|
1
|
Abbasizadeh N, Burns CS, Verrinder R, Ghazali F, Seyedhassantehrani N, Spencer JA. Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan. Front Cell Dev Biol 2024; 12:1441381. [PMID: 39139448 PMCID: PMC11319712 DOI: 10.3389/fcell.2024.1441381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024] Open
Abstract
Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6 weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. Ex vivo imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6 weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6 weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.
Collapse
Affiliation(s)
- Nastaran Abbasizadeh
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Christian S. Burns
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Ruth Verrinder
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Farhad Ghazali
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
| | - Negar Seyedhassantehrani
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
| | - Joel A. Spencer
- Department of Bioengineering, University of California, Merced, Merced, CA, United States
- Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States
- Health Sciences Research Institute, University of California, Merced, Merced, CA, United States
| |
Collapse
|
|
2
|
Jannini-Sá YAP, Creyns B, Hogaboam CM, Parks WC, Hohmann MS. Macrophages in Lung Repair and Fibrosis. Results Probl Cell Differ 2024; 74:257-290. [PMID: 39406909 DOI: 10.1007/978-3-031-65944-7_10] [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: 11/01/2024]
Abstract
Macrophages are key regulators of tissue repair and fibrosis. Following injury, macrophages undergo marked phenotypic and functional changes to play crucial roles throughout the phases of tissue repair. Idiopathic Pulmonary Fibrosis, which is the most common fibrosing lung disease, has been described as an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible aging individual. The marked destruction of the lung architecture results from the excessive secretion of extracellular matrix by activated fibroblasts and myofibroblasts. Accumulating evidence suggests that macrophages have a pivotal regulatory role in pulmonary fibrosis. The origins and characteristics of macrophages in the lung and their role in regulating lung homeostasis, repair, and fibrosis are reviewed herein. We discuss recent studies that have employed single-cell RNA-sequencing to improve the identification and characterization of macrophage populations in the context of homeostatic and fibrotic conditions. We also discuss the current understanding of the macrophage-mediated mechanisms underlying the initiation and progression of pulmonary fibrosis, with a focus on the phenotypic and functional changes that aging macrophages acquire and how these changes ultimately contribute to age-related chronic lung diseases.
Collapse
Affiliation(s)
- Yago A P Jannini-Sá
- Women's Guild Lung Institute, Division of Pulmonary & Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Brecht Creyns
- Women's Guild Lung Institute, Division of Pulmonary & Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Cory M Hogaboam
- Women's Guild Lung Institute, Division of Pulmonary & Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - William C Parks
- Women's Guild Lung Institute, Division of Pulmonary & Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Miriam S Hohmann
- Women's Guild Lung Institute, Division of Pulmonary & Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| |
Collapse
|
|
3
|
Lu K, Wu YM, Shi Q, Gong YQ, Zhang T, Li C. The impact of acute-phase reaction on mortality and re-fracture after zoledronic acid in hospitalized elderly osteoporotic fracture patients. Osteoporos Int 2023; 34:1613-1623. [PMID: 37247006 DOI: 10.1007/s00198-023-06803-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/18/2023] [Indexed: 05/30/2023]
Abstract
This study involving 674 elderly osteoporotic fracture (OPF) patients undergoing orthopedic surgery investigated the long-term outcomes of acute phase reaction (APR) after initial zoledronic acid (ZOL). Those who had an APR had a 97% higher risk of mortality and a 73% lower rate of re-fracture than patients who did not. INTRODUCTION Annual infusion of ZOL efficiently decreases the risk of fracture. A temporary APR, consisting of flu-like symptoms, myalgia, and fever, is frequently observed within 3 days after the first dose. This work aimed to identify whether the occurrence of APR after initial ZOL infusion is a reliable indicator of drug efficacy for mortality and re-fracture in elderly OPF patients undergoing orthopedic surgery. METHODS This retrospectively observed work was constructed on a database prospectively collected from the Osteoporotic Fracture Registry System of a tertiary level A hospital in China. Six hundred seventy-four patients 50 years old or older with newly identified hip/morphological vertebral OPF who received ZOL for the first time after orthopedic surgery were included in the final analysis. APR was identified as a maximum axillary body temperature greater than 37.3 °C for the first 3 days after ZOL infusion. We utilized models of multivariate Cox proportional hazards to compare the risk of all-cause mortality in OPF patients with APR (APR+) and without APR (APR-). Competing risks regression analysis was used to examine the association between the occurrence of APR and re-fracture when mortality was taken into account. RESULTS In a fully adjusted Cox proportional hazards model, APR+ patients had a significantly higher risk of death than APR- patients with a hazard ratio [HR] 1.97 (95% CI, 1.09-3.56; P-value = 0.02). Furthermore, in an adjusted competing risk regression analysis, APR+ patients had a significantly reduced risk of re-fracture compared with APR- patients with a sub-distribution HR, 0.27 (95% CI, 0.11-0.70; P-value = 0.007). CONCLUSIONS Our findings suggested a potential association between the occurrence of APR and increased mortality risk. An initial dose of ZOL following orthopedic surgery was found to be protective against re-fracture in older patients with OPFs.
Collapse
Affiliation(s)
- K Lu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, No. 566 East of Qianjin Road, Suzhou, 215300, Jiangsu, China
| | - Y-M Wu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, No. 566 East of Qianjin Road, Suzhou, 215300, Jiangsu, China
| | - Q Shi
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute of Soochow University, Suzhou, Jiangsu, China
| | - Y-Q Gong
- Information Department, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, China
| | - T Zhang
- Chronic Disease Department, Kunshan Center For Disease Control and Prevention, Suzhou, Jiangsu, China
| | - C Li
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, No. 566 East of Qianjin Road, Suzhou, 215300, Jiangsu, China.
| |
Collapse
|
|
4
|
Kumar N, Saraber P, Ding Z, Kusumbe AP. Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases. Front Immunol 2021; 12:798211. [PMID: 34975909 PMCID: PMC8718446 DOI: 10.3389/fimmu.2021.798211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/19/2021] [Indexed: 12/29/2022] Open
Abstract
The bones and joints in the skeletal system are composed of diverse cell types, including vascular niches, bone cells, connective tissue cells and mineral deposits and regulate whole-body homeostasis. The capacity of maintaining strength and generation of blood lineages lies within the skeletal system. Bone harbours blood and immune cells and their progenitors, and vascular cells provide several immune cell type niches. Blood vessels in bone are phenotypically and functionally diverse, with distinct capillary subtypes exhibiting striking changes with age. The bone vasculature has a special impact on osteogenesis and haematopoiesis, and dysregulation of the vasculature is associated with diverse blood and bone diseases. Ageing is associated with perturbed haematopoiesis, loss of osteogenesis, increased adipogenesis and diminished immune response and immune cell production. Endothelial and perivascular cells impact immune cell production and play a crucial role during inflammation. Here, we discuss normal and maladapted vascular niches in bone during development, homeostasis, ageing and bone diseases such as rheumatoid arthritis and osteoarthritis. Further, we discuss the role of vascular niches during bone malignancy.
Collapse
Affiliation(s)
| | | | | | - Anjali P. Kusumbe
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Tissue and Tumor Microenvironments Group, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
5
|
Marrow failure and aging: The role of "Inflammaging". Best Pract Res Clin Haematol 2021; 34:101283. [PMID: 34404535 DOI: 10.1016/j.beha.2021.101283] [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] [Received: 06/13/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023]
Abstract
Despite aging and the enormous cellular output required of the marrow every day of the lifespan, most aged patients do not suffer significant marrow failure or cytopenias, an attestation to the proliferative capacity of this system. However, as marrow and its hematopoietic stem cells age, a reduction in ability to maintain homeostasis after stress or with exposure to prolonged chronic inflammation, so-called "inflammaging," may contribute to cytopenias, inadequate immune responses, and dysplasia/leukemia. In some instances, these changes may be intrinsic to the stem cell but in others, there may be extrinsic environmental influences. In this review, the role of aging as it relates to stem cell changes, immune function, and anemia are reviewed.
Collapse
|
|
6
|
Quantitative analysis of dysautonomia in patients with autonomic dysreflexia. J Neurol 2021; 268:2985-2994. [PMID: 33634338 DOI: 10.1007/s00415-021-10478-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 10/22/2022]
Abstract
Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.
Collapse
|
|
7
|
Stucker S, Chen J, Watt FE, Kusumbe AP. Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases. Front Cell Dev Biol 2020; 8:602269. [PMID: 33324652 PMCID: PMC7726257 DOI: 10.3389/fcell.2020.602269] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/05/2020] [Indexed: 02/05/2023] Open
Abstract
The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.
