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Asgari F, Nikzamir A, Baghaei K, Masotti A, Rostami-Nejad M. Investigating the therapeutic potential of tryptophan and vitamin A in modulating immune responses in celiac disease: an experimental study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04089-9. [PMID: 40178602 DOI: 10.1007/s00210-025-04089-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 03/21/2025] [Indexed: 04/05/2025]
Abstract
Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation in celiac disease as they are the first immune cells to encounter gliadin. Tryptophan (Trp) and vitamin A (retinol, Ret) are known to influence the immune response of DCs to gliadin and increase their tolerogenicity. CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), which are important for immune tolerance, can be generated from naive T cells in the presence of retinoic acid (RA) and TGF-β.The aim of this study was to determine the combined effect of Ret and Trp in altering the phenotypic and functional maturation of DCs by gliadin and their contribution to the differentiation of Tregs. Monocyte cells derived from the peripheral blood mononuclear cells (PBMCs) of patients with celiac disease were differentiated into DCs and stimulated with PT-gliadin. These cells were then treated with Trp + Ret. The expression of CD11c, CD14, CD83, CD86, PDL1, CD4, CD25 and FOXP3 was examined using flow cytometry. TGF-β, IL-10, IL-12, and TNF-α levels were measured by ELISA. qRT-PCR was used to quantify the mRNA levels of retinaldehyde dehydrogenase 2 (RALDH2), integrin αE (CD103), and NF-κB. Indoleamine 2,3-dioxygenase (IDO) mRNA and protein levels were assessed using qRT-PCR and Western blot assays, respectively. The maturation of DCs by PT-gliadin was defined through co-stimulatory molecule expression (CD83 and CD86) and promotion of TNF-α and IL-12 secretion. We found that after treatment with Ret + Trp, the production levels of IL-12, TNF-α, and NF-κB were significantly reduced, while the expression of IL-10, TGF-β, and the inhibitory markers PDL1, CD103, IDO, and RALDH2 by PT-gliadin-stimulated DCs was significantly increased. Furthermore, in a DC and T cell co-culture system, treatment of DCs with Ret + Trp increased TGF-β expression in DCS and promoted CD4 + CD25 + FOXP3 Treg induction. These results indicate the potential benefit of vitamin A and tryptophan as therapeutic options for individuals with celiac disease. Further research is required to fully understand the mechanisms of action of these substances in these cells.
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Affiliation(s)
- Fatemeh Asgari
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolrahim Nikzamir
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andrea Masotti
- Bambino Gesù Children'S Hospital-IRCCS, Research Laboratories, V.Le San Paolo 15, 00146, Rome, Italy
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhou H, Zheng Z, Fan C, Zhou Z. Mechanisms and strategies of immunosenescence effects on non-small cell lung cancer (NSCLC) treatment: A comprehensive analysis and future directions. Semin Cancer Biol 2025; 109:44-66. [PMID: 39793777 DOI: 10.1016/j.semcancer.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/29/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025]
Abstract
Non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer, remains a leading cause of cancer-related mortality worldwide, particularly among elderly individuals. The phenomenon of immunosenescence, characterized by the progressive decline in immune cell functionality with aging, plays a pivotal role in NSCLC progression and contributes to the diminished efficacy of therapeutic interventions in older patients. Immunosenescence manifests through impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation, collectively fostering a pro-tumorigenic microenvironment. This review provides a comprehensive analysis of the molecular, cellular, and genetic mechanisms of immunosenescence and its impact on immune surveillance and the tumor microenvironment (TME) in NSCLC. We explore how aging affects various immune cells, including T cells, B cells, NK cells, and macrophages, and how these changes compromise the immune system's ability to detect and eliminate tumor cells. Furthermore, we address the challenges posed by immunosenescence to current therapeutic strategies, particularly immunotherapy, which faces significant hurdles in elderly patients due to immune dysfunction. The review highlights emerging technologies, such as single-cell sequencing and CRISPR-Cas9, which offer new insights into immunosenescence and its potential as a therapeutic target. Finally, we outline future research directions, including strategies for rejuvenating the aging immune system and optimizing immunotherapy for older NSCLC patients, with the goal of improving treatment efficacy and survival outcomes. These efforts hold promise for the development of more effective, personalized therapies for elderly patients with NSCLC.
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Affiliation(s)
- Huatao Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China
| | - Zilong Zheng
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China
| | - Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China.
| | - Zijing Zhou
- Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha 410011, China.
