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1
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Atehortua L, Sean Davidson W, Chougnet CA. Interactions Between HDL and CD4+ T Cells: A Novel Understanding of HDL Anti-Inflammatory Properties. Arterioscler Thromb Vasc Biol 2024; 44:1191-1201. [PMID: 38660807 PMCID: PMC11111342 DOI: 10.1161/atvbaha.124.320851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Several studies in animal models and human cohorts have recently suggested that HDLs (high-density lipoproteins) not only modulate innate immune responses but also adaptative immune responses, particularly CD4+ T cells. CD4+ T cells are central effectors and regulators of the adaptive immune system, and any alterations in their homeostasis contribute to the pathogenesis of cardiovascular diseases, autoimmunity, and inflammatory diseases. In this review, we focus on how HDLs and their components affect CD4+ T-cell homeostasis by modulating cholesterol efflux, immune synapsis, proliferation, differentiation, oxidative stress, and apoptosis. While the effects of apoB-containing lipoproteins on T cells have been relatively well established, this review focuses specifically on new connections between HDL and CD4+ T cells. We present a model where HDL may modulate T cells through both direct and indirect mechanisms.
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Affiliation(s)
- Laura Atehortua
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH
| | - W. Sean Davidson
- Division of Experimental Pathology, Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH
| | - Claire A. Chougnet
- Division of Immunobiology, Cincinnati Children’s Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH
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2
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Gong S, Ma C, Ma R, Zhu T, Ge X, Xie R, Tao Q, Ouyang G, Shi C. Elevated pretreatment serum apolipoprotein E level associated with poor prognosis of patients with COVID-19 during the omicron BA.5 and BF.7 wave. J Med Virol 2024; 96:e29673. [PMID: 38767184 DOI: 10.1002/jmv.29673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/22/2024]
Abstract
The SARS-CoV-2 virus is responsible for the human disease known as COVID-19. This virus is capable of generating a spectrum of infections ranging from moderate to severe. Serum apolipoprotein E (ApoE) inhibits inflammation by preserving immune regulatory function. Nonetheless, the relationship between serum ApoE and clinical prognosis in omicron remains elusive. A cohort of 231 patients was observed for 65 days, with death as the primary outcome. Based on their ApoE levels, the patients were categorized into patients with elevated ApoE levels and those with lower ApoE levels. To do statistical comparisons, the log-rank test was utilized, and the Kaplan-Meier method was utilized to estimate survival rates. Cox hazard models, both univariate and multivariate, were employed to examine the prognostic relevance. According to our research, omicron had significantly greater ApoE levels. In mild-to-moderate and severe cases, the study identified a statistically significant variation in ApoE levels. Additionally, there was a drop in overall survival that is statistically significant (OS, p < 0.0001) for patients with greater ApoE levels. Multiple Cox proportional hazards regression analysis indicates that an elevated ApoE level was determined to be an adverse and independent prognostic factor of OS in patients with omicron. Taken together, our study found that the level of serum ApoE at the time of initial diagnosis was substantially connected to the severity and prognosis of omicron. Consequently, we propose that ApoE might be a poor prognostic factor in individuals afflicted with the omicron variant.
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Affiliation(s)
- Shengping Gong
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Chao Ma
- Laboratory of Stem Cell Transplantation, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Ruishuang Ma
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Ting Zhu
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Xiaoqin Ge
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Rongrong Xie
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Qingsong Tao
- Cancer Radiotherapy and Chemotherapy Center, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Guifang Ouyang
- Department of Hematology, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Cong Shi
- Laboratory of Stem Cell Transplantation, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China
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Haruta K, Suzuki T, Yamaguchi M, Fukuda Y, Torii Y, Takahashi Y, Ito Y, Kawada JI. Comparison of plasma proteomic profiles of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and infectious mononucleosis. J Med Virol 2024; 96:e29450. [PMID: 38304956 DOI: 10.1002/jmv.29450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 12/18/2023] [Accepted: 01/23/2024] [Indexed: 02/03/2024]
Abstract
Primary Epstein-Barr virus (EBV) infection occasionally causes EBV-infectious mononucleosis (EBV-IM) and EBV-hemophagocytic lymphohistiocytosis (EBV-HLH). Although EBV-IM is mostly mild and self-limiting, EBV-HLH is a life-threatening disease characterized by excessive immune activation. However, the pathogenesis of EBV-HLH is yet to be fully elucidated. A diagnostic biomarker for EBV-HLH is desirable because early diagnosis and treatment are critical for the effective management of patients. In this study, the proteomic profiling of plasma was performed using liquid chromatography-mass spectrometry to identify proteins specific to EBV-IM and EBV-HLH. Furthermore, pathway analysis was performed for the proteins upregulated in patients with EBV-IM and EBV-HLH. Compared to healthy controls, 63 and 18 proteins were upregulated in patients with EBV-IM and EBV-HLH, respectively. Pathway and process enrichment analyses revealed that the complement system was the most enriched category of upregulated proteins in EBV-IM, whereas proteins related to immune effector processes were the most enriched in EBV-HLH. Among the 18 proteins upregulated in EBV-HLH, seven were exclusive to EBV-HLH. These specific proteins were associated with three pathways, and apolipoprotein E was commonly found in all the pathways. Proteomic analysis may provide new insights into the host response to EBV infection and the pathogenesis of EBV-related diseases.
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Affiliation(s)
- Kazunori Haruta
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takako Suzuki
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Makoto Yamaguchi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuto Fukuda
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuka Torii
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Aichi Medical University, Nagakute, Japan
| | - Jun-Ichi Kawada
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
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4
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Clement M. The association of microbial infection and adaptive immune cell activation in Alzheimer's disease. DISCOVERY IMMUNOLOGY 2023; 2:kyad015. [PMID: 38567070 PMCID: PMC10917186 DOI: 10.1093/discim/kyad015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/31/2023] [Accepted: 09/04/2023] [Indexed: 04/04/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.
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Affiliation(s)
- Mathew Clement
- Division of Infection and Immunity, Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
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Oriá RB, Freitas RS, Roque CR, Nascimento JCR, Silva AP, Malva JO, Guerrant RL, Vitek MP. ApoE Mimetic Peptides to Improve the Vicious Cycle of Malnutrition and Enteric Infections by Targeting the Intestinal and Blood-Brain Barriers. Pharmaceutics 2023; 15:pharmaceutics15041086. [PMID: 37111572 PMCID: PMC10141726 DOI: 10.3390/pharmaceutics15041086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein’s LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections.
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Affiliation(s)
- Reinaldo B. Oriá
- Laboratory of Tissue Healing, Ontogeny and Nutrition, Department of Morphology, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza 60430-270, Brazil
- Correspondence: ; Tel.: +55-85-3366-8239
| | - Raul S. Freitas
- Laboratory of Tissue Healing, Ontogeny and Nutrition, Department of Morphology, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza 60430-270, Brazil
| | - Cássia R. Roque
- Laboratory of Tissue Healing, Ontogeny and Nutrition, Department of Morphology, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza 60430-270, Brazil
| | - José Carlos R. Nascimento
- Laboratory of Tissue Healing, Ontogeny and Nutrition, Department of Morphology, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza 60430-270, Brazil
- Institute of Health Sciences, Medicine, University of International Integration of Afro-Brazilian Lusofonia, Redenção 62790-970, Brazil
| | - Ana Paula Silva
- Institute of Pharmacology and Experimental Therapeutics and Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine and Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - João O. Malva
- Institute of Pharmacology and Experimental Therapeutics and Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine and Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Richard L. Guerrant
- Division of Infectious Diseases and International Health, Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - Michael P. Vitek
- Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA
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6
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Javadifar A, Ghezeldasht SA, Rahimi H, Valizadeh N, Borojerdi ZR, Vahidi Z, Rezaee SR. Possible deterioration of Apolipoproteins expression by HTLV-1 infection in favor of infected leukemic cells in adult T-cell leukemia/lymphoma (ATLL). GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Dai L, Shen Y. Insights into T-cell dysfunction in Alzheimer's disease. Aging Cell 2021; 20:e13511. [PMID: 34725916 PMCID: PMC8672785 DOI: 10.1111/acel.13511] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/22/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022] Open
Abstract
T cells, the critical immune cells of the adaptive immune system, are often dysfunctional in Alzheimer's disease (AD) and are involved in AD pathology. Reports highlight neuroinflammation as a crucial modulator of AD pathogenesis, and aberrant T cells indirectly contribute to neuroinflammation by secreting proinflammatory mediators via direct crosstalk with glial cells infiltrating the brain. However, the mechanisms underlying T‐cell abnormalities in AD appear multifactorial. Risk factors for AD and pathological hallmarks of AD have been tightly linked with immune responses, implying the potential regulatory effects of these factors on T cells. In this review, we discuss how the risk factors for AD, particularly Apolipoprotein E (ApoE), Aβ, α‐secretase, β‐secretase, γ‐secretase, Tau, and neuroinflammation, modulate T‐cell activation and the association between T cells and pathological AD hallmarks. Understanding these associations is critical to provide a comprehensive view of appropriate therapeutic strategies for AD.