Collapse
Affiliation(s)
- Sina Stucker
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Junyu Chen
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fiona E. Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Anjali P. Kusumbe
- Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
8
|
Hormaechea-Agulla D, Le DT, King KY. Common Sources of Inflammation and Their Impact on Hematopoietic Stem Cell Biology. CURRENT STEM CELL REPORTS 2020; 6:96-107. [PMID: 32837857 PMCID: PMC7429415 DOI: 10.1007/s40778-020-00177-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Inflammatory signals have emerged as critical regulators of hematopoietic stem cell (HSC) function. Specifically, HSCs are highly responsive to acute changes in systemic inflammation and this influences not only their division rate but also their lineage fate. Identifying how inflammation regulates HSCs and shapes the blood system is crucial to understanding the mechanisms underpinning these processes, as well as potential links between them. Recent Findings A widening array of physiologic and pathologic processes involving heightened inflammation are now recognized to critically affect HSC biology and blood lineage production. Conditions documented to affect HSC function include not only acute and chronic infections but also autoinflammatory conditions, irradiation injury, and physiologic states such as aging and obesity. Summary Recognizing the contexts during which inflammation affects primitive hematopoiesis is essential to improving our understanding of HSC biology and informing new therapeutic interventions against maladaptive hematopoiesis that occurs during inflammatory diseases, infections, and cancer-related disorders.
Collapse
Affiliation(s)
- Daniel Hormaechea-Agulla
- Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - Duy T. Le
- Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
- Program in Immunology, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX USA
| | - Katherine Y. King
- Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
- Program in Immunology, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX USA
| |
Collapse
|
|
9
|
Marcos-Pérez D, Sánchez-Flores M, Proietti S, Bonassi S, Costa S, Teixeira JP, Fernández-Tajes J, Pásaro E, Laffon B, Valdiglesias V. Association of inflammatory mediators with frailty status in older adults: results from a systematic review and meta-analysis. GeroScience 2020; 42:1451-1473. [PMID: 32803650 DOI: 10.1007/s11357-020-00247-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/30/2020] [Indexed: 10/23/2022] Open
Abstract
Frailty is a geriatric syndrome defined as a status of extreme vulnerability to stressors, leading to a higher risk of negative health-related outcomes. "Inflammaging", an age-related state of low-grade chronic inflammation, is characterized by an increased concentration of pro-inflammatory cytokines and acute phase proteins. Inflammaging has been postulated as an underlying mechanism of frailty, and several studies tested the relationship between frailty and concentration of inflammatory mediators. The aim of this systematic review and meta-analysis was to test whether inflammatory mediators are overproduced in frail older adults. Among the 758 articles identified in the literature search, 50 were included in the systematic review, and 39 in the three meta-analyses, i.e., C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor α. To reduce heterogeneity, meta-analyses were restricted to studies identifying frailty by the Fried et al. [1] [J. Gerontol. A. Biol. Sci. Med. Sci. 56, M146-56] phenotypic criteria. Quantitative analyses measuring the association between frailty and biomarker concentrations showed significant differences when frail subjects were compared to non-frail and pre-frail subjects for CRP and IL6. This work established strong association between inflammatory biomarkers and frailty, confirming the role of age-related chronic inflammation in frailty development.
Collapse
Affiliation(s)
- Diego Marcos-Pérez
- Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología, Facultad de Ciencias de la Educación, Campus Elviña s/n, 15071, A Coruña, Spain.,Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC, Oza, 15071, A Coruña, Spain
| | - María Sánchez-Flores
- Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología, Facultad de Ciencias de la Educación, Campus Elviña s/n, 15071, A Coruña, Spain.,Environmental Health Department, National Health Institute, Rua Alexandre Herculano 321, 4000-055, Porto, Portugal.,EPIUnit -Instituto de Saúde Pública, Universidade do Porto, Rua das Taipas, no 135, 4050-600, Porto, Portugal
| | - Stefania Proietti
- Scientific Direction, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy
| | - Stefano Bonassi
- Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166, Rome, Italy.,Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Via di Val Cannuta, 247, 00166, Rome, Italy
| | - Solange Costa
- Environmental Health Department, National Health Institute, Rua Alexandre Herculano 321, 4000-055, Porto, Portugal.,EPIUnit -Instituto de Saúde Pública, Universidade do Porto, Rua das Taipas, no 135, 4050-600, Porto, Portugal
| | - Joao Paulo Teixeira
- Environmental Health Department, National Health Institute, Rua Alexandre Herculano 321, 4000-055, Porto, Portugal.,EPIUnit -Instituto de Saúde Pública, Universidade do Porto, Rua das Taipas, no 135, 4050-600, Porto, Portugal
| | - Juan Fernández-Tajes
- Wellcome Centre for Human Genetics, McCarthy's group, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.,Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12, SE-214 28, Malmö, Sweden
| | - Eduardo Pásaro
- Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología, Facultad de Ciencias de la Educación, Campus Elviña s/n, 15071, A Coruña, Spain.,Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC, Oza, 15071, A Coruña, Spain
| | - Blanca Laffon
- Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología, Facultad de Ciencias de la Educación, Campus Elviña s/n, 15071, A Coruña, Spain. .,Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC, Oza, 15071, A Coruña, Spain.
| | - Vanessa Valdiglesias
- Instituto de Investigación Biomédica de A Coruña (INIBIC), AE CICA-INIBIC, Oza, 15071, A Coruña, Spain.,EPIUnit -Instituto de Saúde Pública, Universidade do Porto, Rua das Taipas, no 135, 4050-600, Porto, Portugal.,Universidade da Coruña, Grupo DICOMOSA, Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Biología, Facultad de Ciencias, Campus A Zapateira s/n, 15071, A Coruña, Spain
| |
Collapse
|
|
10
|
Abe K, Chiba Y, Hattori S, Tamazawa A, Yoshimi A, Katsuse O, Suda A. Influence of plasma cytokine levels on the conversion risk from MCI to dementia in the Alzheimer's disease neuroimaging initiative database. J Neurol Sci 2020; 414:116829. [PMID: 32289574 DOI: 10.1016/j.jns.2020.116829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 01/29/2023]
Affiliation(s)
- Kie Abe
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan
| | - Yuhei Chiba
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan.
| | - Saki Hattori
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan
| | | | - Asuka Yoshimi
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan
| | - Omi Katsuse
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan
| | - Akira Suda
- Yokohama City University, School of Medicine, Department of Psychiatry, Japan
| | | |
Collapse
|
|
11
|
Hematopoietic Stem and Progenitor Cell (HSPC) Mobilization Responses to Different Exercise Intensities in Young and Older Adults. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/s42978-019-00050-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
|
|
12
|
Irons DL, Meinhardt T, Allers C, Kuroda MJ, Kim WK. Overexpression and activation of colony-stimulating factor 1 receptor in the SIV/macaque model of HIV infection and neuroHIV. Brain Pathol 2019; 29:826-836. [PMID: 31033097 DOI: 10.1111/bpa.12731] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 04/19/2019] [Indexed: 01/09/2023] Open
Abstract
In the present study, we investigated whether colony-stimulating factor 1 receptor (CSF1R) is expressed on brain macrophages and microglia in the human and macaque brain and whether it is upregulated and activated after lentivirus infection in vivo and contributes to development of encephalitic lesions. We examined, using multi-label and semi-quantitative immunofluorescence microscopy, the protein expression level and cellular localization of CSF1R in brain tissues from uninfected controls and SIV-infected adult macaques with or without encephalitis and also from uninfected controls, HIV-infected encephalitic subjects and virally suppressed subjects. In the normal uninfected brain, CSF1R protein was detected only on microglia and brain macrophages but not on neurons, astrocytes or oligodendrocytes. Microglia constitutively expressed CSF1R at low levels, and its expression was largely unchanged in non-encephalitic and encephalitic animals. Brain macrophages, including perivascular macrophages (PVMs), expressed higher levels of CSF1R compared to microglia. Interestingly, we found significantly increased expression of CSF1R on the infected PVMs and lesional macrophages in the brains of encephalitic macaques. Moreover, the per cell expression of CSF1R determined by its mean pixel intensity (MPI) correlated positively with the MPI of SIV Gag p28 in SIV-infected PVMs. Using phosphorylated CSF1R at tyrosine residue 723 and phosphorylated signal transducer and activator of transcription 5 at tyrosine reside 694 as markers for CSF1R activation, we found selective activation of CSF1R signaling in infected brain macrophages in encephalitis. We also found colocalization of CSF1R and its ligand CSF1 in PVMs and lesional macrophages in the brains of encephalitic macaques and humans. Notably, elevated brain CSF1R expression was found in virally suppressed subjects. These findings point to opportunities for developing a specific approach targeting infected brain macrophages, with several brain-penetrant CSF1R inhibitors that are available now, in order to eliminate central nervous system macrophage reservoirs, while not affecting resting uninfected microglia and PVMs that show no CSF1R activation.
Collapse
Affiliation(s)
- Derek L Irons
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA
| | - Timothy Meinhardt
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA
| | - Carolina Allers
- The Division of Immunology, Tulane National Primate Research Center, Covington, LA
| | - Marcelo J Kuroda
- The Division of Immunology, Tulane National Primate Research Center, Covington, LA
| | - Woong-Ki Kim
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA
| |
Collapse
|
|
13
|
Denstaedt SJ, Singer BH, Standiford TJ. Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation. Front Immunol 2018; 9:2446. [PMID: 30459764 PMCID: PMC6232897 DOI: 10.3389/fimmu.2018.02446] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/03/2018] [Indexed: 12/16/2022] Open
Abstract
Sepsis is a leading cause of death worldwide. After initial trials modulating the hyperinflammatory phase of sepsis failed, generations of researchers have focused on evaluating hypo-inflammatory immune phenotypes. The main goal has been to develop prognostic biomarkers and therapies to reduce organ dysfunction, nosocomial infection, and death. The depressed host defense in sepsis has been characterized by broad cellular reprogramming including lymphocyte exhaustion, apoptosis, and depressed cytokine responses. Despite major advances in this field, our understanding of the dynamics of the septic host response and the balance of inflammatory and anti-inflammatory cellular programs remains limited. This review aims to summarize the epidemiology of nosocomial infections and characteristic immune responses associated with sepsis, as well as immunostimulatory therapies currently under clinical investigation.