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Doan VTH, Imai T, Kawazoe N, Chen G, Yoshitomi T. Regulation of antigen presentation and interleukin 10 production in murine dendritic cells via the oxidative stimulation of cell membrane using a polycation-porphyrin-conjugate-immobilized cell culture dish. Acta Biomater 2025; 193:231-241. [PMID: 39788307 DOI: 10.1016/j.actbio.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/13/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
Tolerogenic dendritic cells with professional antigen presentation via major histocompatibility complex molecules, co-stimulatory molecules (CD80/86), and interleukin 10 production have attracted significant attention as cellular therapies for autoimmune, allergic, and graft-versus-host diseases. In this study, we developed a cell culture dish equipped with polycation-porphyrin-conjugate-immobilized glass (PA-HP-G) to stimulate immature murine dendritic cell (iDCs). Upon irradiation with a red light at 635 nm toward the PA-HP-G surface, singlet oxygen was generated by the immobilized porphyrins on the PA-HP-G surface. When iDCs were cultured on the PA-HP-G surface, moderate light irradiation generated lipid radicals without excessive generation of reactive oxygen species in the cytoplasm and nucleus, which led to the oxidative stimulation of the iDC cell membrane without cell death. Light irradiation changed the morphology of dendritic cells on the PA-HP-G surface to a tree-like structure with dendrites, accelerated their maturation, and enhanced the antigen-presenting ability for the ovalbumin peptide via major histocompatibility complex class I molecules. Additionally, the antigen-presenting dendritic cells on the PA-HP-G surface produced the anti-inflammatory cytokine interleukin 10 upon light irradiation. These results indicated that upon moderate light irradiation, the PA-HP-G surface regulated the maturation of iDCs into tolerogenic dendritic cells. STATEMENT OF SIGNIFICANCE: • Cell culture dish is developed for selective oxidative stimulus of cell membrane. • 1O2 is generated from polycation/porphyrin-immobilized glass by light irradiation. • Lipid radicals are generated without generation of ROS in cytoplasm and nuclei. • Immature dendritic cells are maturated by oxidative stimulation of cell membrane. • Oxidative membrane stimulus enhances antigen-presentation and IL-10 secretion.
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Affiliation(s)
- Van Thi Hong Doan
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
| | - Takashi Imai
- Department of Parasitology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640 Japan; Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo 189-0002, Japan; Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aobacho, Higashimurayama, Tokyo 189-0002, Japan
| | - Naoki Kawazoe
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
| | - Guoping Chen
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
| | - Toru Yoshitomi
- Research Center for Macromolecules and Biomaterials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
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Fang S, Jiang M, Jiao J, Zhao H, Liu D, Gao D, Wang T, Yang Z, Yuan H. Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease. Aging Dis 2025:AD.2024.1253. [PMID: 39812539 DOI: 10.14336/ad.2024.1253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.
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Affiliation(s)
- Sihang Fang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Mingjun Jiang
- Respiratory Department, Beijing Children's Hospital, Capital Medical University, China National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, China
| | - Juan Jiao
- Department of Clinical Laboratory, the Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Hongye Zhao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Dizhi Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Tenger Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China
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Amoriello R, Nenciarini S, Cavalieri D, Ballerini C. In Vitro Interaction Between Yeast Extracellular Vesicles and Human Monocyte-Derived Dendritic Cells. Methods Mol Biol 2025; 2857:137-146. [PMID: 39348062 DOI: 10.1007/978-1-0716-4128-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Extracellular vesicles (EVs) are lipid-bound particles produced by a wide variety of cells from different biological species. EVs can carry molecules, such as nucleic acids and metabolites, and are involved in cell functioning, communication, and signaling. Recent literature reported that pathogenic or commensal yeast strains can produce EVs targeting the host's immune system and exerting immunomodulatory actions. In humans, yeast EVs can be endocytosed by dendritic cells (DCs), characterized by phagocyting and migrating capabilities with the role of capturing antigens to present to T lymphocytes, triggering the immune response. Physiological or disease-associated immunosenescence impairs both DC functionality and gut microbiota; thus investigating the interaction between commensal microorganisms and the host's immune system would help elucidate the impact of aging on the immune system-microbiota interplay. We hereby present a protocol for the incubation of in vitro-generated human monocyte-derived DCs with EVs purified from different yeast strains isolated from fermented milk. The protocol includes flow cytometry analysis on DC activation markers and endocytosis assay.