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Affiliation(s)
- Linbin Dai
- Institute on Aging and Brain Disorders The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Sciences and Technology of China Hefei China
- Neurodegenerative Disease Research Center University of Science and Technology of China Hefei China
- Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Hefei China
| | - Yong Shen
- Institute on Aging and Brain Disorders The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Sciences and Technology of China Hefei China
- Neurodegenerative Disease Research Center University of Science and Technology of China Hefei China
- Hefei National Laboratory for Physical Sciences at the Microscale University of Science and Technology of China Hefei China
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8
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Flores‐Bellver M, Mighty J, Aparicio‐Domingo S, Li KV, Shi C, Zhou J, Cobb H, McGrath P, Michelis G, Lenhart P, Bilousova G, Heissel S, Rudy MJ, Coughlan C, Goodspeed AE, Becerra SP, Redenti S, Canto‐Soler MV. Extracellular vesicles released by human retinal pigment epithelium mediate increased polarised secretion of drusen proteins in response to AMD stressors. J Extracell Vesicles 2021; 10:e12165. [PMID: 34750957 PMCID: PMC8575963 DOI: 10.1002/jev2.12165] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 10/06/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Drusen are key contributors to the etiology of AMD and the ability to modulate drusen biogenesis could lead to therapeutic strategies to slow or halt AMD progression. The mechanisms underlying drusen biogenesis, however, remain mostly unknown. Here we demonstrate that under homeostatic conditions extracellular vesicles (EVs) secreted by retinal pigment epithelium (RPE) cells are enriched in proteins associated with mechanisms involved in AMD pathophysiology, including oxidative stress, immune response, inflammation, complement system and drusen composition. Furthermore, we provide first evidence that drusen-associated proteins are released as cargo of extracellular vesicles secreted by RPE cells in a polarised apical:basal mode. Notably, drusen-associated proteins exhibited distinctive directional secretion modes in homeostatic conditions and, differential modulation of this directional secretion in response to AMD stressors. These observations underpin the existence of a finely-tuned mechanism regulating directional apical:basal sorting and secretion of drusen-associated proteins via EVs, and its modulation in response to mechanisms involved in AMD pathophysiology. Collectively, our results strongly support an active role of RPE-derived EVs as a key source of drusen proteins and important contributors to drusen development and growth.
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Affiliation(s)
- Miguel Flores‐Bellver
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
| | - Jason Mighty
- Lehman CollegeBronxNew YorkUSA
- Biology Doctoral ProgramThe Graduate School and University CenterCity University of New YorkNew YorkNew YorkUSA
| | - Silvia Aparicio‐Domingo
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
| | - Kang V. Li
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
| | - Cui Shi
- Lehman CollegeBronxNew YorkUSA
- Biology Doctoral ProgramThe Graduate School and University CenterCity University of New YorkNew YorkNew YorkUSA
| | | | - Hannah Cobb
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
| | - Patrick McGrath
- Department of DermatologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - German Michelis
- Section of Protein Structure and FunctionNEINIHBethesdaMarylandUSA
| | - Patricia Lenhart
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
| | - Ganna Bilousova
- Department of DermatologyUniversity of Colorado School of MedicineAuroraColoradoUSA
- Charles C. Gates Center for Regenerative MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
- Linda Crnic Institute for Down SyndromeUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Søren Heissel
- Proteomics Resource CenterThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Michael J. Rudy
- Department of NeurologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Christina Coughlan
- University of Colorado Alzheimer's and Cognition CenterDepartment of NeurologyLinda Crnic Institute for Down SyndromeUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Andrew E. Goodspeed
- Department of PharmacologyUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
- University of Colorado Cancer CenterUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | | | - Stephen Redenti
- Lehman CollegeBronxNew YorkUSA
- Biology Doctoral ProgramThe Graduate School and University CenterCity University of New YorkNew YorkNew YorkUSA
- Biochemistry Doctoral ProgramThe Graduate SchoolCity University of New YorkNew YorkNew YorkUSA
| | - M. Valeria Canto‐Soler
- CellSight Ocular Stem Cell and Regeneration ProgramDepartment of OphthalmologySue Anschutz‐Rodgers Eye CenterUniversity of Colorado, School of MedicineAuroraColoradoUSA
- Charles C. Gates Center for Regenerative MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
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Freitas RS, Roque CR, Matos GA, Belayev L, de Azevedo OGR, Alvarez-Leite JI, Guerrant RL, Oriá RB. Immunoinflammatory role of apolipoprotein E4 in malnutrition and enteric infections and the increased risk for chronic diseases under adverse environments. Nutr Rev 2021; 80:1001-1012. [PMID: 34406390 DOI: 10.1093/nutrit/nuab063] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Apolipoprotein E plays a crucial role in cholesterol metabolism. The immunomodulatory functions of the human polymorphic APOE gene have gained particular interest because APOE4, a well-recognized risk factor for late-onset Alzheimer's disease, has also been recently linked to increased risk of COVID-19 infection severity in a large UK biobank study. Although much is known about apoE functions in the nervous system, much less is known about APOE polymorphism effects on malnutrition and enteric infections and the consequences for later development in underprivileged environments. In this review, recent findings are summarized of apoE's effects on intestinal function in health and disease and the role of APOE4 in protecting against infection and malnutrition in children living in unfavorable settings, where poor sanitation and hygiene prevail, is highlighted. The potential impact of APOE4 on later development also is discussed and gaps in knowledge are identified that need to be addressed to protect children's development under adverse environments.
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Affiliation(s)
- Raul S Freitas
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Ceará, Brazil
| | - Cássia R Roque
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Ceará, Brazil
| | - Gabriella A Matos
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Ceará, Brazil
| | - Ludmila Belayev
- Neuroscience Center of Excellence, School of Medicine, Health Sciences Center, Louisiana State University, Baton Rouge, Louisiana, United States
| | - Orleâncio G R de Azevedo
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Ceará, Brazil
| | | | - Richard L Guerrant
- Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, United States
| | - Reinaldo B Oriá
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Ceará, Brazil
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10
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Nascimento JCR, Pereira LC, Rêgo JMC, Dias RP, Silva PGB, Sobrinho SAC, Coelho GR, Brasil IRC, Oliveira-Filho EF, Owen JS, Toniutto P, Oriá RB. Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis. World J Gastroenterol 2021; 27:1064-1075. [PMID: 33776373 PMCID: PMC7985730 DOI: 10.3748/wjg.v27.i11.1064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/19/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is responsible for a chronic liver inflammation, which may cause end-stage liver disease and hepatocellular carcinoma. Apolipoprotein E (protein: ApoE, gene: APOE), a key player in cholesterol metabolism, is mainly synthesized in the liver and APOE polymorphisms may influence HCV-induced liver damage.
AIM To determine whether APOE alleles affect outcomes in HCV-infected patients with liver cirrhosis following orthotopic liver transplantation (OLT).
METHODS This was a cohort study in which 179 patients, both genders and aged 34-70 years, were included before or after (up to 10 years follow-up) OLT. Liver injury severity was assessed using different criteria, including METAVIR and models for end-stage liver disease. APOE polymorphisms were analyzed by quantitative real-time polymerase chain reaction.
RESULTS The APOE3 allele was the most common (67.3%). In inflammation severity of biopsies from 89 OLT explants and 2 patients in pre-transplant, the degree of severe inflammation (A3F4, 0.0%) was significantly less frequent than in patients with minimal and moderate degree of inflammation (≤ A2F4, 16.2%) P = 0.048, in patients carrying the APOE4 allele when compared to non-APOE4. In addition, a significant difference was also found (≤ A2F4, 64.4% vs A3F4, 0.0%; P = 0.043) and (A1F4, 57.4% vs A3F4, 0.0%; P = 0.024) in APOE4 patients when compared to APOE3 carriers. The fibrosis degree of the liver graft in 8 of 91 patients and the lack of the E4 allele was associated with more moderate fibrosis (F2) (P = 0.006).
CONCLUSION Our results suggest that the E4 allele protects against progression of liver fibrosis and degree of inflammation in HCV-infected patients.
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Affiliation(s)
- José Carlos Rodrigues Nascimento
- Department of Anesthesia and Surgery Liver Transplantation, Fortaleza General Hospital, Fortaleza 60150-160, CE, Brazil
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | - Lianna C Pereira
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | - Juliana Magalhães C Rêgo
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | - Ronaldo P Dias
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | | | - Silvio Alencar C Sobrinho
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | - Gustavo R Coelho
- Department of Surgery, Liver Transplant Unit of Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
| | | | | | - James S Owen
- UCL Medical School, Royal Free Campus, London NW3 2PF, United Kingdom
| | - Pierluigi Toniutto
- Department of Specialized Medicine, Hepatology Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata of Udine, Udine I-33100, Italy
| | - Reinaldo B Oriá
- Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceará, Fortaleza 60430-270, CE, Brazil
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11
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Lundåsen T, Pedrelli M, Bjørndal B, Rozell B, Kuiper RV, Burri L, Pavanello C, Turri M, Skorve J, Berge RK, Alexson SEH, Tillander V. The PPAR pan-agonist tetradecylthioacetic acid promotes redistribution of plasma cholesterol towards large HDL. PLoS One 2020; 15:e0229322. [PMID: 32176696 PMCID: PMC7075573 DOI: 10.1371/journal.pone.0229322] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 02/04/2020] [Indexed: 12/16/2022] Open
Abstract
Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the β-position. This modification renders TTA unable to undergo complete β-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.
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Affiliation(s)
- Thomas Lundåsen
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Matteo Pedrelli
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Sports, Physical activity and Food, Faculty of Education, Arts and Sports, Western Norway University of Applied Sciences, Bergen, Norway
- * E-mail: (BB); (VT)
| | - Björn Rozell
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Raoul V. Kuiper
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Lena Burri
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Chiara Pavanello
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro Enrica Grossi Paoletti, Università degli Studi di Milano, Milan, Italy
| | - Marta Turri
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro Enrica Grossi Paoletti, Università degli Studi di Milano, Milan, Italy
| | - Jon Skorve
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Rolf K. Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | | | - Veronika Tillander
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
- * E-mail: (BB); (VT)
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12
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Singhal A, Subramanian M. Colony stimulating factors (CSFs): Complex roles in atherosclerosis. Cytokine 2019; 122:154190. [DOI: 10.1016/j.cyto.2017.10.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 12/11/2022]
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13
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The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity. Genes (Basel) 2019; 10:genes10030222. [PMID: 30884759 PMCID: PMC6471373 DOI: 10.3390/genes10030222] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/01/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer's disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.