Collapse
Affiliation(s)
| | | | - Theodore J. Standiford
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| |
Collapse
|
|
14
|
Chang H, Wang X, Yang S. miR-350-3p Contributes to Age-Associated Impairment of IL-6 Production by Macrophages. Immunol Invest 2018; 47:790-800. [PMID: 30260716 DOI: 10.1080/08820139.2018.1508227] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aging-associated dysfunction of the immune system contributes to the increase in pathophysiological processes that occur with age. Numerous studies have shown that microRNAs regulate immune responses, although their role in age-related macrophage dysfunction remains elusive. Here, we found that miR-350-3p is expressed at lower levels in peritoneal macrophages from aged mice compared with young mice, and that lipopolysaccharide (LPS) stimulation downregulates miR-350-3p expression to a greater extent in young macrophages compared with aged macrophages. Consequently, LPS-stimulated aged macrophages express more miR-350-3p than do similarly treated young macrophages. Luciferase reporter assays showed that interleukin (IL)-6 mRNA is a miR-350-3p target in macrophages. Furthermore, although LPS induces less IL-6 production by aged macrophages than by young macrophages, the aged cell response is rescued by production miR-350-3p inhibition. These findings suggest that miR-350-3p may contribute to age-related impairment of macrophage function and could be a novel target for the treatment of age-related inflammatory diseases.
Collapse
Affiliation(s)
- Huiying Chang
- a Department of Cardiology , The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University , Harbin , P.R. China
| | - Xu Wang
- a Department of Cardiology , The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University , Harbin , P.R. China
| | - Shusen Yang
- a Department of Cardiology , The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University , Harbin , P.R. China
| |
Collapse
|
|
15
|
Lira-Junior R, Åkerman S, Gustafsson A, Klinge B, Boström EA. Colony stimulating factor-1 in saliva in relation to age, smoking, and oral and systemic diseases. Sci Rep 2017; 7:7280. [PMID: 28779164 PMCID: PMC5544729 DOI: 10.1038/s41598-017-07698-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 07/03/2017] [Indexed: 12/17/2022] Open
Abstract
Colony stimulating factor (CSF)-1 is a growth factor that stimulates the survival, proliferation and differentiation of mononuclear phagocytes, which has been implicated in several inflammatory diseases. This study evaluated the possible influence of age, sex, smoking, periodontitis, caries, and several systemic conditions on salivary levels of CSF-1. Four-hundred and forty-one individuals were enrolled in this study. All participants answered a health questionnaire and underwent a comprehensive oral examination. Stimulated saliva was collected and CSF-1 levels were analysed by enzyme-linked immunosorbent assay. Salivary levels of CSF-1 were significantly increased in participants over 64 years old and in non-smoking individuals, whereas no difference was observed between men and women. Individuals having periodontitis and manifest caries had significantly higher levels of CSF-1. Participants with muscle and joint disease exhibited increased CSF-1 levels as compared to those without. Age, smoking, percentage of pockets ≥4 mm, number of manifest caries lesions, and presence of tumor were associated with CSF-1 levels. Salivary levels of CSF-1 are associated with age, smoking, periodontitis, manifest caries, and the presence of muscle and joint diseases and tumors. CSF-1 might be a promising biomarker candidate in saliva of both local and systemic conditions that needs further investigation.
Collapse
Affiliation(s)
- Ronaldo Lira-Junior
- Karolinska Institutet, Department of Dental Medicine, Division of Periodontology, Stockholm, Sweden
- Rio de Janeiro State University, Faculty of Odontology, Department of Periodontology, Rio de Janeiro, Brazil
| | - Sigvard Åkerman
- Malmö University, Faculty of Odontology, Department of Orofacial Pain and Jaw Function, Malmö, Sweden
| | - Anders Gustafsson
- Karolinska Institutet, Department of Dental Medicine, Division of Periodontology, Stockholm, Sweden
| | - Björn Klinge
- Karolinska Institutet, Department of Dental Medicine, Division of Periodontology, Stockholm, Sweden
- Malmö University, Faculty of Odontology, Department of Periodontology, Malmö, Sweden
| | - Elisabeth A Boström
- Karolinska Institutet, Department of Dental Medicine, Division of Periodontology, Stockholm, Sweden.
| |
Collapse
|
|
16
|
The association between etanercept serum concentration and psoriasis severity is highly age-dependent. Clin Sci (Lond) 2017; 131:1179-1189. [PMID: 28420676 DOI: 10.1042/cs20170048] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 04/07/2017] [Accepted: 04/18/2017] [Indexed: 12/13/2022]
Abstract
The association between etanercept serum concentration and psoriasis disease severity is poorly investigated, and currently etanercept serum concentration monitoring that is aiming to optimize the psoriasis treatment lacks evidence. In this prospective study, we investigated the relation between etanercept exposure and disease severity via measuring etanercept concentrations at five consecutive time points in 56 psoriasis patients. Disease severity assessments included the Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Physician Global Assessment (PGA), and etanercept and anti-etanercept antibody concentrations were determined every 3 months for a period of 1 year. The present study demonstrated that the association between etanercept concentration and psoriasis severity is age-dependent: when patients were stratified into three groups, patients in the youngest age group (-50 years) showed a lower PASI at a higher etanercept concentration (β = -0.26), whereas patients in the oldest age group (+59 years) showed the opposite trend (β =0.22). Similar age effects were observed in the relation of etanercept concentration with BSA (P=0.02) and PGA (P=0.02). The influence of age and length of time in therapy on the etanercept concentration-disease severity relation was unaffected by body mass index (BMI) or any other possible confounder. Incidence of anti-etanercept antibodies was low (2%). The age-dependent relation between etanercept serum concentrations is both unexpected and intriguing and needs further investigation.
Collapse
|
|
17
|
Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front Immunol 2016; 7:502. [PMID: 27895645 PMCID: PMC5107568 DOI: 10.3389/fimmu.2016.00502] [Citation(s) in RCA: 259] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/27/2016] [Indexed: 12/19/2022] Open
Abstract
All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis.
Collapse
Affiliation(s)
- Larisa V Kovtonyuk
- Division of Hematology, University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Kristin Fritsch
- Division of Hematology, University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Xiaomin Feng
- International Research Center for Medical Sciences , Kumamoto , Japan
| | - Markus G Manz
- Division of Hematology, University Hospital Zurich, University of Zurich , Zurich , Switzerland
| | - Hitoshi Takizawa
- International Research Center for Medical Sciences , Kumamoto , Japan
| |
Collapse
|
|
18
|
Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. ANNALS OF TRANSLATIONAL MEDICINE 2015. [PMID: 26207229 DOI: 10.3978/j.issn.2305-5839.2015.03.49] [Citation(s) in RCA: 538] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles. However, increasing evidences demonstrated that neuroinflammatory changes, including chronic microgliosis are key pathological components of AD. Microglia, the resident immune cells of the brain, is constantly survey the microenvironment under physiological conditions. In AD, deposition of β-amyliod (Aβ) peptide initiates a spectrum of cerebral neuroinflammation mediated by activating microglia. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Emerging studies have demonstrated that up-regulation of pro-inflammatory cytokines play multiple roles in both neurodegeneration and neuroprotection. Understanding the pro-inflammatory cytokines signaling pathways involved in the regulation of AD is crucial to the development of strategies for therapy. This review will discuss the mechanisms and important role of pro-inflammatory cytokines in the pathogenesis of AD, and the ongoing drug targeting pro-inflammatory cytokine for therapeutic modulation.
Collapse
Affiliation(s)
- Wen-Ying Wang
- 1 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China ; 2 Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266071, China ; 3 Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Meng-Shan Tan
- 1 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China ; 2 Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266071, China ; 3 Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Jin-Tai Yu
- 1 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China ; 2 Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266071, China ; 3 Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Lan Tan
- 1 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China ; 2 Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266071, China ; 3 Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing 210006, China
| |
Collapse
|
|
19
|
Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol Neurobiol 2014; 50:534-44. [PMID: 24567119 PMCID: PMC4182618 DOI: 10.1007/s12035-014-8657-1] [Citation(s) in RCA: 339] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 02/04/2014] [Indexed: 12/23/2022]
Abstract
This article gives a comprehensive overview of cytokine and other inflammation associated protein levels in plasma, serum and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). We reviewed 118 research articles published between 1989 and 2013 to compare the reported levels of 66 cytokines and other proteins related to regulation and signaling in inflammation in the blood or CSF obtained from MCI and AD patients. Several cytokines are evidently regulated in (neuro-) inflammatory processes associated with neurodegenerative disorders. Others do not display changes in the blood or CSF during disease progression. However, many reports on cytokine levels in MCI or AD are controversial or inconclusive, particularly those which provide data on frequently investigated cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). The levels of several cytokines are possible indicators of neuroinflammation in AD. Some of them might increase steadily during disease progression or temporarily at the time of MCI to AD conversion. Furthermore, elevated body fluid cytokine levels may correlate with an increased risk of conversion from MCI to AD. Yet, research results are conflicting. To overcome interindividual variances and to obtain a more definite description of cytokine regulation and function in neurodegeneration, a high degree of methodical standardization and patients collective characterization, together with longitudinal sampling over years is essential.