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Affiliation(s)
- Roberta Amoriello
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
| | | | | | - Clara Ballerini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Vasilieva MI, Shatalova RO, Matveeva KS, Shindyapin VV, Minskaia E, Ivanov RA, Shevyrev DV. Senolytic Vaccines from the Central and Peripheral Tolerance Perspective. Vaccines (Basel) 2024; 12:1389. [PMID: 39772050 PMCID: PMC11680330 DOI: 10.3390/vaccines12121389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Preventive medicine has proven its long-term effectiveness and economic feasibility. Over the last century, vaccination has saved more lives than any other medical technology. At present, preventative measures against most infectious diseases are successfully used worldwide; in addition, vaccination platforms against oncological and even autoimmune diseases are being actively developed. At the same time, the development of medicine led to an increase in both life expectancy and the proportion of age-associated diseases, which pose a heavy socio-economic burden. In this context, the development of vaccine-based approaches for the prevention or treatment of age-related diseases opens up broad prospects for extending the period of active longevity and has high economic potential. It is well known that the development of age-related diseases is associated with the accumulation of senescent cells in various organs and tissues. It has been demonstrated that the elimination of such cells leads to the restoration of functions, rejuvenation, and extension of the lives of experimental animals. However, the development of vaccines against senescent cells is complicated by their antigenic heterogeneity and the lack of a unique marker. In addition, senescent cells are the body's own cells, which may be the reason for their low immunogenicity. This mini-review discusses the mechanisms of central and peripheral tolerance that may influence the formation of an anti-senescent immune response and be responsible for the accumulation of senescent cells with age.
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Affiliation(s)
- Mariia I. Vasilieva
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
| | - Rimma O. Shatalova
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
| | - Kseniia S. Matveeva
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
- Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia;
| | - Vadim V. Shindyapin
- Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia;
| | - Ekaterina Minskaia
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
| | - Roman A. Ivanov
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
| | - Daniil V. Shevyrev
- Research Center for Translational Medicine, Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, Sirius 354349, Russia
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Tang Y, Jiang J, Zhao Y, Du D. Aging and chronic kidney disease: epidemiology, therapy, management and the role of immunity. Clin Kidney J 2024; 17:sfae235. [PMID: 40034487 PMCID: PMC11873799 DOI: 10.1093/ckj/sfae235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) is now an unquestionable progressive condition that affects more than 10% of the general population worldwide, and has emerged as one of the most important causes of global mortality. It is clear that the prevalence of CKD among the aging population is significantly elevated. It involves a broad range of complex and poorly understood concerns in older adults such as frailty, malnutrition, sarcopenia, and even cognitive and mental dysfunction. In kidneys, renal function such as glomerular filtration, urine concentration and dilution, and homeostasis of sodium and potassium, can be influenced by the aging process. In addition, it is worth noting that CKD and end-stage kidney disease patients often have accompanying activation of immune system and inflammation, involving both the innate and adaptive immune system. Based on this background, in this review article we attempt to summarize the epidemiological characteristics of CKD in the aging population, discuss the immunological mechanisms in aging-related CKD, and furnish the reader with processes for the therapy and management of elderly patients with CKD.
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Affiliation(s)
- Yukun Tang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Wuhan, China
| | - Jipin Jiang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Wuhan, China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China
| | - Dunfeng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences; Wuhan, China
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Dou L, Peng Y, Zhang B, Yang H, Zheng K. Immune Remodeling during Aging and the Clinical Significance of Immunonutrition in Healthy Aging. Aging Dis 2024; 15:1588-1601. [PMID: 37815906 PMCID: PMC11272210 DOI: 10.14336/ad.2023.0923] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/23/2023] [Indexed: 10/12/2023] Open
Abstract
Aging is associated with changes in the immune system and the gut microbiota. Immunosenescence may lead to a low-grade, sterile chronic inflammation in a multifactorial and dynamic way, which plays a critical role in most age-related diseases. Age-related changes in the gut microbiota also shape the immune and inflammatory responses. Nutrition is a determinant of immune function and of the gut microbiota. Immunonutrion has been regarded as a new strategy for disease prevention and management, including many age-related diseases. However, the understanding of the cause-effect relationship is required to be more certain about the role of immunonutrition in supporting the immune homeostasis and its clinical relevance in elderly individuals. Herein, we review the remarkable quantitative and qualitative changes during aging that contribute to immunosenescence, inflammaging and microbial dysbiosis, and the effects on late-life health conditions. Furthermore, we discuss the clinical significance of immunonutrition in the treatment of age-related diseases by systematically reviewing its modulation of the immune system and the gut microbiota to clarify the effect of immunonutrition-based interventions on the healthy aging.
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Affiliation(s)
- Lei Dou
- Department of Geriatrics, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
- Department of Surgery, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Yang Peng
- Department of Geriatrics, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Bin Zhang
- Department of Surgery, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Huiyuan Yang
- Department of Surgery, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Kai Zheng
- Department of Geriatrics, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan 430030, China.
