmacol 2015; 10:528-46. [PMID: 25946987 DOI: 10.1007/s11481-015-9614-0] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 04/29/2015] [Indexed: 12/17/2022]
Abstract
Multiple sclerosis (MS) is the prototypic inflammatory disease of the central nervous system (CNS) characterized by multifocal areas of demyelination, axonal damage, activation of glial cells, and immune cell infiltration. Despite intensive years of research, the etiology of this neurological disorder remains elusive. Nevertheless, the abundance of immune cells such as T lymphocytes and their products in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder. An important body of evidence gathered from MS animal models such as experimental autoimmune encephalomyelitis (EAE), points to the central contribution of CD4 T lymphocytes in disease pathogenesis. Both Th1 (producing interferon-γ) and Th17 (producing interleukin 17) CD4 T lymphocytes targeting CNS self-antigens have been implicated in MS and EAE pathobiology. Moreover, several publications suggest that CD8 T lymphocytes also participate in the development of MS lesions. The migration of activated T lymphocytes from the periphery into the CNS has been identified as a crucial step in the formation of MS lesions. Several factors promote such T cell extravasation including: molecules (e.g., cell adhesion molecules) implicated in the T cell-blood brain barrier interaction, and chemokines produced by neural cells. Finally, once in the CNS, T lymphocytes need to be reactivated by local antigen presenting cells prior to enter the parenchyma where they can initiate damage. Further investigations will be necessary to elucidate the impact of environmental factors (e.g., gut microbiota) and CNS intrinsic properties (e.g., microglial activation) on this inflammatory neurological disease.
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31
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Levy O, Mortensen LJ, Boquet G, Tong Z, Perrault C, Benhamou B, Zhang J, Stratton T, Han E, Safaee H, Musabeyezu J, Yang Z, Multon MC, Rothblatt J, Deleuze JF, Lin CP, Karp JM. A small-molecule screen for enhanced homing of systemically infused cells. Cell Rep 2015; 10:1261-1268. [PMID: 25732817 DOI: 10.1016/j.celrep.2015.01.057] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 12/14/2014] [Accepted: 01/24/2015] [Indexed: 12/13/2022] Open
Abstract
Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies.
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Affiliation(s)
- Oren Levy
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Luke J Mortensen
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Gerald Boquet
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | - Zhixiang Tong
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Christelle Perrault
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | - Brigitte Benhamou
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | - Jidong Zhang
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | - Tara Stratton
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Edward Han
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Helia Safaee
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Juliet Musabeyezu
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Zijiang Yang
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
| | - Marie-Christine Multon
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | | | - Jean-Francois Deleuze
- Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France
| | - Charles P Lin
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Jeffrey M Karp
- Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139
- Harvard Stem Cell Institute, Cambridge, MA 02139
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139
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Kurpios-Piec D, Grosicka-Maciąg E, Woźniak K, Kowalewski C, Kiernozek E, Szumiło M, Rahden-Staroń I. Thiram activates NF-kappaB and enhances ICAM-1 expression in human microvascular endothelial HMEC-1 cells. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2015; 118:82-89. [PMID: 25752435 DOI: 10.1016/j.pestbp.2014.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 12/02/2014] [Accepted: 12/03/2014] [Indexed: 06/04/2023]
Abstract
Thiram (TMTD) is a fungicidal and bactericidal agent used as antiseptic, seed disinfectant and animal repellent. In the light of known properties, thiram is considered to be used as an inhibitor of angiogenesis and/or inflammation. Since angiogenesis requires the growth of vascular endothelial cells we have used microvascular endothelial cell line HMEC-1 to elucidate the effect of thiram on normal and stimulated cells. We cultured HMEC-1 cells in the presence of thiram at low concentration (0.5 µg/mL or 2 µg/mL) (0.2 µM or 0.8 µM) or TNF-α (10 ng/mL) alone, and thiram together with TNF-α. TNF-α was used as a cytokine that triggers changes characteristic for inflammatory state of the cell. We carried out an in vitro study aimed at assessing generation of reactive oxygen species (ROS), activation of NF-κB, and expression of cell adhesion molecules ICAM-1, VCAM-1, PECAM-1. It was found that TMTD produced ROS and activated NF-κB. Activation of NF-κB was concurrent with an increase in ICAM-1 expression on the surface of HMEC-1 cells. ICAM-1 reflects intensity of inflammation in endothelial cell milieu. The expression of VCAM-1 and PECAM-1 on these cells was not changed by thiram. It was also found that stimulation of the HMEC-1 cells with the pro-inflammatory cytokine TNF-α caused activation of ICAM-1 and VCAM-1 expression with concomitant decrease of PECAM-1 cell surface expression above the control levels. Treatment with thiram and TNF-α changed cellular response compared with effects observed after treatment with TNF-α alone, i.e. further increase of ICAM-1 expression and impairment of the TNF-α effect on PECAM-1 and VCAM-1 expression. This study demonstrated that thiram acts as a pro-oxidant, and elicits in endothelial cell environment effects characteristic for inflammation. However, when it is present concurrently with pro-inflammatory cytokine TNF-α interferes with its action.