Collapse
|
|
20
|
Combined in silico, in vivo, and in vitro studies shed insights into the acute inflammatory response in middle-aged mice. PLoS One 2013; 8:e67419. [PMID: 23844008 PMCID: PMC3699569 DOI: 10.1371/journal.pone.0067419] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 05/17/2013] [Indexed: 11/19/2022] Open
Abstract
We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2−/NO3− data from “middle-aged” (6–8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for “young” (2–3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging.
Collapse
|
|
21
|
Pirrone V, Libon DJ, Sell C, Lerner CA, Nonnemacher MR, Wigdahl B. Impact of age on markers of HIV-1 disease. Future Virol 2013; 8:81-101. [PMID: 23596462 PMCID: PMC3625689 DOI: 10.2217/fvl.12.127] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Aging is a complicated process characterized by a progressive loss of homeostasis, which results in an increased vulnerability to multiple diseases. HIV-1-infected patients demonstrate a premature aging phenotype and develop certain age-related diseases earlier in their lifespan than what is seen in the general population. Age-related comorbidities may include the development of bone disease, metabolic disorders, neurologic impairment and immunosenescence. Age also appears to have an effect on traditional markers of HIV-1 disease progression, including CD4+ T-cell count and viral load. These effects are not only a consequence of HIV-1 infection, but in many cases, are also linked to antiretroviral therapy. This review summarizes the complex interplay between HIV-1 infection and aging, and the impact that aging has on markers of HIV-1 disease.
Collapse
Affiliation(s)
- Vanessa Pirrone
- Department of Microbiology & Immunology, Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
- Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
| | - David J Libon
- Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Christian Sell
- Department of Pathology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Chad A Lerner
- Department of Pathology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
| | - Michael R Nonnemacher
- Department of Microbiology & Immunology, Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
- Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
| | - Brian Wigdahl
- Department of Microbiology & Immunology, Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
- Drexel University College of Medicine, 245 N 15th Street, New College Building, Philadelphia, PA 19102, USA
| |
Collapse
|
|
22
|
Hearps AC, Angelovich TA, Jaworowski A, Mills J, Landay AL, Crowe SM. HIV infection and aging of the innate immune system. Sex Health 2012; 8:453-64. [PMID: 22127030 DOI: 10.1071/sh11028] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 06/05/2011] [Indexed: 12/17/2022]
Abstract
The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.
Collapse
Affiliation(s)
- Anna C Hearps
- Burnet Institute for Medical Research and Public Health, Melbourne, Australia
| | | | | | | | | | | |
Collapse
|
|
23
|
Humpel C, Hochstrasser T. Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease. World J Psychiatry 2011; 1:8-18. [PMID: 24175162 PMCID: PMC3782169 DOI: 10.5498/wjp.v1.i1.8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 10/14/2011] [Accepted: 12/26/2011] [Indexed: 02/05/2023] Open
Abstract
Due to an ever aging society and growing prevalence of Alzheimer’s disease (AD), the challenge to meet social and health care system needs will become increasingly difficult. Unfortunately, a definite ante mortem diagnosis is not possible. Thus, an early diagnosis and identification of AD patients is critical for promising, early pharmacological interventions as well as addressing health care needs. The most advanced and most reliable markers are β-amyloid, total tau and phosphorylated tau in cerebrospinal fluid (CSF). In blood, no single biomarker has been identified despite an intense search over the last decade. The most promising approaches consist of a combination of several blood-based markers increasing the reliability, sensitivity and specificity of the AD diagnosis. However, contradictory data make standardized testing methods in longitudinal and multi-center studies extremely difficult. In this review, we summarize a range of the most promising CSF and blood biomarkers for diagnosing AD.
Collapse
Affiliation(s)
- Christian Humpel
- Christian Humpel, Tanja Hochstrasser, Laboratory for Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry and Psychotherapy, Innsbruck Medical University, 6020 Innsbruck, Austria
| | | |
Collapse
|
|
24
|
Cui Z, Zhao MH. In Reply to ‘The Influence of Age on the Clinical Features and Outcomes of Anti–Glomerular Basement Membrane Disease’. Am J Kidney Dis 2011. [DOI: 10.1053/j.ajkd.2011.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
|
|
25
|
Kim SM, Song J, Kim S, Han C, Park MH, Koh Y, Jo SA, Kim YY. Identification of peripheral inflammatory markers between normal control and Alzheimer's disease. BMC Neurol 2011; 11:51. [PMID: 21569380 PMCID: PMC3120663 DOI: 10.1186/1471-2377-11-51] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 05/12/2011] [Indexed: 12/16/2022] Open
Abstract
Background Multiple pathogenic factors may contribute to the pathophysiology of Alzheimer's disease (AD). Peripheral blood markers have been used to assess biochemical changes associated with AD and mild cognitive impairment (MCI) and involved in their pathophysiology. Methods Plasma samples and clinical data were obtained from participants in the Ansan Geriatric Study (AGE study). Plasma concentrations of four candidate biomarkers were measured in the normal control (NC), MCI, and AD group: interleukin-8 (IL-8), IL-10, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). Body mass index (BMI), MMSE (Mini Mental State Examination), CDR(Clinical Dementia Rating) score and homocystein level were recorded with social and demographic information. Results Total of 59 subjects were randomly selected for this analysis [NC (n = 21), MCI(n = 20) and AD(n = 18)]. In demographic data, educational year was correlated with the diagnosis states (p < 0.0001). No significant differences in cardiovascular disease, BMI and use of NSAIDs were found in MCI or AD group compared with NC group, respectively. The involvement of inflammatory illness or conditions in subjects, WBC count, fibrinogen and homocystein of the three groups, but no significant differences were found in each groups. The plasma IL-8 level was lower in MCI and AD patients compared with the normal control group (respectively, p < 0.0001). The MCI and AD patients had similar MCP-1, IL-10, and TNF-α level. Conclusions Our study suggests the existence of an independent and negative relationship between plasma IL-8 levels and functional status in MCI and AD patients.
Collapse
Affiliation(s)
- Sam-Moon Kim
- Center for Biomedical Science, Division of Brain Diseases, National Institute of Health in Korea (KNIH), Osong Health Technology Administration Complex 643 Yeonje-ri, Gangoe-myeon, Chungcheongbuk-do, 363-951, Republic of Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Jia S, Kaldunski M, Jailwala P, Geoffrey R, Kramer J, Wang X, Hessner MJ. Use of transcriptional signatures induced in lymphoid and myeloid cell lines as an inflammatory biomarker in Type 1 diabetes. Physiol Genomics 2011; 43:697-709. [PMID: 21406607 DOI: 10.1152/physiolgenomics.00235.2010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Inflammation is common to many disorders and responsible for tissue and organ damage. In many disorders, the associated peripheral cytokine milieu is dilute and difficult to measure, necessitating development of more sensitive and informative biomarkers for mechanistic studies, earlier diagnosis, and monitoring therapeutic interventions. Previously, we have shown that plasma of recent-onset (RO) Type 1 diabetes patients induces a disease-specific proinflammatory transcriptional profile in fresh peripheral blood mononuclear cells (PBMC) compared with that of healthy controls (HC). To eliminate assay variance introduced through the use of multiple donors or multiple draws of the same person over time, we evaluated human leukemia cell lines as potential surrogates for fresh PBMC. We 1) tested seven different cell lines in their power to differentiate RO from HC plasma and 2) compared the similarity of the signatures generated across the seven cell lines to that obtained with fresh PBMC. While each cell line tested exhibited a distinct transcriptional response when cultured with RO or HC plasma, the expression profile induced in any single cell line shared little identity with that of the other cell lines or fresh PBMC. In terms of regulated biological pathways, the transcriptional response of each cell line shared varying degrees of functional identity with fresh PBMC. These results indicate that use of human leukemia cell lines as surrogates for fresh PBMC has potential in detecting perturbations to the peripheral cytokine milieu. However, the response of each is distinct, possessing varying degrees of functional relatedness to that observed with PBMC.