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14
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Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis. J Pers Med 2018; 8:jpm8040034. [PMID: 30282955 PMCID: PMC6313318 DOI: 10.3390/jpm8040034] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/26/2018] [Accepted: 09/27/2018] [Indexed: 01/14/2023] Open
Abstract
Atherosclerosis affects millions of people worldwide. However, the wide variety of limitations in the current therapeutic options leaves much to be desired in future lipid-lowering therapies. For example, although statins, which are the first-line treatment for coronary heart disease (CHD), reduce the risk of cardiovascular events in a large percentage of patients, they lead to optimal levels of low density lipoprotein-cholesterol (LDL-C) in only about one-third of patients. A new promising research direction against atherosclerosis aims to improve lipoprotein metabolism. Novel therapeutic approaches are being developed to increase the levels of functional high density lipoprotein (HDL) particles. This review aims to highlight the atheroprotective potential of the in vitro synthesized reconstituted HDL particles containing apolipoprotein E (apoE) as their sole apolipoprotein component (rHDL-apoE). For this purpose, we provide: (1) a summary of the atheroprotective properties of native plasma HDL and its apolipoprotein components, apolipoprotein A-I (apoA-I) and apoE; (2) an overview of the anti-atherogenic functions of rHDL-apoA-I and apoA-I-containing HDL, i.e., natural HDL isolated from transgenic Apoa1−/− × Apoe−/− mice overexpressing human apoA-I (HDL-apoA-I); and (3) the latest developments and therapeutic potential of HDL-apoE and rHDL-apoE. Novel rHDL formulations containing apoE could possibly present enhanced biological functions, leading to improved therapeutic efficacy against atherosclerosis.
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15
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Apolipoprotein E and Atherosclerosis: From Lipoprotein Metabolism to MicroRNA Control of Inflammation. J Cardiovasc Dev Dis 2018; 5:jcdd5020030. [PMID: 29789495 PMCID: PMC6023389 DOI: 10.3390/jcdd5020030] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 05/08/2018] [Accepted: 05/18/2018] [Indexed: 12/26/2022] Open
Abstract
Apolipoprotein (apo) E stands out among plasma apolipoproteins through its unprecedented ability to protect against atherosclerosis. Although best recognized for its ability to mediate plasma lipoprotein clearance in the liver and protect against macrophage foam cell formation, our recent understanding of the influence that apoE can exert to control atherosclerosis has significantly widened. Among apoE’s newfound athero-protective properties include an ability to control exaggerated hematopoiesis, blood monocyte activation and aortic stiffening in mice with hyperlipidemia. Mechanisms responsible for these exciting new properties extend beyond apoE’s ability to prevent cellular lipid excess. Rather, new findings have revealed a role for apoE in regulating microRNA-controlled cellular signaling in cells of the immune system and vascular wall. Remarkably, infusions of apoE-responsive microRNA mimics were shown to substitute for apoE in protecting against systemic and vascular inflammation to suppress atherosclerosis in mice with hyperlipidemia. Finally, more recent evidence suggests that apoE may control the release of microvesicles that could modulate cellular signaling, inflammation and atherosclerosis at a distance. These exciting new findings position apoE within the emerging field of intercellular communication that could introduce new approaches to control atherosclerosis cardiovascular disease.
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16
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Tudorache IF, Trusca VG, Gafencu AV. Apolipoprotein E - A Multifunctional Protein with Implications in Various Pathologies as a Result of Its Structural Features. Comput Struct Biotechnol J 2017; 15:359-365. [PMID: 28660014 PMCID: PMC5476973 DOI: 10.1016/j.csbj.2017.05.003] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/15/2017] [Accepted: 05/22/2017] [Indexed: 12/31/2022] Open
Abstract
Apolipoprotein E (apoE), a 34 kDa glycoprotein, mediates hepatic and extrahepatic uptake of plasma lipoproteins and cholesterol efflux from lipid-laden macrophages. In humans, three structural different apoE isoforms occur, with subsequent functional changes and pathological consequences. Here, we review data supporting the involvement of apoE structural domains and isoforms in normal and altered lipid metabolism, cardiovascular and neurodegenerative diseases, as well as stress-related pathological states. Studies using truncated apoE forms provided valuable information regarding the regions and residues responsible for its properties. ApoE3 renders protection against cardiovascular diseases by maintaining lipid homeostasis, while apoE2 is associated with dysbetalipoproteinemia. ApoE4 is a recognized risk factor for Alzheimer's disease, although the exact mechanism of the disease initiation and progression is not entirely elucidated. ApoE is also implicated in infections with herpes simplex type-1, hepatitis C and human immunodeficiency viruses. Interacting with both viral and host molecules, apoE isoforms differently interfere with the viral life cycle. ApoE exerts anti-inflammatory effects, switching macrophage phenotype from the proinflammatory M1 to the anti-inflammatory M2, suppressing CD4+ and CD8+ lymphocytes, and reducing IL-2 production. The anti-oxidative properties of apoE are isoform-dependent, modulating the levels of various molecules (Nrf2 target genes, metallothioneins, paraoxonase). Mimetic peptides were designed to exploit apoE beneficial properties. The "structure correctors" which convert apoE4 into apoE3-like molecules have pharmacological potential. Despite no successful strategy is yet available for apoE-related disorders, several promising candidates deserve further improvement and exploitation.
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Key Words
- AD, Alzheimer's disease
- ApoE
- ApoE, Apolipoprotein E
- CVD, cardiovascular disease
- HCV, hepatitis C virus
- HDL, high-density lipoprotein
- HIV, human immunodeficiency virus
- HLP, phospholipid transfer protein
- HSPGs, heparan sulfate proteoglycans
- HSV-1, herpes simplex virus type-1
- Isoform
- LDL, low density lipoprotein
- LPG, lipoprotein glomerulopathy
- LPL, lipoprotein lipase
- Mimetic peptide
- NS5A, nonstructural protein 5A
- PLTP, type III hyperlipoproteinemia
- Structural domain
- TG, triglyceride
- Truncated molecule
- VLDL, very-low-density lipoprotein
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Affiliation(s)
| | | | - Anca Violeta Gafencu
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8 B. P. Hasdeu Street, Sector 5, 050568 Bucharest, Romania
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17
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Subramanian M, Proto JD, Matsushima GK, Tabas I. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression. Sci Rep 2016; 6:39111. [PMID: 27958361 PMCID: PMC5153620 DOI: 10.1038/srep39111] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/17/2016] [Indexed: 01/09/2023] Open
Abstract
AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl-/- or wild-type mice were transplanted into lethally irradiated Ldlr-/- mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr-/- mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis.
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Affiliation(s)
- Manikandan Subramanian
- Department of Medicine, Columbia University Medical Center, New York, USA.,CSIR - Institute of Genomics and Integrative Biology, New Delhi, India
| | - Jonathan D Proto
- Department of Medicine, Columbia University Medical Center, New York, USA
| | - Glenn K Matsushima
- Department of Microbiology &Immunology, UNC Neuroscience Center, Integrative Program in Biological Genome Sciences, University of North Carolina, Chapel Hill, NC, USA
| | - Ira Tabas
- Department of Medicine, Columbia University Medical Center, New York, USA.,Department of Pathology and Cell Biology, Columbia University Medical Center, New York, USA.,Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, USA
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18
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Alvarez P, Genre F, Iglesias M, Augustin JJ, Tamayo E, Escolà-Gil JC, Lavín B, Blanco-Vaca F, Merino R, Merino J. Modulation of autoimmune arthritis severity in mice by apolipoprotein E (ApoE) and cholesterol. Clin Exp Immunol 2016; 186:292-303. [PMID: 27571306 DOI: 10.1111/cei.12857] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2016] [Indexed: 11/28/2022] Open
Abstract
Apolipoprotein E (ApoE) deficiency promoted an exacerbation of autoimmune arthritis in mice by inducing proinflammatory immune responses. In this study we analysed the contribution of hypercholesterolaemia and/or the absence of ApoE anti-inflammatory properties, unrelated to its function in the control of cholesterol metabolism, towards the acceleration of arthritis in these mutant animals. The induction and severity of collagen type II-induced arthritis (CIA) were compared for B10.RIII wild-type (WT), B10.RIII.ApoE+/- , B10.RIII.ApoE-/- and B10.RIII.low-density lipoprotein receptor (LDLR-/- ) mice with different concentrations of circulating ApoE and cholesterol. A 50-70% reduction in serum levels of ApoE was observed in heterozygous B10.RIII.ApoE+/- mice in comparison to B10.RIII.WT, although both strains of mice exhibited similar circulating lipid profiles. This ApoE reduction was associated with an increased CIA severity that remained lower than in homozygous B10.RIII.ApoE-/- mice. An important rise in circulating ApoE concentration was observed in hypercholesterolaemic B10.RIII.LDLR-/- mice fed with a normal chow diet, and both parameters increased further with an atherogenic hypercholesterolaemic diet. However, the severity of CIA in B10.RIII.LDLR-/- mice was similar to that of B10.RIII.WT controls. In conclusion, by comparing the evolution of CIA between several strains of mutant mice with different levels of serum ApoE and cholesterol, our results demonstrate that both hypercholesterolaemia and ApoE regulate the intensity of in-vivo systemic autoimmune responses.