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Thomas R, Jerome JM, Krieger KL, Ashraf N, Rowley DR. The reactive stroma response regulates the immune landscape in prostate cancer. JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS 2024; 8:249-77. [DOI: 10.20517/jtgg.2024.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Prostate cancer remains the most commonly diagnosed and the second leading cause of cancer-related deaths in men in the United States. The neoplastic transformation of prostate epithelia, concomitant with modulations in the stromal compartment, known as reactive stromal response, is critical for the growth, development, and progression of prostate cancer. Reactive stroma typifies an emergent response to disrupted tissue homeostasis commonly observed in wound repair and pathological conditions such as cancer. Despite the significance of reactive stroma in prostate cancer pathobiology, our understanding of the ontogeny, phenotypic and functional heterogeneity, and reactive stromal regulation of the immune microenvironment in prostate cancer remains limited. Traditionally characterized to have an immunologically "cold" tumor microenvironment, prostate cancer presents significant challenges for advancing immunotherapy compared to other solid tumors. This review explores the detrimental role of reactive stroma in prostate cancer, particularly its immunomodulatory function. Understanding the molecular characteristics and dynamic transcriptional program of the reactive stromal populations in tandem with tumor progression could offer insights into enhancing immunotherapy efficacy against prostate cancer.
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Xing D, Jin Y, Jin B. A narrative review on inflammaging and late-onset hypogonadism. Front Endocrinol (Lausanne) 2024; 15:1291389. [PMID: 38298378 PMCID: PMC10827931 DOI: 10.3389/fendo.2024.1291389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 01/02/2024] [Indexed: 02/02/2024] Open
Abstract
The increasing life expectancy observed in recent years has resulted in a higher prevalence of late-onset hypogonadism (LOH) in older men. LOH is characterized by the decline in testosterone levels and can have significant impacts on physical and mental health. While the underlying causes of LOH are not fully understood, there is a growing interest in exploring the role of inflammaging in its development. Inflammaging is a concept that describes the chronic, low-grade, systemic inflammation that occurs as a result of aging. This inflammatory state has been implicated in the development of various age-related diseases. Several cellular and molecular mechanisms have been identified as contributors to inflammaging, including immune senescence, cellular senescence, autophagy defects, and mitochondrial dysfunction. Despite the extensive research on inflammaging, its relationship with LOH has not yet been thoroughly reviewed in the literature. To address this gap, we aim to review the latest findings related to inflammaging and its impact on the development of LOH. Additionally, we will explore interventions that target inflammaging as potential treatments for LOH.
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Affiliation(s)
- Dong Xing
- Medical College of Southeast University, Nanjing, Jiangsu, China
| | - Yihan Jin
- Reproductive Medicine Center, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
| | - Baofang Jin
- Andrology Department of Integrative Medicine, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
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Molnár AÁ, Pásztor DT, Tarcza Z, Merkely B. Cells in Atherosclerosis: Focus on Cellular Senescence from Basic Science to Clinical Practice. Int J Mol Sci 2023; 24:17129. [PMID: 38138958 PMCID: PMC10743093 DOI: 10.3390/ijms242417129] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/30/2023] [Accepted: 12/03/2023] [Indexed: 12/24/2023] Open
Abstract
Aging is a major risk factor of atherosclerosis through different complex pathways including replicative cellular senescence and age-related clonal hematopoiesis. In addition to aging, extracellular stress factors, such as mechanical and oxidative stress, can induce cellular senescence, defined as premature cellular senescence. Senescent cells can accumulate within atherosclerotic plaques over time and contribute to plaque instability. This review summarizes the role of cellular senescence in the complex pathophysiology of atherosclerosis and highlights the most important senotherapeutics tested in cardiovascular studies targeting senescence. Continued bench-to-bedside research in cellular senescence might allow the future implementation of new effective anti-atherosclerotic preventive and treatment strategies in clinical practice.
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Affiliation(s)
- Andrea Ágnes Molnár
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary; (D.T.P.); (Z.T.); (B.M.)
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12
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Syed U, Subramanian A, Wraith DC, Lord JM, McGee K, Ghokale K, Nirantharakumar K, Haroon S. Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care. BMC Med 2023; 21:363. [PMID: 37735654 PMCID: PMC10512476 DOI: 10.1186/s12916-023-03049-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/24/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs). METHODS Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications. RESULTS Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42). CONCLUSIONS SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.