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Affiliation(s)
- Dagmara Kurpios-Piec
- Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Emilia Grosicka-Maciąg
- Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Katarzyna Woźniak
- Department of Dermatology and Immunodermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Cezary Kowalewski
- Department of Dermatology and Immunodermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Ewelina Kiernozek
- Immunology Department, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Maria Szumiło
- Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Iwonna Rahden-Staroń
- Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
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Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, Kyurkchiev S. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells 2014; 6:552-570. [PMID: 25426252 PMCID: PMC4178255 DOI: 10.4252/wjsc.v6.i5.552] [Citation(s) in RCA: 462] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 08/20/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.
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Brunn A, Utermöhlen O, Mihelcic M, Sánchez-Ruiz M, Carstov M, Blau T, Ustinova I, Penfold M, Montesinos-Rongen M, Deckert M. Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immune reactions on murine P0106-125 -induced experimental autoimmune neuritis. Neuropathol Appl Neurobiol 2014; 39:772-87. [PMID: 23452257 DOI: 10.1111/nan.12039] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 02/01/2013] [Indexed: 12/23/2022]
Abstract
AIM The role of chemokines and their receptors, which regulate trafficking and homing of leucocytes to inflamed organs in human or murine autoimmune neuritis, has not yet been elucidated in detail, Therefore, the role of the chemokine receptors CXCR4 and CXCR7 and their ligand CXCL12 was studied in autoimmune-mediated inflammation of the peripheral nervous system. METHODS CXCL12/CXCR4 and/or CXCL12/CXCR7 interactions were specifically inhibited by the compounds AMD3100 or CCX771, respectively, in experimental autoimmune neuritis (EAN) of C57BL/6J mice immunized with P0106-125 peptide. RESULTS Disease activity was significantly suppressed by blocking CXCR7 while antagonization of CXCR4 enhanced disease activity. Enhanced disease activity was accompanied by significantly increased transcription of IFN-γ, IL-12 and TNF-α mRNA in regional lymph nodes and spleen as well as by increased serum levels of IFN-γ. Furthermore, by blocking CXCR4, expression of the cell adhesion molecules ICAM-1 and VCAM-1 was upregulated on vascular endothelial cells of the sciatic nerve, which coincided with significantly increased infiltration of the sciatic nerve by CD4+ T cells and macrophages. Remarkably, combined antagonization of both CXCR4 and CXCR7 significantly suppressed disease activity. This was accompanied by increased frequencies of activated and highly IFN-γ-expressing, P0106-125 -specific T cells in regional lymph nodes and spleen; however, these cells were unable to infiltrate the sciatic nerve. CONCLUSION These data suggest differential and hierarchically ordered roles for CXCR4/CXCL12- vs. CXCR7/CXCL12-dependent effects during EAN: CXCR7/CXCL12 interaction is a gatekeeper for pathogenic cells, regardless of their CXCR4/CXCL12-dependent state of activation.
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Affiliation(s)
- A Brunn
- Department of Neuropathology, University Hospital of Cologne, Cologne, Germany
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Anderson KM, Olson KE, Estes KA, Flanagan K, Gendelman HE, Mosley RL. Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener 2014; 3:25. [PMID: 25671101 PMCID: PMC4323229 DOI: 10.1186/2047-9158-3-25] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 10/28/2014] [Indexed: 12/14/2022] Open
Abstract
Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression.
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Affiliation(s)
- Kristi M Anderson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, The University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Katherine E Olson
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, The University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Katherine A Estes
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, The University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Ken Flanagan
- Prothena Biosciences, South San Francisco, 650 Gateway Boulevard, CA 94080 USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, The University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, The University of Nebraska Medical Center, Omaha, NE 68198 USA
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Tuttolomondo A, Pecoraro R, Pinto A. Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date. Drug Des Devel Ther 2014; 8:2221-2238. [PMID: 25422582 PMCID: PMC4232043 DOI: 10.2147/dddt.s67655] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.