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Affiliation(s)
- P Alvarez
- Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-SODERCAN, Santander, Spain
| | - F Genre
- Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
| | - M Iglesias
- Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
| | - J J Augustin
- Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-SODERCAN, Santander, Spain.,Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
| | - E Tamayo
- Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
| | - J C Escolà-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain, CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain
| | - B Lavín
- Servicio de Análisis Clínicos, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - F Blanco-Vaca
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain, CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain
| | - R Merino
- Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria-SODERCAN, Santander, Spain.,Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
| | - J Merino
- Departamento de Biología Molecular-IDIVAL Universidad de Cantabria, Santander, Spain
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19
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Vellasamy S, Tong CK, Azhar NA, Kodiappan R, Chan SC, Veerakumarasivam A, Ramasamy R. Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation. Cytotherapy 2016; 18:1270-83. [PMID: 27543068 DOI: 10.1016/j.jcyt.2016.06.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 06/29/2016] [Accepted: 06/30/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) have been identified as pan-immunosuppressant in various in vitro and in vivo inflammatory models. Although the immunosuppressive activity of MSCs has been explored in various contexts, the precise molecular signaling pathways that govern inhibitory functions remain poorly elucidated. METHODS By using a microarray-based global gene expression profiling system, this study aimed to decipher the underlying molecular pathways that may mediate the immunosuppressive activity of umbilical cord-derived MSCs (UC-MSCs) on activated T cells. RESULTS In the presence of UC-MSCs, the proliferation of activated T cells was suppressed in a dose-depended manner by cell-to-cell contact mode via an active cell-cycle arrest at the G0/G1 phase of the cell cycle. The microarray analysis revealed that particularly, IFNG, CXCL9, IL2, IL2RA and CCND3 genes were down-regulated, whereas IL11, VSIG4, GFA1, TIMP3 and BBC3 genes were up-regulated by UC-MSCs. The dysregulated gene clusters associated with immune-response-related ontologies, namely, lymphocyte proliferation or activation, apoptosis and cell cycle, were further analyzed. CONCLUSIONS Among the nine canonical pathways identified, three pathways (namely T-helper cell differentiation, cyclins and cell cycle regulation, and gap/tight junction signalling pathways) were highly enriched with these dysregulated genes. The pathways represent putative molecular pathways through which UC-MSCs elicit immunosuppressive activity toward activated T cells. This study provides a global snapshot of gene networks and pathways that contribute to the ability of UC-MSCs to suppress activated T cells.
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Affiliation(s)
- Shalini Vellasamy
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Chih Kong Tong
- Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Nur Atiqah Azhar
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia
| | - Radha Kodiappan
- Perdana University-Royal College of Surgeons in Ireland, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia; Medical Genetics Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia
| | - Soon Choy Chan
- Perdana University Graduate School of Medicine, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia
| | - Abhi Veerakumarasivam
- Perdana University Graduate School of Medicine, Perdana University, Jalan MAEPS Perdana, Serdang, Selangor Darul Ehsan, Malaysia; Medical Genetics Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia
| | - Rajesh Ramasamy
- Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; Stem Cell Research Laboratory, Genetics & Regenerative Medicine Research Centre, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor Darul Ehsan, Malaysia.
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20
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Zhou Y, Zhao W, Al-Muhtasib N, Rebeck GW. APOE Genotype Alters Immunoglobulin Subtypes in Knock-In Mice. J Alzheimers Dis 2016; 46:365-74. [PMID: 25737044 DOI: 10.3233/jad-142184] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Apolipoprotein E (APOE) alleles are strongly related to the risk of Alzheimer's disease (AD). APOE genotype also affects inflammatory processes in response to damage. We tested whether APOE genotype affected the levels of specific immunoglobulins in healthy, uninfected APOE knock-in mice. We measured specific immunoglobulins in brain, spleen, and plasma. Levels of total IgG in brain and spleen were highest in APOE-ɛ3 mice, significantly higher than in APOE-ɛ2 and APOE-ɛ4 mice; no differences were observed for levels of total IgG in plasma. We also measured specific subtypes of IgG. IgG1 was only detectable in plasma and did not differ by APOE genotype. IgG3 was detectable in plasma and spleen, and also did not differ by APOE genotype. IgG2b showed the same pattern as levels of total IgG by APOE genotype, with the highest levels of IgG2b in brain, spleen, and plasma of APOE-ɛ3 mice. IgG2a showed an entirely different pattern, with significantly higher levels in spleen and plasma of APOE-ɛ4 mice compared to APOE-ɛ2 and APOE-ɛ3 mice. We also measured IgM and IgA in spleens and plasma of these mice. In spleen, APOE-ɛ4 mice had the lowest IgA levels and the highest levels of IgM; both being significantly different from APOE-ɛ2 mice. In total, murine IgG2a and IgM were highest in APOE-ɛ4 mice, while total IgG and Ig2b were highest in APOE-ɛ3 mice. These dramatically different distributions of immunoglobulins could allow for human AD risk biomarkers based on specific immunoglobulin subtypes.
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Affiliation(s)
- Ye Zhou
- University of Florida, Gainesville, FL, USA
| | - Wenjuan Zhao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Nour Al-Muhtasib
- Department of Pharmacology, Georgetown University, Washington, DC, USA
| | - G William Rebeck
- Department of Neuroscience, Georgetown University, Washington, DC, USA
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21
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Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice. Inflamm Bowel Dis 2016; 22:841-52. [PMID: 26891260 PMCID: PMC4792726 DOI: 10.1097/mib.0000000000000699] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Apolipoprotein E (ApoE) mediates potent antiinflammatory and immunomodulatory properties in addition to its roles in regulating cholesterol transport and metabolism. However, its role in the intestine, specifically during inflammation, is largely unknown. METHODS Mice (C57BL/6 or ApoE-deficient [ApoE-KO] mice) were administered either single or 4 injections (weekly) of anti-interleukin (IL)-10 receptor monoclonal antibody (1.0 mg/mouse; intraperitoneally) and euthanized 1 week after the last injection. 16S rRNA sequencing was performed in fecal samples to analyze the gut bacterial load and its composition. Microbiota was ablated by administration of broad-spectrum antibiotics in drinking water. IL-10KO mice were cohoused with ApoE-KO mice or their wild-type littermates to monitor the colitogenic potential of gut microbiota harbored in ApoE-KO mice. RESULTS ApoE-KO mice developed severe colitis upon neutralization of IL-10 signaling as assessed by every parameter analyzed. 16S rRNA sequencing revealed that the ApoE-KO mice display elevated and altered gut microbiota that were accompanied with impaired production of intestinal antimicrobial peptides. Interestingly, microbiota ablation ameliorates colitis development in ApoE-KO mice. Exacerbated and accelerated colitis was observed in IL-10KO mice when cohoused with ApoE-KO mice. CONCLUSIONS Our study highlights a novel interplay between ApoE and IL-10 in maintaining gut homeostasis and that such crosstalk may play a critical role in the pathogenesis of inflammatory bowel disease. Gut sterilization and the cohousing experiment suggest that microbiota play a pivotal role in the development of inflammatory bowel disease in mice lacking ApoE.
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22
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Tai LM, Ghura S, Koster KP, Liakaite V, Maienschein‐Cline M, Kanabar P, Collins N, Ben‐Aissa M, Lei AZ, Bahroos N, Green SJ, Hendrickson B, Van Eldik LJ, LaDu MJ. APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 2015; 133:465-88. [PMID: 25689586 PMCID: PMC4400246 DOI: 10.1111/jnc.13072] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 01/12/2023]
Abstract
Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro-inflammatory; A.I., anti-inflammatory.
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Affiliation(s)
- Leon M. Tai
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
| | - Shivesh Ghura
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
| | - Kevin P. Koster
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
| | | | | | - Pinal Kanabar
- UIC Center for Research Informatics University of IllinoisChicagoIllinoisUSA
| | - Nicole Collins
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
| | - Manel Ben‐Aissa
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
| | - Arden Zhengdeng Lei
- UIC Center for Research Informatics University of IllinoisChicagoIllinoisUSA
| | - Neil Bahroos
- UIC Center for Research Informatics University of IllinoisChicagoIllinoisUSA
| | | | - Bill Hendrickson
- UIC Research Resources CenterUniversity of IllinoisChicagoIllinoisUSA
| | | | - Mary Jo LaDu
- Department of Anatomy and Cell BiologyUniversity of IllinoisChicagoIllinoisUSA
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Attenuation of Acute Rat Renal Allograft Rejection by Apolipoprotein E-Mimetic Peptide. Transplantation 2015; 99:925-34. [DOI: 10.1097/tp.0000000000000569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Cudaback E, Yang Y, Montine TJ, Keene CD. APOE genotype-dependent modulation of astrocyte chemokine CCL3 production. Glia 2014; 63:51-65. [PMID: 25092803 DOI: 10.1002/glia.22732] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 07/14/2014] [Indexed: 12/19/2022]
Abstract
Apolipoprotein E (apoE) is well known as a regulator of cholesterol homeostasis, and is increasingly recognized to play a prominent role in the modulation of innate immune response, including cell-to-cell communication and migration. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder characterized by neuroinflammation that appears to be an important component of the pathophysiology of the disease. Astrocytes are the majority cell type in brain, exerting significant influence over a range of central nervous system activities, including microglial-mediated neuroinflammatory responses. As the resident innate immune effector cells of the brain, microglia respond to soluble chemical signals released from tissue during injury and disease by mobilizing to lesion sites, clearing toxic molecules, and releasing chemical signals of their own. While microglial-mediated neuroinflammation in the AD brain remains an area of intense investigation, the mechanisms underlying reinforcement and regulation of these aberrant microglial responses by astrocytes are largely unstudied. Moreover, although inheritance of APOE ɛ4 represents the greatest genetic risk factor for sporadic AD, the mechanism by which apoE isoforms differentially influence AD pathophysiology is unknown. Here we show that APOE ɛ4 genotype specifically modulates astrocyte secretion of potent microglial chemotactic agents, including CCL3, thus providing evidence that APOE modulation of central nervous system (CNS) innate immune response is mediated through astrocytes.