Collapse
Affiliation(s)
- Shuang Jia
- Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin, and The Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 2010; 68:930-41. [PMID: 20692646 DOI: 10.1016/j.biopsych.2010.06.012] [Citation(s) in RCA: 738] [Impact Index Per Article: 49.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Revised: 06/03/2010] [Accepted: 06/08/2010] [Indexed: 12/27/2022]
Abstract
BACKGROUND Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimer's disease (AD) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data. METHODS Original English language peer-reviewed studies measuring cytokine concentrations in AD and healthy control subjects were included. Mean (± standard deviation) cytokine concentrations for AD and control subjects were extracted. RESULTS Forty studies measuring peripheral blood cytokine concentrations and 14 measuring cerebrospinal fluid (CSF) cytokine concentrations were included. In peripheral blood, there were significantly higher concentrations (weighted mean difference [95% confidence interval]) of interleukin (IL)-6 (2.86 [1.68, 4.04] pg/mL, p < .00001, N[AD/control subjects] = 985/680, 14 studies), tumor necrosis factor (TNF)-α (3.25 [.76, 5.74] pg/mL, p = .01, N = 680/447, 14 studies), IL-1β (.55 [.32, .78] pg/mL, p < .00001, N = 574/370, 10 studies), transforming growth factor (TGF)-β (67.23 [28.62, 105.83] pg/mL, p = .0006, N = 190/158, 5 studies), IL-12 (7.60 [5.58, 9.62] pg/mL, p < .00001, N = 148/106, 5 studies), and IL-18 (15.82 [1.98, 29.66] pg/mL, p = .03, N = 131/94, 4 studies) but not of IL-4, IL-8, IL-10, interferon-γ, or C-reactive protein in AD subjects compared with control subjects. There were significantly higher concentrations of TGF-β (7.81 [2.27, 13.35] pg/mL, p =.006, N = 113/114, 5 studies) but not IL-6, TNF-α, and IL-1β in the CSF of AD subjects compared with control subjects. CONCLUSIONS These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β, IL-12 and IL-18 and higher CSF concentrations of TGF-β.
Collapse
Affiliation(s)
- Walter Swardfager
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | | | | |
Collapse
|
|
28
|
TNF-α in CRPS and 'normal' trauma--significant differences between tissue and serum. Pain 2010; 152:285-290. [PMID: 20947251 DOI: 10.1016/j.pain.2010.09.024] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 08/03/2010] [Accepted: 09/15/2010] [Indexed: 01/01/2023]
Abstract
Posttraumatic TNF-alpha signaling may be one of the factors responsible for pain and hyperalgesia in complex regional pain syndromes (CRPS). In order to further specify the role of TNF-alpha we investigated tissue (skin) and serum concentrations in three different patient groups: patients with osteoarthritis and planned surgery, with acute traumatic upper limb bone fracture waiting for surgery, and with CRPS I. Thirty patients (10 in each group) were recruited. Mean CRPS duration was 36.1 ± 8.1 weeks (range 8- 90 weeks). Skin punch biopsies were taken at the beginning of the surgery in osteoarthritis and fracture patients and from the affected side in CRPS patients. Blood samples were taken before the respective procedures. Skin and serum TNF-alpha levels were quantified by ELISA. Compared to patients with osteoarthritis, skin TNF-alpha was significantly elevated in CRPS (p<0.001) and fracture patients (p<0.04). Skin TNF-alpha in CRPS patients was higher than in patients with acute bone fracture (p<0.02). In contrast, serum TNF-alpha values were the same in osteoarthritis and CRPS, and lower in fracture patients (p<0.03). Our results indicate a local but not systemic increase of TNF-alpha in CRPS patients. This increase persists for months after limb trauma and may offer the opportunity for targeted treatment.
Collapse
|
|
29
|
Increased soluble TNF receptor 2 in antidepressant-free patients with late-life depression. J Psychiatr Res 2010; 44:917-20. [PMID: 20338581 DOI: 10.1016/j.jpsychires.2010.02.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Revised: 02/12/2010] [Accepted: 02/16/2010] [Indexed: 01/22/2023]
Abstract
Increased pro-inflammatory state has been implicated in the pathophysiology of major depressive disorder. The aim of this study was to determine serum levels of TNF-α and soluble TNF-α receptors 1 and 2 (sTNFR1 and sTNFR2) in anti-depressant free depressed elderly patients as compared to healthy controls. Sixty-seven older adults (28 with major depression and 39 controls) were enrolled to this study. Participants were assessed by the SCID and diagnosis of major depressive episode was made according to the DSM-IV criteria. Serum TNF-α, sTNFR1 and sTNFR2 were determined by ELISA. Anti-depressant free patients with late-life depression showed an increased level of the sTNFR2 as compared to controls (p = 0.03). No significant differences were found in serum TNF-α and sTNFR1 levels (p = 0.1 and p = 0.4, respectively). There was no correlation between serum levels of these inflammatory markers and the severity of depression. Our findings provide additional evidence of the involvement of abnormal pro-inflammatory state in late-life depression.
Collapse
|
|
30
|
Haberthur K, Engelman F, Barron A, Messaoudi I. Immune senescence in aged nonhuman primates. Exp Gerontol 2010; 45:655-61. [PMID: 20558288 PMCID: PMC2926233 DOI: 10.1016/j.exger.2010.06.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Revised: 05/27/2010] [Accepted: 06/03/2010] [Indexed: 12/22/2022]
Abstract
Aging is accompanied by a general dysregulation in immune system function, commonly referred to as 'immune senescence'. This progressive deterioration affects both innate and adaptive immunity, although accumulating evidence indicates that the adaptive arm of the immune system may exhibit more profound changes. Most of our current understanding of immune senescence stems from clinical and rodent studies. More recently, the use of nonhuman primates (NHPs) to investigate immune senescence and test interventions aimed at delaying/reversing age-related changes in immune function has dramatically increased. These studies have been greatly facilitated by several key advances in our understanding of the immune system of old world monkeys, specifically the rhesus macaques. In this review we describe the hallmarks of immune senescence in this species and compare them to those described in humans. We also discuss the impact of immune senescence on the response to vaccination and the efficacy of immuno-restorative interventions investigated in this model system.
Collapse
Affiliation(s)
- Kristen Haberthur
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Graduate Program in Molecular Microbiology and Immunology, Oregon Health and Science University
| | - Flora Engelman
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Division of Pathobiology and Immunology, Oregon National Primate Research Center
| | - Alex Barron
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Division of Pathobiology and Immunology, Oregon National Primate Research Center
| | - Ilhem Messaoudi
- Vaccine and Gene Therapy Institute, Oregon Health and Science University
- Graduate Program in Molecular Microbiology and Immunology, Oregon Health and Science University
- Division of Pathobiology and Immunology, Oregon National Primate Research Center
| |
Collapse
|
|
31
|
Agarwal S, Busse PJ. Innate and adaptive immunosenescence. Ann Allergy Asthma Immunol 2010; 104:183-90; quiz 190-2, 210. [PMID: 20377107 DOI: 10.1016/j.anai.2009.11.009] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To review the effect of increasing age on the immune system and some of its clinical implications. DATA SOURCES MEDLINE and PubMed searches were performed cross-referencing the keywords immunosenescence, aging, and immunity. Articles were reviewed for additional citations. STUDY SELECTION Articles were reviewed and selected based on relevance to subject matter. RESULTS The study of immunosenescence is complex and not completely understood. Aging affects both the innate and adaptive arms of the immune response. With increased age, there may be a decrease in phagocytosis, alteration of cellular migration, changes in cell populations and numbers, and a decreased ability to produce specific antibodies. Clinically, these changes potentially increase morbidity and mortality in elderly individuals through an increased rate of infections, malignancy, and autoimmunity. CONCLUSIONS The process of aging is accompanied by diverse changes in immunity. Several therapeutic approaches are under investigation, including cytokine therapy, hormonal replacement, antioxidant supplementation, and caloric restriction, to attenuate or potentially reverse immunosenescence.
Collapse
Affiliation(s)
- Shradha Agarwal
- Division of Clinical Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA
| | | |
Collapse
|
|
32
|
Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 2010; 207:1067-80. [PMID: 20439540 PMCID: PMC2867291 DOI: 10.1084/jem.20091419] [Citation(s) in RCA: 619] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2009] [Accepted: 04/01/2010] [Indexed: 12/25/2022] Open
Abstract
Proinflammatory cytokines have been shown to impair cognition; consequently, immune activity in the central nervous system was considered detrimental to cognitive function. Unexpectedly, however, T cells were recently shown to support learning and memory, though the underlying mechanism was unclear. We show that one of the steps in the cascade of T cell-based support of learning and memory takes place in the meningeal spaces. Performance of cognitive tasks led to accumulation of IL-4-producing T cells in the meninges. Depletion of T cells from meningeal spaces skewed meningeal myeloid cells toward a proinflammatory phenotype. T cell-derived IL-4 was critical, as IL-4(-/-) mice exhibited a skewed proinflammatory meningeal myeloid cell phenotype and cognitive deficits. Transplantation of IL-4(-/-) bone marrow into irradiated wild-type recipients also resulted in cognitive impairment and proinflammatory skew. Moreover, adoptive transfer of T cells from wild-type into IL-4(-/-) mice reversed cognitive impairment and attenuated the proinflammatory character of meningeal myeloid cells. Our results point to a critical role for T cell-derived IL-4 in the regulation of cognitive function through meningeal myeloid cell phenotype and brain-derived neurotrophic factor expression. These findings might lead to the development of new immune-based therapies for cognitive impairment associated with immune decline.