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Affiliation(s)
- Antonino Tuttolomondo
- Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy
| | - Rosaria Pecoraro
- Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy
| | - Antonio Pinto
- Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy
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Singh A, Singh AK, Singh SK, Paliwal VK, Gupta RK, Prasad KN. Association of ICAM-1 K469E polymorphism with neurocysticercosis. J Neuroimmunol 2014; 276:166-71. [PMID: 25128351 DOI: 10.1016/j.jneuroim.2014.07.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 05/29/2014] [Accepted: 07/24/2014] [Indexed: 10/24/2022]
Abstract
Neurocysticercosis (NCC), a central nervous system (CNS) disease is caused by the larval stage of Taenia solium. The disease is heterogeneous in clinical presentation; some infected individuals develop symptoms and others may remain symptom free. Impaired blood brain barrier allows recruitment of immune cells in the CNS during infection and soluble intercellular adhesion molecule-1 (sICAM-1) plays an important role in the recruitment of immune cells. We studied ICAM-1 K469E polymorphism among symptomatic and asymptomatic NCC patients. The study revealed that individuals with variant (EE) genotype were more susceptible to symptomatic NCC and also had an elevated level of sICAM-1.
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Affiliation(s)
- Amrita Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Aloukick K Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Satyendra K Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Vimal K Paliwal
- Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,Uttar Pradesh 226014, India
| | - Rakesh K Gupta
- Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,Uttar Pradesh 226014, India
| | - Kashi N Prasad
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
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d'Arcy R, Tirelli N. Fishing for fire: strategies for biological targeting and criteria for material design in anti-inflammatory therapies. POLYM ADVAN TECHNOL 2014. [DOI: 10.1002/pat.3264] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Richard d'Arcy
- School of Medicine/Institute of Inflammation and Repair; University of Manchester; Manchester M13 9PT UK
| | - Nicola Tirelli
- School of Medicine/Institute of Inflammation and Repair; University of Manchester; Manchester M13 9PT UK
- School of Materials; University of Manchester; Manchester M13 9PT UK
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Kudryavtsev IV, Garnyuk VV, Nadeev AD, Goncharov NV. Hydrogen peroxide modulates expression of surface antigens by human umbilical vein endothelial cells in vitro. BIOCHEMISTRY MOSCOW SUPPLEMENT SERIES A-MEMBRANE AND CELL BIOLOGY 2014. [DOI: 10.1134/s1990747813050103] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Adukpo S, Kusi KA, Ofori MF, Tetteh JKA, Amoako-Sakyi D, Goka BQ, Adjei GO, Edoh DA, Akanmori BD, Gyan BA, Dodoo D. High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria. PLoS One 2013; 8:e84181. [PMID: 24386348 PMCID: PMC3873986 DOI: 10.1371/journal.pone.0084181] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 11/12/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM-1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. METHODOLOGY/PRINCIPAL FINDINGS Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p<0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p>0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. CONCLUSIONS/SIGNIFICANCE High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.
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Affiliation(s)
- Selorme Adukpo
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
- Department of Animal Biology and Conservation Science, University of Ghana, Legon, Accra, Ghana
- * E-mail:
| | - Kwadwo A. Kusi
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Michael F. Ofori
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - John K. A. Tetteh
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Daniel Amoako-Sakyi
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Bamenla Q. Goka
- Department of Child Health, University of Ghana Medical School, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - George O. Adjei
- Department of Child Health, University of Ghana Medical School, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Dominic A. Edoh
- Department of Animal Biology and Conservation Science, University of Ghana, Legon, Accra, Ghana
| | - Bartholomew D. Akanmori
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Ben A. Gyan
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Daniel Dodoo
- Immunology Department, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
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Lee SR, Wang X, Tsuji K, Lo EH. Extracellular proteolytic pathophysiology in the neurovascular unit after stroke. Neurol Res 2013; 26:854-61. [PMID: 15727269 DOI: 10.1179/016164104x3806] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The NINDS Stroke Progress Review Group recommended a shift in emphasis from a purely neurocentric view of cell death towards a more integrative approach whereby responses in all brain cells and matrix are considered. The neurovascular unit (fundamentally comprising endothelium, astrocyte, and neuron) provides a conceptual framework where cell-cell and cell-matrix signaling underlies the overall tissue response to stroke and its treatments. Here, we briefly review recent data on extracellular proteolytic dysfunction in the neurovascular unit after a stroke. The breakdown of neurovascular matrix initiates blood-brain barrier disruption with edema and/or hemorrhage. Endothelial dysfunction amplifies inflammatory responses. Perturbation of cell-matrix homeostasis triggers multiple cell death pathways. Interactions between the major classes of extracellular proteases from the plasminogen and matrix metalloprotease families may underlie processes responsible for some of the hemorrhagic complications of thrombolytic stroke therapy. Targeting the proteolytic imbalance within the neurovascular unit may provide new approaches for improving the safety and efficacy of thrombolytic reperfusion therapy for stroke.