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Affiliation(s)
- Eiron Cudaback
- Department of Pathology, University of Washington, Seattle, Washington
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Apolipoprotein E gene polymorphism and serum lipid profile in Saudi patients with psoriasis. DISEASE MARKERS 2014; 2014:239645. [PMID: 24782577 PMCID: PMC3981009 DOI: 10.1155/2014/239645] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 02/16/2014] [Accepted: 02/21/2014] [Indexed: 11/18/2022]
Abstract
Background/Aim. Apolipoprotein E (APOE) gene variants have been reported to influence psoriasis risk. However, data is limited to a few ethnicities and no similar study has been performed in middle eastern populations. We investigated this association in Saudi psoriasis patients. Methods. Saudi subjects (294) were genotyped for APOE gene using APOE StripAssay kit. Results. The frequencies of alleles ε2, ε4, and genotypes ε3/ε4 and ε3/ε2 were significantly higher in psoriasis patients compared with those in controls. The frequency of ε3 allele and ε3/ε3 genotype was significantly lower in patients. Other genotypes, ε2/ε4, ε2/ε2, and ε4/ε4, were absent in both groups. The serum cholesterol, triglycerides, and LDL levels were significantly higher in psoriasis patients contrary to HDL level. Patients with APOE ε4 had significantly higher levels of total cholesterol and LDL cholesterol, whereas those with the ε2 had higher HDL cholesterol, and triglycerides. Conclusion. APOE alleles ε2, ε4, and genotypes ε2/ε3 and ε4/ε3 are associated with psoriasis and can be a risk factor while allele ε3 and genotype ε3/ε3 may be protective for psoriasis in Saudis. Results of lipid profile support that psoriasis is one of the independent risk factors for hyperlipidemia and emphasize the need of screening cardiovascular diseases in psoriatic patients.
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Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M. ApoE production in human monocytes and its regulation by inflammatory cytokines. PLoS One 2013; 8:e79908. [PMID: 24244577 PMCID: PMC3828220 DOI: 10.1371/journal.pone.0079908] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 09/28/2013] [Indexed: 11/25/2022] Open
Abstract
The apoE production by tissue macrophages is crucial for the prevention of atherosclerosis and the aim of this study was to further elucidate how this apolipoprotein is regulated by cytokines present during inflammation. Here we studied apoE production in peripheral blood mononuclear cells (PBMC) and analysis was made with a newly developed apoE ELISpot assay. In PBMC, apoE secretion was restricted to monocytes with classical (CD14++CD16−) and intermediate (CD14+CD16+) monocytes being the main producers. As earlier described for macrophages, production was strongly upregulated by TGF-β and downregulated by bacterial lipopolysaccharide (LPS) and the inflammatory cytokines IFN-γ, TNF-α and IL-1β. We could here show that a similar down-regulatory effect was also observed with the type I interferon, IFN-α, while IL-6, often regarded as one of the more prominent inflammatory cytokines, did not affect TGF-β-induced apoE production. The TNF-α inhibitor Enbrel could partly block the down-regulatory effect of IFN-γ, IFN-α and IL-1β, indicating that inhibition of apoE by these cytokines may be dependent on or synergize with TNF-α. Other cytokines tested, IL-2, IL-4, IL-12, IL-13, IL-17A and IL-23, had no inhibitory effect on apoE production. In contrast to the effect on monocytes, apoE production by primary hepatocytes and the hepatoma cell line HepG2 was more or less unaffected by treatment with cytokines or LPS.
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Affiliation(s)
| | | | - Christian Smedman
- Mabtech and Center for Molecular Medicine, Infectious Diseases Unit L8:01, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Sohel Mia
- Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Makiko Kumagai-Braesch
- Mabtech and CLINTEC, Division of Transplantation Surgery, Karolinska Institutet, Stockholm, Sweden
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Prazosin, an α1-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease. Neurobiol Aging 2013; 34:1105-15. [DOI: 10.1016/j.neurobiolaging.2012.09.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 09/05/2012] [Accepted: 09/07/2012] [Indexed: 01/16/2023]
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Kaneva AM, Bojko ER, Potolitsyna NN, Odland JO. Plasma levels of apolipoprotein-E in residents of the European North of Russia. Lipids Health Dis 2013; 12:43. [PMID: 23537337 PMCID: PMC3621782 DOI: 10.1186/1476-511x-12-43] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 03/21/2013] [Indexed: 01/29/2023] Open
Abstract
Background Apolipoprotein-E (apoE) is one of the metabolically active apoproteins and plays an important role in lipid metabolism. However, there are no data on levels of apoE in residents of the North in spite of the fact that specific features of lipid metabolism in the northerners are described. The present work was designed to study plasma levels of apoE in residents of the European North of Russia. Methods A total of 937 native residents of the European North of Russia (463 men and 474 women) aged 13–60 years were included in the study. ApoE concentrations in the blood plasma were measured by immunoturbidimetric method. Results Plasma levels of apoE in residents of the European North of Russia were low. ApoE concentrations below the defined normal values were detected in 57.0% of the men and in 59.2% of the women. The mean plasma levels of apoE did not significantly differ in men and women (2.80 mg/dl vs 2.87 mg/dl). Plasma apoE concentrations in residents of the European North of Russia changed with age. Plasma levels of apoE decreased from 13 to 21 years in men and from 13 to 35 years in women and then increased in both sexes (p < 0.001). Conclusion The limits of variation of plasma apoE levels in residents of the European North of Russia shift towards lower values. Plasma levels of apoE below normal values were observed in approximately half of investigation subjects.
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Affiliation(s)
- Anastasiya M Kaneva
- Institute of Physiology, Komi Science Center, Ural Branch of Russian Academy of Sciences, Syktyvkar, Russia.
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Abstract
PURPOSE OF REVIEW Apolipoprotein (apo) E is a multifunctional protein that has long been recognized for its ability to safeguard against atherosclerosis. Among its pleiotropic roles known to suppress atherosclerosis, mechanisms by which apoE regulates cells of the immune system have remained elusive. Because atherosclerosis is a chronic inflammatory disease that remains on the rise, understanding in more detail how apoE controls immune cell activation and function is of much interest. RECENT FINDINGS Literature reported in the past year introduces apoE as a regulator of monocyte and macrophage plasticity. Through signals delivered by its interaction with cell surface receptors, apoE has been shown to influence the polarity and inflammatory phenotypes of the macrophage. By promoting cellular cholesterol efflux in a cell autonomous manner and through its ability to enhance HDL function in hyperlipidemic plasma, apoE is now known to suppress atherosclerosis by controlling myeloid cell proliferation, monocyte activation and their capacity to infiltrate the vascular wall. Lastly, the structural basis for apoE isoform-specific effects in macrophage dysfunction and atherosclerosis susceptibility is beginning to emerge. SUMMARY Collectively, these findings introduce a new dimension to our understanding of how apoE links lipoprotein biology to monocyte and macrophage function in atherosclerosis susceptibility.
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Affiliation(s)
- Robert L Raffai
- Department of Surgery, University of California San Francisco, and Veterans Affairs Medical Center, San Francisco, California 94121, USA.
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30
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Ahn SJ, Kim DK, Kim SS, Bae CB, Cho HJ, Kim HG, Kim YJ, Lee JH, Lee HJ, Lee MY, Kim KB, Cho JH, Cho SW, Cheong JY. Association between apolipoprotein E genotype, chronic liver disease, and hepatitis B virus. Clin Mol Hepatol 2012; 18:295-301. [PMID: 23091810 PMCID: PMC3467433 DOI: 10.3350/cmh.2012.18.3.295] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 08/13/2012] [Accepted: 08/13/2012] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/AIMS Apolipoprotein E (ApoE) plays an important role in regulating lipid and lipoprotein metabolism, and ApoE genotypes are known to affect plasma lipoprotein concentrations. We investigated whether ApoE genotype determines the disease outcome in hepatitis B virus (HBV)-infected individuals, and verified the association between ApoE genotype and the occurrence of hepatocellular carcinoma (HCC) in patients with chronic liver diseases of various etiologies. METHODS This hospital-based, case-controlled study enrolled 156 subjects (47 healthy controls, 50 HBV-related liver cirrhosis patients, and 59 HCC patients). ApoE genotypes were determined using PCR-based ApoE genotyping kits. The biological significance of ApoE genotype was verified by measuring serum ApoE levels using an ELISA kits. RESULTS The ε3 allele was the most common allele, with allele frequencies among the entire cohort of 5.8%, 84.3%, and 9.9% for the ε2, ε3, and ε4 alleles, respectively. Significantly more of those patients carrying the ε3/3 genotype had developed liver cirrhosis compared to the control subjects. Being an ApoE4 carrier was associated with a lower probability of developing liver cirrhosis. The allele frequencies and genotype distribution of ApoE did not differ significantly between the liver cirrhosis and HCC patients. The serum level of ApoE was significantly higher in patients with liver cirrhosis than in the healthy controls, but did not differ significantly with the ApoE genotype. CONCLUSIONS The ApoE ε3/3 genotype frequency was higher in patients with HBV-associated liver cirrhosis than in the controls.
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Affiliation(s)
- Seun Joo Ahn
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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Targeted In Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein. Cardiol Res Pract 2012; 2012:148796. [PMID: 22645694 PMCID: PMC3356902 DOI: 10.1155/2012/148796] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 01/30/2012] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the leading worldwide cause of death. Apolipoprotein E (ApoE) is a 34-kDa circulating glycoprotein, secreted by the liver and macrophages with pleiotropic antiatherogenic functions and hence a candidate to treat hypercholesterolaemia and atherosclerosis. Here, we describe atheroprotective properties of ApoE, though also potential proatherogenic actions, and the prevalence of dysfunctional isoforms, outline conventional gene transfer strategies, and then focus on gene correction therapeutics that can repair defective APOE alleles. In particular, we discuss the possibility and potential benefit of applying in combination two technical advances to repair aberrant APOE genes: (i) an engineered endonuclease to introduce a double-strand break (DSB) in exon 4, which contains the common, but dysfunctional, ε2 and ε4 alleles; (ii) an efficient and selectable template for homologous recombination (HR) repair, namely, an adeno-associated viral (AAV) vector, which harbours wild-type APOE sequence. This technology is applicable ex vivo, for example to target haematopoietic or induced pluripotent stem cells, and also for in vivo hepatic gene targeting. It is to be hoped that such emerging technology will eventually translate to patient therapy to reduce CVD risk.