Collapse
Affiliation(s)
- Noël C. Derecki
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Amber N. Cardani
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Chun Hui Yang
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Kayla M. Quinnies
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Anastasia Crihfield
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Kevin R. Lynch
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| | - Jonathan Kipnis
- Department of Neuroscience and Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, Graduate Program in Neuroscience and Graduate Program in Immunology, University of Virginia, Charlottesville, VA 22908
| |
Collapse
|
|
33
|
Guinjoan SM, Vigo DE, Castro MN, Tateosian N, Chuluyan E, Costanzo E, Fahrer R, Grancelli H, Leiguarda R, Cardinali DP. Mood, Th-1/Th-2 cytokine profile, and autonomic activity in older adults with acute/decompensated heart failure: preliminary observations. World J Biol Psychiatry 2010; 10:913-8. [PMID: 18937152 DOI: 10.1080/15622970802432153] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
In order to assess the relationships among mood, peripheral autonomic output and circulating immunoinflammatory mediators in older individuals with decompensated heart failure (CHF), 20 consecutive patients (78+/-7 years, 35% women) admitted to the coronary care unit with a clinical diagnosis of acute/decompensated CHF of coronary origin were examined. Mood was evaluated by the 21-item Hamilton Depression Scale (HAM-D). Four patients met the criteria for major depression. Heart rate variability (HRV) analysis and the levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-4, IL-6 and IL-10 were measured within 24-72 h of admission. A significant positive relationship between score in HAM-D and serum IL-6 levels was detected with a similar trend as far as IL-2 levels. Circulating IL-2 levels were strongly associated with the HRV L/H quotient, an index of increased sympathetic and/or decreased parasympathetic thoracic activity. A negative correlation between vagal activity (as assessed by HRV) and IL-4 occurred. Neither TNF-alpha nor IL-10 were detectable in this group of elderly patients. The results add to the concept that mood and autonomic unbalance are associated with increased systemic inflammation in old patients with decompensated CHF, a potential mechanism for mood-related worsened prognosis of heart failure at an advanced age.
Collapse
Affiliation(s)
- Salvador M Guinjoan
- Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Buenos Aires, Argentina
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Craig-Schapiro R, Fagan AM, Holtzman DM. Biomarkers of Alzheimer's disease. Neurobiol Dis 2009; 35:128-40. [PMID: 19010417 PMCID: PMC2747727 DOI: 10.1016/j.nbd.2008.10.003] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 10/08/2008] [Accepted: 10/13/2008] [Indexed: 02/06/2023] Open
Abstract
Although a battery of neuropsychological tests is often used in making a clinical diagnosis of Alzheimer's disease (AD), definitive diagnosis still relies on pathological evaluation at autopsy. The identification of AD biomarkers may allow for a less invasive and more accurate diagnosis as well as serve as a predictor of future disease progression and treatment response. Importantly, biomarkers may also allow for the identification of individuals who are already developing the underlying pathology of AD such as plaques and tangles yet who are not yet demented, i.e. "preclinical" AD. Attempts to identify biomarkers have included fluid and imaging studies, with a number of candidate markers showing significant potential. More recently, better reagent availability and novel methods of assessment have further spurred the search for biomarkers of AD. This review will discuss promising fluid and imaging markers to date.
Collapse
Affiliation(s)
| | - Anne M. Fagan
- Dept. of Neurology, Washington University School of Medicine, St. Louis, MO 63110
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110
- Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110
| | - David M. Holtzman
- Dept. of Neurology, Washington University School of Medicine, St. Louis, MO 63110
- Dept. of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110
- Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110
| |
Collapse
|
|
35
|
Grassi-Oliveira R, Brietzke E, Pezzi JC, Lopes RP, Teixeira AL, Bauer ME. Increased soluble tumor necrosis factor-alpha receptors in patients with major depressive disorder. Psychiatry Clin Neurosci 2009; 63:202-8. [PMID: 19175760 DOI: 10.1111/j.1440-1819.2008.01918.x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM Several lines of evidence suggest that major depressive disorder is associated with an inflammatory status. Tumor necrosis factor-alpha has been investigated as a potential molecular target in mood disorders. Tumor necrosis factor-alpha exerts its activity through binding to specific cell membrane receptors named as TNFR1 and TNFR2. The aim of the present study was to investigate soluble plasma TNFR1 (sTNFR1) and TNFR2 levels (sTNFR2) in major depressive disorder patients. METHODS Female outpatients with major depressive disorder (n = 30) were compared with a healthy control group (n = 19). Severity of depressive symptoms was evaluated on Beck Depression Inventory; post-traumatic stress disorder (PTSD) symptoms were evaluated on PTSD Checklist-Civilian Version; and childhood abuse and neglect on the Childhood Trauma Questionnaire. Plasma tumor necrosis factor-alpha and its soluble receptors were measured by ELISA. RESULTS Patients had no changes in tumor necrosis factor-alpha concentrations but did have increased sTNFR1 (P < 0.001) and sTNFR2 (P < 0.001) levels compared to controls. Plasma level of sTNFR1 was positively predicted by age (B = 0.25, P = 0.05) and PTSD-like symptoms (B = 0.41, P = 0.002) and plasma levels of sTNFR2 by depression severity (B = 0.67, P < 0.001). CONCLUSIONS Soluble tumor necrosis factor-alpha receptors could be reliable markers of inflammatory activity in major depression.
Collapse
Affiliation(s)
- Rodrigo Grassi-Oliveira
- Postgraduate Program of Psychology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.
| | | | | | | | | | | |
Collapse
|
|
36
|
Paduch R, Niedziela P. TGF-β1 influence on TNF-α production and sTNF-Rs shedding in a coculture of colon carcinoma cell spheroids with normal cells. In Vitro Cell Dev Biol Anim 2009; 45:371-7. [DOI: 10.1007/s11626-009-9190-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Accepted: 02/12/2009] [Indexed: 11/28/2022]
|
|
37
|
Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S, Hansson O. Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging 2008; 31:1877-84. [PMID: 19070941 DOI: 10.1016/j.neurobiolaging.2008.10.012] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Revised: 10/09/2008] [Accepted: 10/24/2008] [Indexed: 12/31/2022]
Abstract
OBJECTIVE There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Aβ) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia. METHODS We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4-6 years with an incidence of Alzheimer's disease (AD) or vascular dementia (VaD) of 15% per year. RESULTS The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p<0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with β-site APP-cleaving enzyme 1 (BACE1) activity (r(s)=0.53-0.68, p<0.01) and Aβ 40 levels (r(s)=0.59-0.71, p<0.001). Similarly, both sTNFRs were associated with Aβ 40 (r(s)=0.39-0.46, p<0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r(s)=0.57-0.83, p<0.001). CONCLUSION TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism.
Collapse
Affiliation(s)
- Peder Buchhave
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sweden; Neuropsychiatric Clinic, Malmö University Hospital, Sweden
| | | | | | | | | | | |
Collapse
|
|
38
|
Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J. Inflammaging as a prodrome to Alzheimer's disease. J Neuroinflammation 2008; 5:51. [PMID: 19014446 PMCID: PMC2615427 DOI: 10.1186/1742-2094-5-51] [Citation(s) in RCA: 211] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2008] [Accepted: 11/11/2008] [Indexed: 12/13/2022] Open
Abstract
Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-γ and other pro-inflammatory cytokines interact with processing and production of Aβ peptide, the pathological hallmark feature of Alzheimer's disease (AD), suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1) human umbilical cord blood cells (HUCBC), (2) flavanoids, and (3) Aβ vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.
Collapse
Affiliation(s)
- Brian Giunta
- Neuroimmunology Laboratory, Department of Psychiatry, Behavioral Medicine, Institute for Research in Psychiatry, University of South Florida, College of Medicine, Tampa, FL 33613, USA.
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Denollet J, Vrints CJ, Conraads VM. Comparing Type D personality and older age as correlates of tumor necrosis factor-alpha dysregulation in chronic heart failure. Brain Behav Immun 2008; 22:736-43. [PMID: 18068948 DOI: 10.1016/j.bbi.2007.10.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Revised: 10/26/2007] [Accepted: 10/27/2007] [Indexed: 10/22/2022] Open
Abstract
Tumor necrosis factor-alpha (TNF-alpha) and its soluble receptors 1 (sTNFR1) and 2 (sTNFR2) have been shown to be implicated in the pathogenesis of chronic heart failure (CHF). Ageing is accompanied by increased plasma levels of pro-inflammatory cytokines. We hypothesized that Type D personality (joint tendency to experience negative emotions and to inhibit self-expression) and age may have similar pro-inflammatory effects in the context of CHF. Participants in this study were 130 consecutive outpatients with CHF (76% men); there were 70 relatively younger (<or=59 years) and 60 relatively older (>or=60 years) patients. They all completed the 14-item Type D Scale (DS14); 43 patients (33%) had a Type D personality. A multivariate model of cytokine levels indicated an independent overall effect of both older age [F(1,128)=9.11, p=.003] and Type D personality [F(1,128)=8.28, p=.005]. Stratifying patients in age/personality subgroups showed that younger non-Type D patients had the lowest and older Type D patients the highest sTNFR1 and sTNFR2 levels (986+/-318 vs 1661+/-1128 pg/ml and 1838+/-777 vs 2823+/-1439 pg/ml, p<.0001). Importantly, the mean sTNFR1 level in younger Type D patients (1359+/-660 pg/ml) was equivalent to that in older non-Type D patients (1360+/-440 pg/ml, p=.99) who were on average 18 years older. Younger Type D and older non-Type D patients also had similar sTNFR2 levels (2406+/-1329 vs 2448+/-812 pg/ml, p=.88). Only older Type D patients had a higher mean TNF-alpha level as compared to patients who were younger or who were not Type D (5.4+/-2.9 vs 3.9+/-2.4 pg/ml, p=.008). A logistic regression model including sex, severity of CHF, systolic heart failure and ischemic etiology indicated that the combined risk category of older age or Type D was independently associated with substantially increased sTNFR1 and sTNFR2 levels. Hence, Type D personality was associated with increased TNF-alpha activity. This disease-promoting effect of Type D matched the pro-inflammatory effect of ageing.