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Affiliation(s)
- Sun-Ryung Lee
- Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, MA 02129, USA
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Alvarez JI, Katayama T, Prat A. Glial influence on the blood brain barrier. Glia 2013; 61:1939-58. [PMID: 24123158 PMCID: PMC4068281 DOI: 10.1002/glia.22575] [Citation(s) in RCA: 407] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 08/13/2013] [Accepted: 08/19/2013] [Indexed: 12/14/2022]
Abstract
The Blood Brain Barrier (BBB) is a specialized vascular structure tightly regulating central nervous system (CNS) homeostasis. Endothelial cells are the central component of the BBB and control of their barrier phenotype resides on astrocytes and pericytes. Interactions between these cells and the endothelium promote and maintain many of the physiological and metabolic characteristics that are unique to the BBB. In this review we describe recent findings related to the involvement of astroglial cells, including radial glial cells, in the induction of barrier properties during embryogenesis and adulthood. In addition, we describe changes that occur in astrocytes and endothelial cells during injury and inflammation with a particular emphasis on alterations of the BBB phenotype. GLIA 2013;61:1939–1958
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Affiliation(s)
- Jorge Ivan Alvarez
- Neuroimmunology unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
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Atukeren P, Kemerdere R, Kacira T, Hanimoglu H, Ozlen F, Yavuz B, Tanriverdi T, Gumustas K, Canbaz B. Expressions of some vital molecules: glioblastoma multiforme versus normal tissues. Neurol Res 2013; 32:492-501. [DOI: 10.1179/174313209x459075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Vitreous mediators in retinal hypoxic diseases. Mediators Inflamm 2013; 2013:935301. [PMID: 23365490 PMCID: PMC3556845 DOI: 10.1155/2013/935301] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Revised: 10/19/2012] [Accepted: 12/01/2012] [Indexed: 12/31/2022] Open
Abstract
The causes of retinal hypoxia are many and varied. Under hypoxic conditions, a variety of soluble factors are secreted into the vitreous cavity including growth factors, cytokines, and chemokines. Cytokines, which usually serve as signals between neighboring cells, are involved in essentially every important biological process, including cell proliferation, inflammation, immunity, migration, fibrosis, tissue repair, and angiogenesis. Cytokines and chemokines are multifunctional mediators that can direct the recruitment of leukocytes to sites of inflammation, promote the process, enhance immune responses, and promote stem cell survival, development, and homeostasis. The modern particle-based flow cytometric analysis is more direct, stable and sensitive than the colorimetric readout of the conventional ELISA but, similar to ELISA, is influenced by vitreous hemorrhage, disruption of the blood-retina barrier, and high serum levels of a specific protein. Finding patterns in the expression of inflammatory cytokines specific to a particular disease can substantially contribute to the understanding of its basic mechanism and to the development of a targeted therapy.
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Chen C, Diao D, Guo L, Shi M, Gao J, Hu M, Yu M, Qian L, Guo N. All-trans-retinoic acid modulates ICAM-1 N-glycan composition by influencing GnT-III levels and inhibits cell adhesion and trans-endothelial migration. PLoS One 2012; 7:e52975. [PMID: 23300837 PMCID: PMC3530489 DOI: 10.1371/journal.pone.0052975] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 11/26/2012] [Indexed: 11/25/2022] Open
Abstract
Changes in the expression of glycosyltransferases directly influence the oligosaccharide structures and conformations of cell surface glycoproteins and consequently cellular phenotype transitions and biological behaviors. In the present study, we show that all-trans-retinoic acid (ATRA) modulates the N-glycan composition of intercellular adhesion molecule-1 (ICAM-1) by manipulating the expression of two N-acetylglucosaminyltransferases, GnT-III and GnT-V, via the ERK signaling pathway. Exposure of various cells to ATRA caused a remarkable gel mobility down-shift of ICAM-1. Treatment with PNGase F confirmed that the reduction of the ICAM-1 molecular mass is attributed to the decreased complexity of N-glycans. We noticed that the expression of the mRNA encoding GnT-III, which stops branching, was significantly enhanced following ATRA exposure. In contrast, the level of the mRNA encoding GnT-V, which promotes branching, was reduced following ATRA exposure. Silencing of GnT-III prevented the molecular mass shift of ICAM-1. Moreover, ATRA induction greatly inhibited the adhesion of SW480 and U937 cells to the HUVEC monolayer, whereas knock-down of GnT-III expression effectively restored cell adhesion function. Treatment with ATRA also dramatically reduced the trans-endothelial migration of U937 cells. These data indicate that the alteration of ICAM-1 N-glycan composition by ATRA-induced GnT-III activities hindered cell adhesion and cell migration functions simultaneously, pinpointing a unique regulatory role of specific glycosyltransferases in the biological behaviors of tumor cells and a novel function of ATRA in the modulation of ICAM-1 N-glycan composition.