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Sharifov OF, Nayyar G, Garber DW, Handattu SP, Mishra VK, Goldberg D, Anantharamaiah GM, Gupta H. Apolipoprotein E mimetics and cholesterol-lowering properties. Am J Cardiovasc Drugs 2012; 11:371-81. [PMID: 22149316 DOI: 10.2165/11594190-000000000-00000] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Apolipoprotein E (apoE) is a ligand for clearance of lipoprotein remnants such as chylomicrons and very low-density lipoproteins. It has anti-atherogenic and anti-inflammatory properties. Therefore, there is extensive ongoing research to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states, including Alzheimer disease. However, peptides that clear atherogenic lipoproteins, analogous to apoE, via enhanced hepatic uptake have not been previously reviewed. Toward this end, we describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH(2). This peptide consists of residues 141-150, the putative receptor-binding region of human apoE, covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol levels in dyslipidemic mouse and rabbit models. We discuss the scientific rationale and review the literature for the design and efficacy of the peptide. Analogous to apoE, this peptide bypasses the low-density lipoprotein receptor for the hepatic uptake of atherogenic lipoproteins via heparan sulfate proteoglycan (HSPG). ApoE mimetics such as Ac-hE18A-NH(2) may therefore restore or replace ligands in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional low-density lipoprotein receptors. Therefore, this and similar peptides may be useful in the treatment of dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis.
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Affiliation(s)
- Oleg F Sharifov
- Departments of Medicine, Biochemistry and Molecular Genetics and the Atherosclerosis Research Unit, University of Alabama at Birmingham, USA
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Annema W, Dikkers A, Freark de Boer J, Gautier T, Rensen PCN, Rader DJ, Tietge UJF. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma. J Lipid Res 2012; 53:929-940. [PMID: 22383685 DOI: 10.1194/jlr.m020743] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with (3)H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P < 0.05), fecal neutral sterol excretion (P < 0.05), and in vivo RCT (P < 0.01), specifically within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.
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Affiliation(s)
- Wijtske Annema
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands
| | - Arne Dikkers
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Thomas Gautier
- INSERM UMR866 Lipides, Nutrition, Cancer, Faculté de Médecine, Dijon, France
| | - Patrick C N Rensen
- Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; and
| | - Daniel J Rader
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Uwe J F Tietge
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
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Toms TE, Smith JP, Panoulas VF, Blackmore H, Douglas KMJ, Kitas GD. Apolipoprotein E gene polymorphisms are strong predictors of inflammation and dyslipidemia in rheumatoid arthritis. J Rheumatol 2011; 39:218-25. [PMID: 22174202 DOI: 10.3899/jrheum.110683] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Rheumatoid arthritis (RA), a condition with a strong genetic etiology, is associated with excess cardiovascular disease (CVD). Dyslipidemia in RA may be driven by inflammation and genetic factors. Apolipoprotein E (ApoE) is important for the regulation of lipid levels and CVD risk and immune function in the general population. We compared the frequency of 2 ApoE single-nucleotide polymorphisms (SNP) in patients with RA and controls, and studied the relationship of ApoE genotypes with lipids and inflammation in RA. METHODS A total of 387 patients with well-characterized RA and 420 non-RA controls were studied. Two ApoE SNP, rs7412 (ApoE2) and rs429358 (ApoE4), were identified. RESULTS Genotypic (p = 0.908) and allelic (p = 0.894) frequencies did not differ between RA and controls. Within RA, the E2 allele was associated with the lowest and E4 allele with the highest levels of total cholesterol (p = 0.007), low-density lipoproteins (p = 0.004), and apolipoprotein B (p = 0.009). The E4 allele was also associated with lower C-reactive protein (p = 0.007), erythrocyte sedimentation rate (p = 0.001), and Disease Activity Score (p = 0.015) compared to the E3 allele. E2 or E4 alleles were not associated with CVD in RA, although a trend was observed (p = 0.074). CONCLUSION The frequency of ApoE polymorphisms did not differ between patients with RA and controls. ApoE genotypes are strongly linked to inflammation and lipid levels in RA, raising interest in the prognostic implications of ApoE genotypes.
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Affiliation(s)
- Tracey E Toms
- Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands, DY1 2HQ, UK
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Muller O, Delrue L, Hamilos M, Vercauteren S, Ntalianis A, Trana C, Mangiacapra F, Dierickx K, De Bruyne B, Wijns W, Behfar A, Barbato E, Terzic A, Vanderheyden M, Bartunek J. Transcriptional fingerprint of human whole blood at the site of coronary occlusion in acute myocardial infarction. EUROINTERVENTION 2011; 7:458-66. [PMID: 21764664 DOI: 10.4244/eijv7i4a75] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
AIMS Transcriptome patterns associated with acute myocardial infarction at the site of coronary occlusion are largely unknown. The aim of this study was to decipher the angiogenic, atherosclerotic, and inflammatory mRNA profiles in whole blood samples collected at the site of coronary occlusion in patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS In five consecutive patients with STEMI, blood was sampled at the site of occlusion (local) and in the systemic circulation (peripheral) during primary percutaneous coronary intervention. RNA was extracted from whole blood samples. Among 221 genes involved in angiogenesis, inflammation and atherosclerosis, 24 were shown to be differentially modulated locally, by analysis with custom-designed DNA array technology. Validation in 28 distinct STEMI patients using real-time quantitative PCR identified seven out of these 24 genes to be consistently and significantly upregulated in local versus peripheral blood (p<0.05). Three genes were chemokine family members (CCL2, CCL18 and CXCL12), three genes belonged to the cell-cell and cell-extracellular matrix family (FN1, CDH5 and SPP1), and one gene was representative of the lipoprotein family (APOE). CONCLUSIONS We identified a set of whole blood transcripts induced at the site of coronary occlusion in the acute phase of myocardial infarction. Resolved genes indicate a predominant role for chemokines, cell-extracellular matrix, and lipoprotein alterations in the pathophysiology of acute myocardial infarction and the initial response to myocardial injury.
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Affiliation(s)
- Olivier Muller
- Cardiovascular Center and Translational Cardiology Unit, Aalst, Belgium
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Owens AP, Rateri DL, Howatt DA, Moore KJ, Tobias PS, Curtiss LK, Lu H, Cassis LA, Daugherty A. MyD88 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation independent of signaling through Toll-like receptors 2 and 4. Arterioscler Thromb Vasc Biol 2011; 31:2813-9. [PMID: 21960563 DOI: 10.1161/atvbaha.111.238642] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE The purpose of this study was to determine whether myeloid differentiation factor 88 (MyD88) and its related Toll-like receptors (TLRs) 2 and 4 contributed to the development of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) and atherosclerosis. METHODS AND RESULTS AngII was infused into either apoE(-/-) or LDL receptor (LDLR)(-/-) male mice that were either MyD88(+/+) or (-/-). MyD88 deficiency profoundly reduced AngII-induced AAAs and atherosclerosis in both strains. To define whether deficiency of specific TLRs had similar effects, AngII was infused into LDLR(-/-) mice that were also deficient in either TLR2 or TLR4. TLR2 deficiency had no effect on AAA development but inhibited atherosclerosis. In contrast, TLR4 deficiency attenuated both AAAs and atherosclerosis. To resolve whether MyD88 and TLR4 exerted their effects through cells of hematopoietic lineage, LDLR(-/-) mice were lethally irradiated and repopulated with bone marrow-derived cells from either MyD88 or TLR4 strains. MyD88 deficiency in bone marrow-derived cells profoundly reduced both AngII-induced AAAs and atherosclerosis. However, TLR4 deficiency in bone marrow-derived cells had no effect on either pathology. CONCLUSIONS These studies demonstrate that MyD88 deficiency in leukocytes profoundly reduces AngII-induced AAAs and atherosclerosis via mechanisms independent of either TLR2 or TLR4.
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Affiliation(s)
- A Phillip Owens
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USA
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Zhuang K, Zhang W, Zhang X, Wu F, Cheng L. Effects of SNPs at newly identified lipids loci on blood lipid levels and risk of coronary heart disease in Chinese Han population: a case control study. ACTA ACUST UNITED AC 2011; 31:452. [PMID: 21823004 DOI: 10.1007/s11596-011-0472-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Indexed: 11/28/2022]
Abstract
Associations between "lipid-related" candidate genes, blood lipid concentrations and coronary artery disease (CHD) risk are not clear. We aimed to investigate the effect of three newly identified lipids loci from genome-wide association studies on CHD and blood lipid levels in Chinese Han population. The genotypes of SNPs at three newly identified lipid loci and blood lipids concentrations were examined in 1360 CHD patients and 1360 age- and sex-frequency matched controls from an unrelated Chinese Han population. Allele T of rs16996148 occurred less frequently in CHD patients with the odds ratio (OR) being 0.64 (95% CI 0.50 to 0.81), after adjusting for conventional risk factors and was associated with a 33% decreased CHD risk (P<0.01) comparing with the major allele G. Individuals with GT genotype had the lowest CHD risk. No associations were found between the polymorphisms of other two loci with CHD risk and all three SNPs had no effect on lipid profile in this population. SNP rs16996148 on chromosome 19p13 is significantly associated with lower risk for CHD in Chinese Han population. However, it remains unresolved why these lipid-related loci had significantly less effects than the correspondingly expected effects on blood lipids levels in this population.