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Affiliation(s)
- Umer Syed
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Anuradhaa Subramanian
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
| | - David C Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
| | - Janet M Lord
- NIHR Birmingham Biomedical Research Centre, University Hospital Birmingham and University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Kirsty McGee
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Krishna Ghokale
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Krishnarajah Nirantharakumar
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Shamil Haroon
- Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
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Identify Key Genes Correlated to Ischemia-Reperfusion Injury in Aging Livers. DISEASE MARKERS 2023; 2023:4352313. [PMID: 36845012 PMCID: PMC9949953 DOI: 10.1155/2023/4352313] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/14/2023] [Accepted: 01/28/2023] [Indexed: 02/18/2023]
Abstract
Background With the intensification of population aging, the proportion of aging livers in the donor pool is increasing rapidly. Compared with young livers, aging livers are more susceptible to ischemia-reperfusion injury (IRI) during liver transplantation, which greatly affects the utilization rate of aging livers. The potential risk factors associated with IRI in aging livers have not been fully elucidated. Methods In this work, five human liver tissue expression profiling datasets (GSE61260, GSE107037, GSE89632, GSE133815, and GSE151648) and a total of 28 young and aging liver tissues of human (N = 20) and mouse (N = 8) were used to screen and verify the potential risk factors associated with aging livers being more prone to IRI. DrugBank Online was used to screen drugs with potential to alleviate IRI in aging livers. Results The gene expression profile and immune cell composition between young and aging livers had significant differences. Among the differentially expressed genes, aryl hydrocarbon receptor nuclear translocator-like (ARNTL), BTG antiproliferation factor 2 (BTG2), C-X-C motif chemokine ligand 10 (CXCL10), chitinase 3-like 1 (CHI3L1), immediate early response 3 (IER3), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A), mainly involved in the regulation of cell proliferation, metabolism, and inflammation, were also dysregulated in liver tissues suffered from IRI and could form a FOS-centered interaction network. Nadroparin was screened out with the potential to target FOS in DrugBank Online. In addition, the proportion of dendritic cells (DCs) was significantly upregulated in aging livers. Conclusions We combined the expression profiling datasets of liver tissues and samples collected in our hospital for the first time to reveal that the changes in the expression of ARNTL, BTG2, CXCL10, CHI3L1, IER3, FOS, and PPARGC1A and the proportion of dendritic cells may be associated with aging livers being more prone to IRI. Nadroparin may be used to mitigate IRI in aging livers by targeting FOS, and regulation of DC activity may also reduce IRI.
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14
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Xiong YT, Wang JF, Niu XX, Fu YM, Wang KX, Wang CY, Li QQ, Wang JJ, Zhao J, Ji D. Autoimmunity associates with severity of illness in elderly patients with drug-induced liver injury. Front Pharmacol 2023; 14:1071709. [PMID: 36874016 PMCID: PMC9978525 DOI: 10.3389/fphar.2023.1071709] [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: 10/16/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Background: Drug-induced liver injury (DILI) is a potentially serious adverse drug reaction. Due to the lack of definite etiology, specific clinical manifestations, and diagnostic methods, its prediction and diagnosis are challenging. Elderly individuals are deemed to be at high risk for DILI due to abnormal pharmacokinetics, aging tissue repair function, comorbidities, and taking multiple drugs. This study aimed to identify the clinical characteristics and explore the risk factors associated with the severity of illness in elderly patients with DILI. Methods: In the present study, the clinical characteristics at the time of liver biopsy of consecutive patients with biopsy-proven DILI who presented at our hospital from June 2005 to September 2022 were evaluated. Hepatic inflammation and fibrosis were assessed according to the Scheuer scoring system. The presence of autoimmunity was considered if IgG level >1.1 × ULN (1826 mg/dL), or high titer (>1:80) of ANA, or SMA. Results: In total, 441 patients were enrolled, and the median age was 63.3 years (IQR, 61.0-66.0); 122 (27.7%), 195 (44.2%), or 124 (28.1%) were classified as having minor, moderate, or severe hepatic inflammation, respectively; and 188 (42.6%), 210 (47.6%) or 43 (9.8%) patients presented minor, significant fibrosis or cirrhosis, respectively. Female sex (73.5%) and the cholestatic pattern (47.6%) were dominant in elderly DILI patients. Autoimmunity existed in 201 patients (45.6%). Comorbidities were not directly associated with the severity of DILI. PLT (OR: 0.994, 95% CI: 0.991-0.997; p < 0.001), AST (OR: 1.001, 95% CI: 1.000-1.003, p = 0.012), TBIL (OR: 1.006, 95% CI: 1.003-1.010, p < 0.001), and autoimmunity (OR: 1.831, 95% CI: 1.258-2.672, p = 0.002) were associated with the degree of hepatic inflammation. Meanwhile, PLT (OR: 0.990, 95% CI: 0.986-0.993, p < 0.001), TBIL (OR: 1.004, 95% CI: 1.000-1.007, p = 0.028), age (OR: 1.123, 95% CI: 1.067-1.183, p < 0.001), and autoimmunity (OR: 1.760, 95% CI: 1.191-2.608, p = 0.005) were associated with the stage of hepatic fibrosis. Conclusion: This study revealed that the presence of autoimmunity represents a more serious illness state of DILI, deserving more intensive monitoring and progressive treatment.