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Affiliation(s)
- Changguo Chen
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
- Department of Clinical Laboratory, the Navy General Hospital, No. 6 Fucheng Road, Beijing, P.R. China
| | - Dekun Diao
- Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, P.R. China
| | - Liang Guo
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
| | - Ming Shi
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
| | - Jie Gao
- Institute of Basic Medicine, Shandong Academy of Medical Science, Jinan, P.R. China
| | - Meiru Hu
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
| | - Ming Yu
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
| | - Lu Qian
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
- * E-mail: (LQ); (NG)
| | - Ning Guo
- Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, P.R. China
- * E-mail: (LQ); (NG)
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Liu KKY, Dorovini-Zis K. Differential regulation of CD4+ T cell adhesion to cerebral microvascular endothelium by the β-chemokines CCL2 and CCL3. Int J Mol Sci 2012. [PMID: 23203188 PMCID: PMC3546682 DOI: 10.3390/ijms131216119] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
In Multiple sclerosis (MS), circulating lymphocytes cross the blood–brain barrier (BBB) and accumulate at sites of antigenic challenge. This process depends on specific interactions between lymphocytes and cerebral microvascular endothelium that involve endothelial activation by cytokines and the presence of chemokines. Chemokines play a key role in the orchestration of immune responses, acting both as chemoattractants and activators of leukocyte subsets. In the present study, we investigated the effects of the β-chemokines, CCL2 and CCL3, on the adhesion of CD4+ T cell subsets to human brain microvessel endothelial cells (HBMEC). Chemokines added to the lower compartment of a two-chamber chemotaxis system under confluent resting or cytokine-activated HBMEC, diffused through the culture substrate and bound to the basal surface of HBMEC. The low rate of adhesion of naïve, resting and memory CD4+ T cells to resting HBMEC was significantly upregulated following treatment of HBMEC with TNF-α and IFN-γ. Recently activated CD4+ T cells readily adhered to resting monolayers. Concentration gradients of CCL2 upregulated the adhesion of activated CD4+ T cells to cytokine treated but not resting HBMEC. The presence of CCL3 in the lower chamber increased the adhesion of memory T cells to both unstimulated and cytokine-treated HBMEC. These findings emphasize the importance of brain endothelial cell activation and the role of CCL2 and CCL3 in regulating the adhesion of CD4+ T cell subsets to BBB endothelium, thus contributing to the specificity of immune responses in MS.