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Affiliation(s)
- Ke Zhuang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wencai Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaobo Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fangqin Wu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Longxian Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Postigo J, Genre F, Iglesias M, Fernández-Rey M, Buelta L, Carlos Rodríguez-Rey J, Merino J, Merino R. Exacerbation of type II collagen-induced arthritis in apolipoprotein E-deficient mice in association with the expansion of Th1 and Th17 cells. ACTA ACUST UNITED AC 2011; 63:971-80. [PMID: 21225684 DOI: 10.1002/art.30220] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVE To explore the bidirectional relationship between the development of rheumatoid arthritis (RA) and atherosclerosis using bovine type II collagen (CII)-immunized B10.RIII apoE(-/-) mice, a murine model of spontaneous atherosclerosis and collagen-induced arthritis (CIA). METHODS Male B10.RIII apoE(-/-) mice and wild-type controls were immunized with 150 μg of CII emulsified in Freund's complete adjuvant (CFA). The clinical, radiologic, and histopathologic severity of CIA, the levels of circulating IgG1 and IgG2a anti-CII antibodies, the expression of proinflammatory and antiinflammatory cytokines in the joints, and the percentages of Th1, Th17, and Treg lymphocytes in the draining lymph nodes were evaluated during CIA induction. In addition, the size of atherosclerotic lesions was assessed in these mice 8 weeks after CIA induction. RESULTS B10.RIII apoE(-/-) mice that were immunized with CII and CFA developed an exacerbated CIA that was accompanied by increased joint expression of multiple proinflammatory cytokines and by the expansion in the draining lymph nodes of Th1 and Th17 cells. In contrast, the size of vascular lesions in B10.RIII apoE(-/-) mice was not affected by the development of CIA. CONCLUSION Our findings indicate that a deficiency in apolipoprotein E and/or its consequences in cholesterol metabolism act as accelerating factors in autoimmunity by promoting Th1 and Th17 inflammatory responses.
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Zhang HL, Mao XJ, Zhang XM, Li HF, Zheng XY, Adem A, Mix E, Zhu J. APOE ε3 attenuates experimental autoimmune neuritis by modulating T cell, macrophage and Schwann cell functions. Exp Neurol 2011; 230:197-206. [PMID: 21550340 DOI: 10.1016/j.expneurol.2011.04.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 04/01/2011] [Accepted: 04/17/2011] [Indexed: 12/01/2022]
Abstract
Human apolipoprotein E (apoE) is a 34.2kDa glycosylated protein with three isoforms (apoE2, apoE3 and apoE4). Experimental autoimmune neuritis (EAN), an animal model for human Guillain-Barré syndrome, is an immune-mediated experimental disorder of the peripheral nervous system (PNS). Increased susceptibility to EAN in apoE deficient mice has been previously found. To elucidate the isoform-dependent effects of apoE on EAN, we used human apoE2, E3 and E4 transgenic mice (Tg) immunized with P0 peptide 180-199, as well as T cell proliferation test, macrophage and Schwann cell (SC) cultures to investigate the effects of apoE isoforms on the functions of T cells, macrophages and SCs both under naïve conditions and in EAN. Clinical signs of EAN were most severe in wild type (WT) C57BL/6 mice and apoE4 Tg mice, followed by apoE2 Tg mice and apoE3 Tg mice (WT≈E4>E2>E3, p<0.01). At the nadir of EAN, spleen weight and lymphocyte proliferation were in line with the clinical severity of the disease. Proliferation tests of purified T cells from naive mice stimulated with phytohemagglutinin or interleukin-12 showed isoform-specific differences (WT≈E4>E3≈E2, p<0.01). Macrophages from both naïve and EAN mice produced nitric oxide upon inflammatory stimulation with lipopolysaccharide, interferon-γ, polyinosinic:polycytidylic acid or combinations thereof, in an isoform-dependent manner (WT≈E4>E2>E3, p<0.01). Generalized intervention with 1400W, a specific inducible nitric oxide synthase inhibitor, significantly suppressed the clinical course of EAN in apoE2, E3 and E4 Tg mice and in WT mice. During the recovery stage of disease, the highest expression of CD178 (FasL) on SCs was found in apoE3 Tg mice. Our data support an isoform-dependent effect of apoE on EAN. This might be due to the isoform-specific effects of apoE on functions of T cells, macrophages and SCs, which contribute to the distinct clinical courses of EAN. ApoE3 might not only inhibit the onset and suppress the clinical severity of EAN, but also enhance the termination of immune responses in the PNS.
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Affiliation(s)
- Hong-Liang Zhang
- Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
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Christensen DJ, Ohkubo N, Oddo J, Van Kanegan MJ, Neil J, Li F, Colton CA, Vitek MP. Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. THE JOURNAL OF IMMUNOLOGY 2011; 186:2535-42. [PMID: 21289314 DOI: 10.4049/jimmunol.1002847] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The molecular mechanism by which apolipoprotein E (apoE) suppresses inflammatory cytokine and NO production is unknown. Using an affinity purification approach, we found that peptide mimetics of apoE, derived from its receptor binding domain residues 130-150, bound to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). Both holo-apoE protein and apoE-mimetic peptides bound to the C-terminal region of SET, which is then associated with an increase in PP2A-mediated phosphatase activity. As physiological substrates for PP2A, the LPS-induced phosphorylation status of signaling MAPK and Akt kinase is reduced following treatment with apoE-mimetic peptides. On the basis of our previous report, in which apoE-mimetic peptides reduced I-κB kinase and NF-κB activation, we also demonstrate a mechanism for reduced production of inducible NO synthase protein and its NO product. These data provide evidence for a novel molecular mechanism by which apoE and apoE-mimetic peptides antagonize SET, thereby enhancing endogenous PP2A phosphatase activity, which reduces levels of phosphorylated kinases, signaling, and inflammatory response.
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The Fat-Fed Apolipoprotein E Knockout Mouse Brachiocephalic Artery in the Study of Atherosclerotic Plaque Rupture. J Biomed Biotechnol 2011; 2011:379069. [PMID: 21076539 PMCID: PMC2975993 DOI: 10.1155/2011/379069] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 10/11/2010] [Accepted: 10/11/2010] [Indexed: 11/17/2022] Open
Abstract
Atherosclerosis has been studied in animals for almost a century, yet the events leading up to the rupture of an atherosclerotic plaque (the underlying cause of the majority of fatal thrombosis formation) have only been studied in the past decade, due in part to the development of a mouse model of spontaneous plaque rupture. Apolipoprotein E knockout mice, when fed a high-fat diet, consistently develop lesions in the brachiocephalic artery that rupture at a known time point. It is therefore now possible to observe the development of lesions to elucidate the mechanisms behind the rupture of plaques. Critics argue that the model does not replicate the appearance of human atherosclerotic plaque ruptures. The purpose of this review is to highlight the reasons why we should be looking to the apolipoprotein E knockout mouse to further our understanding of plaque rupture.
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Lee Y, Kockx M, Raftery MJ, Jessup W, Griffith R, Kritharides L. Glycosylation and sialylation of macrophage-derived human apolipoprotein E analyzed by SDS-PAGE and mass spectrometry: evidence for a novel site of glycosylation on Ser290. Mol Cell Proteomics 2010; 9:1968-81. [PMID: 20511397 DOI: 10.1074/mcp.m900430-mcp200] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Apolipoprotein E (apoE) is a 34-kDa glycoprotein secreted from various cells including hepatocytes and macrophages and plays an important role in remnant lipoprotein clearance, immune responses, Alzheimer disease, and atherosclerosis. Cellular apoE and plasma apoE exist as multiple glycosylated and sialylated glycoforms with plasma apoE being less glycosylated/sialylated than cell-derived apoE. Some of the glycan structures on plasma apoE are characterized; however, the more complicated structures on plasma and cellular/secreted apoE remain unidentified. We investigated glycosylation and sialylation of cellular and secreted apoE from primary human macrophages by one- and two-dimensional gel electrophoresis and mass spectrometry. Our results identify eight different glycoforms with (HexNAc)(2)-Hex(2)-(NeuAc)(2) being the most complex glycan detected on Thr(194) in both cellular and secreted apoE. Four additional glycans were identified on apoE(283-299), and using beta-elimination/alkylation by methylamine in vitro, we identified Ser(290) as a novel site of glycan attachment. Comparison of plasma and cellular/secreted apoE from the same donor confirmed that cell-derived apoE is more extensively sialylated than plasma apoE. Given the importance of the C terminus of apoE in regulating apoE solubility, stability, and lipid binding, these results may have important implications for our understanding of apoE biochemistry.
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Affiliation(s)
- Youra Lee
- Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, Australia
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The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis. J Biomed Biotechnol 2010; 2010:357412. [PMID: 20182542 PMCID: PMC2825561 DOI: 10.1155/2010/357412] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 12/20/2009] [Indexed: 11/24/2022] Open
Abstract
Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN).
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Kuhlmann I, Minihane AM, Huebbe P, Nebel A, Rimbach G. Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review. Lipids Health Dis 2010; 9:8. [PMID: 20109174 PMCID: PMC2830997 DOI: 10.1186/1476-511x-9-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 01/28/2010] [Indexed: 01/22/2023] Open
Abstract
Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimer's disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex.ApoE4 seems to be protective against chronic hepatitis C virus infection and retards fibrosis progression. In contrast apoE4 enhances the fusion rate of human immunodeficiency virus with target cell membranes, resulting in accelerated cell entry and faster disease progression. Its association with human immunodeficiency virus-associated dementia remains controversial. Regarding herpes simplex virus infection, apoE4 intensifies virus latency and is associated with increased oxidative damage of the central nervous system, and there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with an increased risk of Alzheimer's disease. In addition to reviewing available data from human trials, evidence derived from a variety of cell culture and animal models are considered in this review in order to provide mechanistic insights into observed association between apoE4 genotype and viral disease infection and pathology.