Collapse
Affiliation(s)
- Johan Denollet
- CoRPS-Centre of Research on Psychology in Somatic diseases, Department of Medical Psychology, Tilburg University, Tilburg, The Netherlands.
| | | | | |
Collapse
|
|
40
|
Sullivan DH, Roberson PK, Johnson LE, Mendiratta P, Bopp MM, Bishara O. Association between Inflammation-Associated Cytokines, Serum Albumins, and Mortality in the Elderly. J Am Med Dir Assoc 2007; 8:458-63. [PMID: 17845949 DOI: 10.1016/j.jamda.2007.04.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2007] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To investigate the association between serum albumin, prealbumin, various serum inflammation associated-cytokines, and mortality in older geriatric recuperative care patients. DESIGN A prospective cohort study. SETTING A geriatric rehabilitation unit of a university-affiliated Department of Veterans Affairs hospital. PARTICIPANTS Participants were 53 geriatric patients (mean age 78 +/- 7.3, 96% male) admitted to a Geriatric Evaluation and Management (GEM) unit. Patients with documented near-terminal medical disorder, overt infections, and any systemic or localized inflammatory disorders were excluded. MEASUREMENTS Inflammation-associated cytokines (IL-8, IL-1beta, IL-6, IL-10, TNF-alpha), albumin, prealbumin, and C-reactive protein were measured at hospital discharge and each subject was then tracked for 1 year. MAIN RESULTS By Cox Proportional-Hazards Regression analysis, the strongest predictor of mortality within 6 months of study entry was the serum IL-6. For each log increase in IL-6, there was nearly a 9-fold greater 6-month mortality risk (RR 8.99, 95% CI 1.65 to 49.03). The association between albumin and mortality was no longer significant after controlling for IL-6. There was a strong inverse correlation between IL-6 and both albumin (R2 0.39, P < .001) and prealbumin (R2 0.41, P < .001). CONCLUSION Subclinical inflammation appears to be an important factor contributing to low serum albumins in older recuperative care patients and may confound the association between albumin and mortality in this population. More in-depth studies of these associations are warranted.
Collapse
Affiliation(s)
- Dennis H Sullivan
- Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
| | | | | | | | | | | |
Collapse
|
|
41
|
Britschgi M, Wyss-Coray T. Systemic and acquired immune responses in Alzheimer's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2007; 82:205-33. [PMID: 17678963 DOI: 10.1016/s0074-7742(07)82011-3] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by a progressive cognitive decline and dementia. AD brains are marked by amyloid plaques and neurofibrillary tangles, neuronal cell loss, and a prominent activation of glial cells, and innate immune responses. A growing number of studies in AD have also reported alterations in systemic immune responses including changes in lymphocyte and macrophage distribution and activation, the presence of autoantibodies, or abnormal cytokine production. Studies in animal models for AD support the notion that immune cells infiltrate the brain and may modulate the disease. Here we will review evidence for systemic alterations in immune responses and a role for acquired immunity in AD and discuss their potential contribution to the disease.
Collapse
Affiliation(s)
- Markus Britschgi
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
| | | |
Collapse
|
|
42
|
O'Rourke RW, Kay T, Lyle EA, Traxler SA, Deveney CW, Jobe BA, Roberts CT, Marks D, Rosenbaum JT. Alterations in peripheral blood lymphocyte cytokine expression in obesity. Clin Exp Immunol 2006; 146:39-46. [PMID: 16968396 PMCID: PMC1809726 DOI: 10.1111/j.1365-2249.2006.03186.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Obesity is characterized by alterations in immune and inflammatory function. In order to evaluate the potential role of cytokine expression by peripheral blood mononuclear cells (PBMC) in obesity-associated inflammation, we studied serum protein levels and mRNA levels in PBMC of interleukin (IL)-6, IL-1beta, tumour necrosis factor (TNF)-alpha and IL-1Ra in nine lean and 10 obese subjects. Serum IL-1beta was undetectable, IL-1Ra serum levels were elevated, serum levels of TNF-alpha were decreased and serum levels of IL-6 were similar in obese subjects compared to lean subjects, while transcript levels of IL-6, IL-1beta and TNF-alpha, but not IL-1Ra, were decreased in PBMC from obese subjects. PBMC from obese subjects did, however, up-regulate cytokine expression in response to leptin. Thus, obesity-associated changes in IL-1Ra serum levels and IL-6 mRNA levels were not correlated with changes in cognate mRNA and serum levels, respectively, while TNF-alpha serum levels and PBMC mRNA levels were both decreased in obese patients. While immune alterations in obesity are manifest in peripheral blood lymphocytes, the general lack of correlation between altered serum levels and altered PBMC gene expression suggests that PBMC may not be the source of aberrant serum cytokine levels in obesity.
Collapse
Affiliation(s)
- R W O'Rourke
- Department of Surgery, Oregon Health and Science University, Portland, OR 97239, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
Collapse
Affiliation(s)
- John E Morley
- Division of Geriatric Medicine, Saint Louis University School of Medicine, 1042 South Grand Boulevard M238, St Louis, MO 63104, USA.
| | | | | |
Collapse
|
|
44
|
Fulop T, Larbi A, Douziech N, Levesque I, Varin A, Herbein G. Cytokine receptor signalling and aging. Mech Ageing Dev 2006; 127:526-37. [PMID: 16530252 DOI: 10.1016/j.mad.2006.01.025] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2005] [Revised: 10/01/2005] [Accepted: 01/16/2006] [Indexed: 01/22/2023]
Abstract
With ageing the immune system is deregulated and this leads to the development of immunosenescence mainly affecting the adaptive immune response. There is much knowledge accumulated concerning various receptor functions and signalling with ageing such as TCR, FcRs, TLRs. Cytokines are playing a major role in haematopoietic cell functions and in the harmonious and integrated coordination of the innate and adaptive immune response. There exists a large amount of data on cytokine production changes with ageing, as IL-2 production is decreasing, while IL-6 production is increasing. In contrast, there is only scarce knowledge concerning the cytokine receptors and their signalling in ageing. However, there is some evidence that the signalling of IL-2 receptors is altered in T cells and macrophages, mainly in relation to the JAK/STAT pathway. We present here evidence that the IL-6 induced signalling is also altered in T cells with ageing. An alteration in the JAKs and STATs activations in T cells and macrophages was demonstrated. The exact cause of these altered activations is not known and future studies are needed to elucidate them. In this review we summarise our present knowledge on cytokine signalling with ageing, mainly focusing on IL-2 and IL-6 receptors signalling.
Collapse
Affiliation(s)
- T Fulop
- Centre de Recherche sur le vieillissement, Service de Gériatrie, Département de Médecine, Université de Sherbrooke, Sherbrooke, Que., Canada.
| | | | | | | | | | | |
Collapse
|
|
45
|
Glossop JR, Dawes PT, Nixon NB, Mattey DL. Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis. Arthritis Res Ther 2005; 7:R1227-34. [PMID: 16277675 PMCID: PMC1297570 DOI: 10.1186/ar1816] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2005] [Revised: 07/28/2005] [Accepted: 08/10/2005] [Indexed: 11/10/2022] Open
Abstract
Levels of soluble tumour necrosis factor receptors (sTNFRs) are elevated in the circulation of patients with rheumatoid arthritis (RA). Although these receptors can act as natural inhibitors of tumour necrosis factor-alpha, levels of sTNFRs in RA appear to be insufficient to prevent tumour necrosis factor-alpha induced inflammation. The factors that regulate circulating levels of sTNFRs are unclear, but polymorphisms in the tumour necrosis factor receptor genes may play a role. We investigated the relationship between polymorphisms in the tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) genes and levels of sTNFRs in two groups of Caucasian RA patients: one with early (disease duration < or = 2 years; n = 103) and one with established disease (disease duration > or = 5 years; n = 151). PCR restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNF-RI gene and the T676G polymorphism in TNF-RII. Levels of sTNFRs were measured using ELISA. We also isolated T cells from peripheral blood of 58 patients with established RA with known TNF-R genotypes, and release of sTNFRs into the culture medium was measured in cells incubated with or without phytohaemagglutinin. Serum levels of the two sTNFRs (sTNF-RI and sTNF-RII) were positively correlated in both populations, and the level of each sTNFR was significantly higher in the patients with established disease (P < 0.0001). Multiple regression analyses corrected for age, sex and disease duration revealed a significant trend toward decreasing sTNF-RI and sTNF-RII levels across the TNF-RII genotypes (TT > TG > GG) of patients with established disease (P for trend = 0.01 and P for trend = 0.03, respectively). A similar nonsignificant trend was seen for early disease. No relationship with the TNF-RI A36G polymorphism was observed. sTNFRs released by isolated T cells exhibited a similar trend toward decreasing levels according to TNF-RII genotype, although only the association with levels of sTNF-RII was significant. Strong correlations were found between levels of circulating sTNFRs and levels released by T cells in vitro. Our data indicate that the T676G polymorphism in TNF-RII is associated with levels of sTNFRs released from peripheral blood T cells, and with circulating levels of sTNFR in patients with RA.