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Affiliation(s)
- Kenneth KY Liu
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC V5Z-1M9, Canada; E-Mail:
| | - Katerina Dorovini-Zis
- Division of Neuropathology, Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC V5Z 1M9, Canada
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1-604-875-4127; Fax: +1-604-875-4477
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He CL, Yi PF, Fan QJ, Shen HQ, Jiang XL, Qin QQ, Song Z, Zhang C, Wu SC, Wei XB, Li YL, Fu BD. Xiang-Qi-Tang and its active components exhibit anti-inflammatory and anticoagulant properties by inhibiting MAPK and NF-κB signaling pathways in LPS-treated rat cardiac microvascular endothelial cells. Immunopharmacol Immunotoxicol 2012; 35:215-24. [DOI: 10.3109/08923973.2012.744034] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Zhang X, Wang B, O’Callaghan P, Hjertström E, Jia J, Gong F, Zcharia E, Nilsson LNG, Lannfelt L, Vlodavsky I, Lindahl U, Li JP. Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain. Acta Neuropathol 2012; 124:465-78. [PMID: 22692572 PMCID: PMC3444710 DOI: 10.1007/s00401-012-0997-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Revised: 05/11/2012] [Accepted: 05/11/2012] [Indexed: 12/24/2022]
Abstract
Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer’s disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood–brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes. To study the role of heparan sulfate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglucuronidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic challenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-β peptide, implicated in Alzheimer’s disease. Lipopolysaccharide-treated control mice showed massive activation of resident microglia as well as recruitment of monocyte-derived macrophages into the brain parenchyma. Microinjection of aggregated amyloid-β elicited a similar inflammatory response, albeit restricted to the injection site, which led to dispersion and clearance of the amyloid. In the heparanase-overexpressing mice, all aspects of immune cell recruitment and activation were significantly attenuated in both inflammation models, as was amyloid dispersion. Accordingly, an in vitro blood–brain barrier model constructed from heparanase-overexpressing cerebral vascular cells showed impaired transmigration of monocytes compared to a corresponding assembly of control cells. Our data indicate that intact heparan sulfate chains are required at multiple sites to mediate neuroinflammatory responses, and further point to heparanase as a modulator of this process, with potential implications for Alzheimer’s disease.
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Li J, Ye L, Wang X, Liu J, Wang Y, Zhou Y, Ho W. (-)-Epigallocatechin gallate inhibits endotoxin-induced expression of inflammatory cytokines in human cerebral microvascular endothelial cells. J Neuroinflammation 2012; 9:161. [PMID: 22768975 PMCID: PMC3408337 DOI: 10.1186/1742-2094-9-161] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 07/06/2012] [Indexed: 12/18/2022] Open
Abstract
Background (−)-Epigallocatechin gallate (EGCG) is a major polyphenol component of green tea that has antioxidant activities. Lipopolysaccharide (LPS) induces inflammatory cytokine production and impairs blood–brain barrier (BBB) integrity. We examined the effect of EGCG on LPS-induced expression of the inflammatory cytokines in human cerebral microvascular endothelial cells (hCMECs) and BBB permeability. Methods The expression of TNF-α, IL-1β and monocyte chemotactic protein-1 (MCP-1/CCL2) was determined by quantitative real time PCR (qRT-PCR) and ELISA. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule (VCAM) in hCMECs were examined by qRT-PCR and Western blotting. Monocytes that adhered to LPS-stimulated endothelial cells were measured by monocyte adhesion assay. Tight junctional factors were detected by qRT-PCR (Claudin 5 and Occludin) and immunofluorescence staining (Claudin 5 and ZO-1). The permeability of the hCMEC monolayer was determined by fluorescence spectrophotometry of transmembrane fluorescin and transendothelial electrical resistance (TEER). NF-kB activation was measured by luciferase assay. Results EGCG significantly suppressed the LPS-induced expression of IL-1β and TNF-α in hCMECs. EGCG also inhibited the expression of MCP-1/CCL2, VCAM-1 and ICAM-1. Functional analysis showed that EGCG induced the expression of tight junction proteins (Occludin and Claudin-5) in hCMECs. Investigation of the mechanism showed that EGCG had the ability to inhibit LPS-mediated NF-κB activation. In addition, 67-kD laminin receptor was involved in the anti-inflammatory effect of EGCG. Conclusions Our results demonstrated that LPS induced inflammatory cytokine production in hCMECs, which could be attenuated by EGCG. These data indicate that EGCG has a therapeutic potential for endotoxin-mediated endothelial inflammation.
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Affiliation(s)
- Jieliang Li
- The Center for Animal Experiment/Animal Biosafety Level III Laboratory, Wuhan University Wuhan, Hubei 430071, People's Republic of China
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Wennström M, Nielsen HM. Cell adhesion molecules in Alzheimer's disease. Degener Neurol Neuromuscul Dis 2012; 2:65-77. [PMID: 30890880 DOI: 10.2147/dnnd.s19829] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Cell adhesion molecules (CAMs) mediate interactions between cells and their surroundings that are vital to processes controlling for cell survival, activation, migration, and plasticity. However, increasing evidence suggests that CAMs also mediate mechanisms involved in several neurological diseases. This article reviews the current knowledge on the role of CAMs in amyloid-β (Aβ) metabolism, cell plasticity, neuroinflammation, and vascular changes, all of which are considered central to the pathogenesis and progression of Alzheimer's disease (AD). This paper also outlines the possible roles of CAMs in current and novel AD treatment strategies.
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Affiliation(s)
- Malin Wennström
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden,
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