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Affiliation(s)
- Inga Kuhlmann
- Institute of Human Nutrition and Food Science, Christian-Albrechts-University, Hermann-Rodewald-Strasse 6, 24098 Kiel, Germany
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Lack of apoE causes alteration of cytokines expression in young mice liver. Mol Biol Rep 2009; 37:2049-54. [PMID: 19644765 DOI: 10.1007/s11033-009-9660-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Accepted: 07/21/2009] [Indexed: 01/30/2023]
Abstract
To investigate the effect of apolipoprotein E (apoE) on cytokine expression profile of the liver of young mice, quantitative RT-PCR (qRT-PCR) assay and cytokine antibody array for multiplex analysis of 62 cytokines have been used to analyze characteristics of expression of cytokines in the liver of 6-week-old apoE-null (apoE(-/-)) mice. The levels of plasma cytokines were also analyzed. The mRNA level of IL-1 beta, IL-2, IL-6, ICAM-1, VCAM-1, MCP-1, NF-kappaB (p65), IFN-gamma and I kappaB-alpha were increased significantly in apoE(-/-) mice comparative to wild-type (WT) mice. IL-4, IL-10 and GM-CSF, however, were slightly decreased. Compared with WT, levels of 21 cytokines altered twofold or more in apoE(-/-) mice, including 10 cytokines increased and 11 decreased. Expression patterns of IL-1 beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma and VCAM-1 showed identical trend between cytokine antibody array and qRT-PCR analysis. Moreover, levels of IL-1 beta, IFN-gamma and IL-6 in the plasma were elevated, while IL-4 was lightly decreased in apoE(-/-) mice compared to those in WT mice. These results implied that promotion of type I immune response in the liver of young apoE(-/-) mice due to alteration of these cytokines, and the phenotypes may be caused by the regulation of NF-kappaB. The inflammation and lipid metabolism dysfunction in the liver cooperated in dysfunction of the liver in young apoE(-/-) mice.
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Karpouzis A, Caridha R, Tripsianis G, Michailidis C, Martinis G, Veletza SV. Apolipoprotein E gene polymorphism in psoriasis. Arch Dermatol Res 2009; 301:405-10. [DOI: 10.1007/s00403-009-0968-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2008] [Revised: 05/16/2009] [Accepted: 05/19/2009] [Indexed: 01/15/2023]
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Wu K, Joffre C, Li X, MacVeigh-Aloni M, Hom M, Hwang J, Ding C, Gregoire S, Bretillon L, Zhong JF, Hamm-Alvarez SF. Altered expression of genes functioning in lipid homeostasis is associated with lipid deposition in NOD mouse lacrimal gland. Exp Eye Res 2009; 89:319-32. [PMID: 19345210 DOI: 10.1016/j.exer.2009.03.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 03/17/2009] [Accepted: 03/24/2009] [Indexed: 02/06/2023]
Abstract
Functional atrophy and accompanying lymphocytic infiltration and destruction of the lacrimal gland (LG) are characteristics of Sjögren's Syndrome (SjS). The male NOD mouse is an experimental model for the autoimmune exocrinopathy that develops in the LG of SjS patients. Acinar cells in LG of male NOD mice aged 3-4 months were previously shown to accumulate lipid droplets. In the current study, analysis of lipid components revealed that the accumulated lipids were mostly cholesteryl esters (CE). Gene expression microarray analysis followed by real-time RT-PCR revealed alterations in the expression of several genes involved in lipid homeostasis in LG of 12-week-old male NOD mice relative to matched BALB/c controls. A series of upregulated genes including apolipoprotein E, apolipoprotein F, hepatic lipase, phosphomevalonate kinase, ATP-binding cassette D1 and ATP-binding cassette G1 were identified. Comparison of liver mRNAs to LG mRNAs in BALB/c and NOD mice revealed that the differential expressions were LG-specific. Gene expression profiles were also characterized in LGs of female mice, younger mice and immune-incompetent NOD SCID mice. Investigation of the cellular distribution of Apo-E and Apo-F proteins suggested that these proteins normally coordinate to mediate lipid efflux from the acinar cells but that dysfunction of these processes due to missorting of Apo-F may contribute to CE deposition. Finally, the initiation and extent of lipid deposition were correlated with lymphocytic infiltration in the LG of male NOD mice. We propose that impaired lipid efflux contributes to lipid deposition, an event that may contribute to the development and/or progression of dacryoadenitis in the male NOD mouse.
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Affiliation(s)
- Kaijin Wu
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, CA 90089, USA
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Parks BW, Srivastava R, Yu S, Kabarowski JHS. ApoE-dependent modulation of HDL and atherosclerosis by G2A in LDL receptor-deficient mice independent of bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2009; 29:539-47. [PMID: 19164809 DOI: 10.1161/atvbaha.108.179937] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Deletion of the lysophospholipid-sensitive receptor, G2A, in low-density lipoprotein receptor knockout (LDLR(-/-)) mice elevates plasma high-density lipoprotein (HDL) cholesterol and suppresses atherosclerosis. However, chemotactic action of G2A in monocytes/macrophages, in addition to its modulatory effect on HDL, may contribute to the proatherogenic action of G2A. METHODS AND RESULTS We determined that deletion of G2A in LDLR(-/-) mice increases the ApoA1, ApoE, and cholesterol content of plasma HDL fractions. Hepatocytes were shown to express G2A and hepatocytes from G2A-deficient LDLR(-/-) mice secreted more ApoA1 and ApoE in HDL fractions compared to their G2A-sufficient counterparts. The atheroprotective and HDL modulatory effects of G2A deficiency were dependent on the presence of ApoE, as deletion of G2A in ApoE(-/-) and ApoE(-/-)LDLR(-/-) mice failed to raise HDL and did not suppress atherosclerosis. G2A deficiency in bone marrow-derived cells of LDLR(-/-) mice had no effect on atherosclerosis or HDL, whereas G2A deficiency in resident tissues was sufficient to raise HDL and suppress atherosclerosis. CONCLUSIONS These data demonstrate that the chemotactic function of G2A in bone marrow-derived monocytes does not modulate atherosclerosis in LDLR(-/-) mice and suggest an ApoE-dependent function for G2A in the control of hepatic HDL metabolism that might contribute to its proatherogenic action.
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Affiliation(s)
- Brian W Parks
- Department of Microbiology, University of Alabama at Birmingham, Birmingham AL 35294-2170, USA
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Stephens TA, Nikoopour E, Rider BJ, Leon-Ponte M, Chau TA, Mikolajczak S, Chaturvedi P, Lee-Chan E, Flavell RA, Haeryfar SMM, Madrenas J, Singh B. Dendritic cell differentiation induced by a self-peptide derived from apolipoprotein E. THE JOURNAL OF IMMUNOLOGY 2008; 181:6859-71. [PMID: 18981105 DOI: 10.4049/jimmunol.181.10.6859] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dendritic cells (DCs) are professional APCs and potent stimulators of naive T cells. Since DCs have the ability to immunize or tolerize T cells they are unique candidates for use in immunotherapy. Our laboratory has discovered that a naturally processed self-peptide from apolipoprotein E, Ep1.B, induces DC-like morphology and surface marker expression in a murine monocytic cell line (PU5-1.8), human monocytic cell line (U937), murine splenocytes, and human peripheral blood monocytes. Microscopy and flow cytometric analysis revealed that Ep1.B-treated cells display decreased adherence to plastic and increased aggregation, dendritic processes, and expression of DC surface markers, including DEC-205, CD11c, B7.1, and B7.2. These effects were observed in both PU5-1.8 cells and splenocytes from various mouse strains including BALB/c, C57BL/6, NOD/Lt, and C3H/HeJ. Coadministration of Ep1.B with OVA antigenic peptide functions in dampening specific immune response to OVA. Ep1.B down-regulates proliferation of T cells and IFN-gamma production and stimulates IL-10 secretion in immunized mice. Ep1.B-induced differentiation resulted in the activation of PI3K and MAPK signaling pathways, including ERK1/2, p38, and JNK. We also found that NF-kappaB, a transcription factor essential for DC differentiation, is critical in mediating the effects of Ep1.B. Ep1.B-induced differentiation is independent of MyD88-dependent pathway of TLR signaling. Cumulatively, these findings suggest that Ep1.B acts by initiating a signal transduction cascade in monocytes leading to their differentiation into DCs.
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Affiliation(s)
- Tracey A Stephens
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
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Park JH, Park SM, Park SH, Cho KH, Lee ST. Cleavage and functional loss of human apolipoprotein E by digestion of matrix metalloproteinase-14. Proteomics 2008; 8:2926-35. [PMID: 18655030 DOI: 10.1002/pmic.200700487] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
By means of a degradomic approach applying proteomic techniques, we previously suggested that apolipoprotein E (apoE) is a substrate of matrix metalloproteinase-14 (MMP-14). Here we confirm that apoE is, in fact, a substrate of MMP-14 and also of MMP-7 and MMP-2 to a lesser extent. The 34 kDa apoE protein was initially processed by MMP-14 into fragments with molecular masses of 28, 23, 21, and 11 kDa. MMP-14 cleavage sites within the apoE protein were determined by C-terminal labeling of MMP-14-digested apoE fragments with isotope ((18)O/(16)O = 1:1) and identification of the doublet fragments or peptides showing 2 Da difference by MS, along with N-terminal sequencing of the fragments. It was determined that the primary MMP-14 cleavage sites were A(176)-I(177), P(183)-L(184), P(202)-L(203), and Q(249)-I(250). The MMP-14-mediated cleavage of apoE was consistent regardless of whether apoE existed in its lipid-bound or lipid-free form. Upon digestion with MMP-14, apoE loses its ability to suppress the platelet-derived growth factor-induced migration of rat vascular smooth muscle cells. Considering the important role of apoE for lipid metabolism and atherosclerosis protection, our findings suggest that MMP-14 plays an essential role for the development of hyperlipidemia and atherosclerosis as a result of degradation of apoE.
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Affiliation(s)
- Jun Hyoung Park
- Department of Biochemistry, College of Life Science and Biotechnology, Protein Network Research Center, Yonsei University, Seoul, Korea
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