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Affiliation(s)
- Yu-Ting Xiong
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,307 Clinical Medical College of PLA, Anhui Medical University, Beijing, China
| | - Jian-Fei Wang
- Emergency Department, Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-Xia Niu
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yi-Ming Fu
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ke-Xin Wang
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,307 Clinical Medical College of PLA, Anhui Medical University, Beijing, China
| | - Chun-Yan Wang
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qian-Qian Li
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jian-Jun Wang
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jun Zhao
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,Chinese PLA Medical School, Beijing, China
| | - Dong Ji
- Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,307 Clinical Medical College of PLA, Anhui Medical University, Beijing, China.,Chinese PLA Medical School, Beijing, China
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15
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Mishra S, Raval M, Kachhawaha AS, Tiwari BS, Tiwari AK. Aging: Epigenetic modifications. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:171-209. [PMID: 37019592 DOI: 10.1016/bs.pmbts.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
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16
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Vellasamy DM, Lee SJ, Goh KW, Goh BH, Tang YQ, Ming LC, Yap WH. Targeting Immune Senescence in Atherosclerosis. Int J Mol Sci 2022; 23:13059. [PMID: 36361845 PMCID: PMC9658319 DOI: 10.3390/ijms232113059] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 10/29/2023] Open
Abstract
Atherosclerosis is one of the main underlying causes of cardiovascular diseases (CVD). It is associated with chronic inflammation and intimal thickening as well as the involvement of multiple cell types including immune cells. The engagement of innate or adaptive immune response has either athero-protective or atherogenic properties in exacerbating or alleviating atherosclerosis. In atherosclerosis, the mechanism of action of immune cells, particularly monocytes, macrophages, dendritic cells, and B- and T-lymphocytes have been discussed. Immuno-senescence is associated with aging, viral infections, genetic predispositions, and hyperlipidemia, which contribute to atherosclerosis. Immune senescent cells secrete SASP that delays or accelerates atherosclerosis plaque growth and associated pathologies such as aneurysms and coronary artery disease. Senescent cells undergo cell cycle arrest, morphological changes, and phenotypic changes in terms of their abundances and secretome profile including cytokines, chemokines, matrix metalloproteases (MMPs) and Toll-like receptors (TLRs) expressions. The senescence markers are used in therapeutics and currently, senolytics represent one of the emerging treatments where specific targets and clearance of senescent cells are being considered as therapy targets for the prevention or treatment of atherosclerosis.
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Affiliation(s)
- Danusha Michelle Vellasamy
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Sin-Jye Lee
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Malaysia
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
| | - Yin-Quan Tang
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
| | - Long Chiau Ming
- PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
| | - Wei Hsum Yap
- School of Biosciences, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology, Faculty of Medical and Health Sciences, Taylor’s University, Subang Jaya 47500, Malaysia
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17
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Chen B, Yang J, Song Y, Zhang D, Hao F. Skin Immunosenescence and Type 2 Inflammation: A Mini-Review With an Inflammaging Perspective. Front Cell Dev Biol 2022; 10:835675. [PMID: 35281103 PMCID: PMC8908007 DOI: 10.3389/fcell.2022.835675] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
Skin-resident stromal cells, including keratinocytes, fibroblasts, adipocytes, and immune cells including Langerhans cells, dendritic cells, T cells, and innate lymphoid cells, and their functional products work in concert to ensure the realization of skin barrier immunity. However, aging-induced immunosenescence predisposes the elderly to pruritic dermatoses, including type 2 inflammation-mediated. Inflammaging, characterized by chronic low level of pro-inflammatory cytokines released from senescent cells with the senescence-associated secretory phenotype (SASP), may drive immunosenescence and tangle with type 2 inflammatory dermatoses. The present mini-review summarizes current evidence on immunosenescence and type 2 inflammation in the skin and further focuses on future needs from an inflammaging perspective to clarify their complexity.