Collapse
Affiliation(s)
- John R Glossop
- Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent, UK
| | - Peter T Dawes
- Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent, UK
| | - Nicola B Nixon
- Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent, UK
| | - Derek L Mattey
- Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent, UK
| |
Collapse
|
|
46
|
Prinz PN. Age impairments in sleep, metabolic and immune functions. Exp Gerontol 2004; 39:1739-43. [PMID: 15582290 DOI: 10.1016/j.exger.2004.06.023] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2004] [Accepted: 06/28/2004] [Indexed: 11/16/2022]
Abstract
Age-related sleep impairments are chronic and common, occurring even in the absence of diagnosable disorders. Additional loss of sleep occurs with clinical sleep disorders, many of which can be ameliorated. This literature, reviewed below, raises the question of the possible biological consequences of age-related, chronic sleep loss, an area that is poorly understood at present. Some of the more age-relevant theories about sleep loss will be explored in a review of current research on sleep deprivation arising from normal aging, experimental induction and pathology. The biological consequences of sleep deprivation in young adults include metabolic, systemic inflammatory and immune changes that are similar to those of aging and age-related disorders. The possibility that chronic sleep impairment contributes to age changes in metabolism, systemic inflammation and immunocompetence is explored.
Collapse
Affiliation(s)
- Patricia N Prinz
- Department of Biobehavioral Nursing and Health Systems, University of Washington, Box 357-266, Seattle, WA 98195, USA.
| |
Collapse
|
|
47
|
Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S. Innate immunity in aging: impact on macrophage function. Aging Cell 2004; 3:161-7. [PMID: 15268749 DOI: 10.1111/j.1474-9728.2004.00102.x] [Citation(s) in RCA: 274] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Innate and adaptive immune functions decline with age, leading to increased susceptibility to infectious diseases and cancer, and reduced responses to preventive vaccination in the elderly population. Macrophages function as 'pathogen sensors' and play an important role in the initiation of inflammatory responses, elimination of pathogens, manipulation of the adaptive immune response and reparation of damaged tissue. In this paper, we review the literature addressing the impact of aging on the macrophage population.
Collapse
Affiliation(s)
- Julie Plowden
- Influenza Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
| | | | | | | | | |
Collapse
|
|
48
|
Allgayer H, Nicolaus S, Schreiber S. Decreased interleukin-1 receptor antagonist response following moderate exercise in patients with colorectal carcinoma after primary treatment. ACTA ACUST UNITED AC 2004; 28:208-13. [PMID: 15225901 DOI: 10.1016/j.cdp.2004.02.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2004] [Indexed: 11/21/2022]
Abstract
Clinical and experimental studies have shown that a moderately increased physical activity level may have beneficial effects in terms of exercise conditioning, resistance to infection and decreased relative risk of cancer. Modulation of the innate and adaptive components of the immune system with a shift of cytokines and their antagonists to a more pro- and less anti-inflammatory response was found to be a prominent feature in non-tumor patients and healthy volunteers. As quantitative data concerning the cytokine/antagonist response following exercise are not available for tumor patients, we compared the effects of a post-operative rehabilitation program with moderate exercise (ME) intensity (0.55-0.65 x maximal aerobic power) with a program with low exercise (LE) intensity (0.30-0.40 x maximal aerobic power) in patients with curatively treated colorectal carcinoma (UICC II and III) measuring pro- (IL-1beta, IL-6, tumour necrosis factor (TNF)) and anti-inflammatory cytokines (IL-1 receptor antagonist, sTNF receptors I and II). Twenty-three patients participated in this prospective trial, N = 13 in the ME group, N = 10 in the LE group. Exercise was performed daily 30-40 min for 2 weeks. Basal (circulating) and LPS-stimulated (phasic) cytokine and antagonist response was determined before exercise and after 1 and 2 weeks using appropriate ELISA tests. The LPS-stimulated interleukin-1 receptor antagonist (IL-1ra) response in the ME group gradually decreased from 31,532.6 (160.0-70,028.0) to 18,033.0 pg/ml (5040.0-52,570.0) after one and to 22,892.0 pg/ml (6376.0-34,726.0) after 2 weeks (P < 0.05) with a concomitant decrease of the corresponding IL-1ra/IL-6 and IL-1ra/IL-1beta ratio: 2.51-1.41 and 4.1-3.1, respectively. In contrast, in the LE group LPS-stimulated cytokines and antagonists did not significantly change during exercise. Circulating cytokines and antagonists remained unchanged in both groups. In providing quantitative data in patients with curatively-treated colorectal cancer, we demonstrated that a short-term rehabilitation program with moderate exercise leads to a decreased LPS-induced antagonist response with a shift to a more pro-inflammatory state (decreased antagonist/cytokine ratio). Whether this change of the phasic immune response to moderate exercise may be clinically beneficial (decreased rates of infection, relapses and/or second tumours) is possible, but has to be investigated in long-term studies.
Collapse
Affiliation(s)
- Hubert Allgayer
- Oncology Department, Rehaklinik Ob der Tauber der LVA Baden-Württemberg, Academic Teaching Hospital, University of Heidelberg, Bismarckstr. 31, D-97980 Bad Mergentheim, Germany.
| | | | | |
Collapse
|
|
49
|
Berdat PA, Wehrle TJ, Küng A, Achermann F, Sutter M, Carrel TP, Nydegger UE. Age-specific analysis of normal cytokine levels in healthy infants. Clin Chem Lab Med 2004; 41:1335-9. [PMID: 14580162 DOI: 10.1515/cclm.2003.204] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
While pathophysiology of elevated cytokines is well delineated, reference values for children are unknown, although they may vary physiologically with age and differ from those of adults. Between June and November 2001, interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha (TNF-alpha) concentrations from blood samples of 79 healthy children in six different age groups (group I: 0-3 months; group II: 4-12 months; group III: 13-24 months; group IV: 25-36 months; group V: 37-48 months; group VI: 49-60 months) were measured with ELISA. TNF-alpha was within 2.2-3.5 pg/ml in all groups with a trend toward higher values in groups II and III (p = ns). IL-6 was significantly lower in group III than in groups IV (p = 0.0165) and VI (p = 0.0147). IL-10 was within 3.3-5.5 pg/ml in all groups (p = ns). In regression analysis no correlation between age and cytokine concentrations was found. Although not statistically significant, IL-6 was lower and TNF-alpha higher than the adult reference values provided by the kit manufacturer. Although reference cytokine levels seem not age-related during early infancy, IL-6 is significantly lower during the second year of life than later. In infants aged 5 years or younger, reference levels of IL-6 should be chosen lower, and those of TNF-alpha higher, than the adult reference values.
Collapse
Affiliation(s)
- Pascal A Berdat
- Clinic for Cardiovascular Surgery, University Hospital, Bern, Switzerland
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Ochi K, Kohriyama T, Higaki M, Ikeda J, Harada A, Nakamura S. Changes in serum macrophage-related factors in patients with chronic inflammatory demyelinating polyneuropathy caused by intravenous immunoglobulin therapy. J Neurol Sci 2003; 208:43-50. [PMID: 12639724 DOI: 10.1016/s0022-510x(02)00422-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a slowly progressive or recurrent neuropathy accompanied by infiltration of macrophages in the peripheral nerves. Macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1) are a macrophage-related cytokine and chemokine, respectively. Although, intravenous immunoglobulin (IVIg) infusion therapy has been used for treating CIDP patients, not all CIDP patients have responded to IVIg infusion therapy. To determine the mechanisms of the action of IVIg, we examined serum M-CSF and MCP-1 levels during and after IVIg infusion therapy in 19 CIDP patients treated with IVIg (0.4 g/kg/day for 5 days). Ten of the 19 patients (52.6%) responded to IVIg therapy. Both M-CSF and MCP-1 concentrations in IVIg responders were significantly higher on day 1 postinfusion than those in nonresponders, but decreased to their pretreatment values on day 5 postinfusion. The results suggest that immunomodulation through M-CSF and MCP-1 is involved in the mechanisms underlying the effect of IVIg infusion therapy in CIDP patients.
Collapse
Affiliation(s)
- Kazuhide Ochi
- Department of Clinical Neuroscience and Therapeutics, Division of Integrated Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Japan.
| | | | | | | | | | | |
Collapse
|