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Affiliation(s)
- Bangtao Chen
- Department of Dermatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Jing Yang
- Department of Dermatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yao Song
- Department of Dermatology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Daojun Zhang
- Department of Dermatology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fei Hao
- Department of Dermatology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Fei Hao,
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18
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Epidermal Barrier Function and Skin Homeostasis in Atopic Dermatitis: The Impact of Age. Life (Basel) 2022; 12:life12010132. [PMID: 35054525 PMCID: PMC8779900 DOI: 10.3390/life12010132] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/03/2022] [Accepted: 01/15/2022] [Indexed: 01/10/2023] Open
Abstract
Skin is damaged in atopic dermatitis (AD) patients. Age is also believed to have a negative effect on epidermal barrier function. The aim of this study was to investigate skin barrier function changes with age in AD patients. A cross-sectional study was conducted including 162 participants, 81 AD patients and 81 healthy volunteers. Skin barrier function parameters, such as transepidermal water loss (TEWL), erythema, temperature, stratum corneum hydration (SCH), pH, and elasticity, were evaluated. Healthy volunteers were evaluated on the volar forearm. AD patients were measured on two regions: on an eczematous lesion on the volar forearm and on a non-involved area 5 cm from the affected area. TEWL was lower on healthy skin than uninvolved AD skin (9.98 vs. 25.51 g·m−2·h−1, p < 0.001) and AD eczematous lesions (9.98 vs. 28.38 g·m−2·h−1, p < 0.001). SCH was lower on AD eczematous lesions than uninvolved AD skin (24.23 vs. 39.36 AU, p < 0.001) and healthy skin (24.23 vs. 44.36 AU, p < 0.001). Elasticity was lower on AD eczematous lesions than uninvolved AD skin (0.69 vs. 0.74, p = 0.038) and healthy skin (0.69 vs. 0.77, p = 0.014). A negative correlation was found between age and elasticity in all the population (r = −0.383, p < 0.001). This correlation was stronger in AD patients (r = −0.494, p < 0.001) than in controls (r = −0.266, p = 0.092). After conducting a linear regression model in AD patients adjusted by age, sex, and SCORing Atopic Dermatitis (SCORAD), it was found that elasticity was impaired by an increasing age (β = −0.004, p < 0.001) and a higher SCORAD (β = −0.003, p < 0.001). The skin barrier function is impaired by age and AD, reflected mainly in poor elasticity values in older AD patients.
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19
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Soda K. Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation. Cells 2022; 11:cells11010164. [PMID: 35011727 PMCID: PMC8750749 DOI: 10.3390/cells11010164] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 02/04/2023] Open
Abstract
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as polyphenols. These include antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. We have first reported that increased polyamine intake (spermidine much more so than spermine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice and extended life span of mice. However, it is unlikely that the life-extending effect of polyamines is exerted by the same bioactivity as polyphenols because most studies using polyphenols and antioxidants have failed to demonstrate their life-extending effects. Recent investigations revealed that aging-associated pathologies and lifespan are closely associated with DNA methylation, a regulatory mechanism of gene expression. There is a close relationship between polyamine metabolism and DNA methylation. We have shown that the changes in polyamine metabolism affect the concentrations of substances and enzyme activities involved in DNA methylation. I consider that the increased capability of regulation of DNA methylation by spermine is a key of healthy long life of humans.
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Affiliation(s)
- Kuniyasu Soda
- Department Cardiovascular Institute for Medical Research, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Saitama-City 330-0834, Saitama, Japan
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20
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Abstract
Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8+ T cell function. Accordingly, in GCA but not in TAK, CD8+ effector T cells play a negligible role and anti-inflammatory CD8+ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.
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21
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Bocheva G, Slominski RM, Slominski AT. The Impact of Vitamin D on Skin Aging. Int J Mol Sci 2021; 22:ijms22169097. [PMID: 34445803 PMCID: PMC8396468 DOI: 10.3390/ijms22169097] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/20/2021] [Accepted: 08/21/2021] [Indexed: 12/11/2022] Open
Abstract
The active metabolites of vitamin D3 (D3) and lumisterol (L3) exert a variety of antiaging and photoprotective effects on the skin. These are achieved through immunomodulation and include anti-inflammatory actions, regulation of keratinocytes proliferation, and differentiation programs to build the epidermal barrier necessary for maintaining skin homeostasis. In addition, they induce antioxidative responses, inhibit DNA damage and induce DNA repair mechanisms to attenuate premature skin aging and cancerogenesis. The mechanism of action would involve interaction with multiple nuclear receptors including VDR, AhR, LXR, reverse agonism on RORα and -γ, and nongenomic actions through 1,25D3-MARRS receptor and interaction with the nongenomic binding site of the VDR. Therefore, active forms of vitamin D3 including its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 derivatives as well as L3 derivatives are promising agents for the prevention, attenuation, or treatment of premature skin aging. They could be administrated orally and/or topically. Other forms of parenteral application of vitamin D3 precursor should be considered to avoid its predominant metabolism to 25(OH)D3 that is not recognized by CYP11A1 enzyme. The efficacy of topically applied vitamin D3 and L3 derivatives needs further clinical evaluation in future trials.
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Affiliation(s)
- Georgeta Bocheva
- Department of Pharmacology and Toxicology, Medical University of Sofia, 1431 Sofia, Bulgaria
- Correspondence: (G.B.); (A.T.S.)
| | - Radomir M. Slominski
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Andrzej T. Slominski
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Veteran Administration Medical Center, Birmingham, AL 35294, USA
- Correspondence: (G.B.); (A.T.S.)
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22
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Parimon T, Hohmann MS, Yao C. Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis. Int J Mol Sci 2021; 22:6214. [PMID: 34207528 PMCID: PMC8227105 DOI: 10.3390/ijms22126214] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/13/2022] Open
Abstract
Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate limited efficacies. Advancing our understanding of the pathogenic mechanisms of lung fibrosis will provide a future path for the cure. Cellular senescence has gained substantial interest in recent decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence-targeted signaling molecules and specific therapies to target senescent cells, known collectively as "senolytic" or "senotherapeutic" agents.
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Affiliation(s)
- Tanyalak Parimon
- Cedars-Sinai Medical Center, Department of Medicine, Women’s Guild Lung Institute, Los Angeles, CA 90048, USA
- Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA 90048, USA
| | - Miriam S. Hohmann
- Cedars-Sinai Medical Center, Department of Medicine, Women’s Guild Lung Institute, Los Angeles, CA 90048, USA
| | - Changfu Yao
- Cedars-Sinai Medical Center, Department of Medicine, Women’s Guild Lung Institute, Los Angeles, CA 90048, USA
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23
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Cheungpasitporn W, Lentine KL, Tan JC, Kaufmann M, Caliskan Y, Bunnapradist S, Lam NN, Schnitzler M, Axelrod DA. Immunosuppression Considerations for Older Kidney Transplant Recipients. CURRENT TRANSPLANTATION REPORTS 2021; 8:100-110. [PMID: 34211822 PMCID: PMC8244945 DOI: 10.1007/s40472-021-00321-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW While kidney transplantation improves the long-term survival of the majority of patients with end-stage kidney disease (ESKD), age-related immune dysfunction and associated comorbidities make older transplant recipients more susceptible to complications related to immunosuppression. In this review, we discuss appropriate management of immunosuppressive agents in older adults to minimize adverse events, avoid acute rejection, and maximize patient and graft survival. RECENT FINDINGS Physiological changes associated with senescence can impact drug metabolism and increase the risk of posttransplant infection and malignancy. Clinical trials assessing the safety and efficacy of immunosuppressive agents in older adults are lacking. Recent findings from U.S. transplant registry-based studies suggest that risk-adjusted death-censored graft failure is higher among older patients who received antimetabolite avoidance, mammalian target of rapamycin inhibitor (mTORi)-based, and cyclosporine-based regimens. Observational data suggest that risk-adjusted mortality may be increased in older patients who receive mTORi-based and cyclosporine-based regimens but lower in those managed with T-cell induction and maintenance steroid avoidance/withdrawal. SUMMARY Tailored immunosuppression management to improve patient and graft survival in older transplant recipients is an important goal of personalized medicine. Lower intensity immunosuppression, such as steroid-sparing regimens, appear beneficial whereas mTORi- and cyclosporine-based maintenance are associated with greater potential for adverse effects. Prospective clinical trials to assess the safety and efficacy of immunosuppression agents in older recipients are urgently needed.
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Elsayed R, Elashiry M, Liu Y, El-Awady A, Hamrick M, Cutler CW. Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells. Front Cell Infect Microbiol 2021; 11:669989. [PMID: 34141629 PMCID: PMC8204290 DOI: 10.3389/fcimb.2021.669989] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Periodontitis is a disease of ageing or inflammaging, and is comorbid with other more severe age-related chronic diseases. With advanced age comes an increase in accumulation of senescent cells that release soluble and insoluble pro-inflammatory factors collectively termed the senescence associated secretory phenotype (SASP). In the present report, we examined whether immune cells typical of those at the oral mucosa-microbe interface, are vulnerable to cellular senescence (CS) and the role of dysbiotic oral pathogen Porphyromonas gingivalis. Bone marrow-derived dendritic cells (DCs) from young (yDCs) and old (oDCs) mice were co-cultured in vitro with CS inducer doxorubicin or P.gingivalis (Pg), plus or minus senolytic agent rapamycin. CS profiling revealed elevated CS mediators SA-β-Gal, p16 INK4A, p53, and p21Waf1/Clip1 in oDCs, or yDCs in response to doxorubicin or P. gingivalis, reversible with rapamycin. Functional studies indicate impaired maturation function of oDCs, and yDC exposed to P. gingivalis; moreover, OVA-driven proliferation of CD4+ T cells from young OTII transgenic mice was impaired by oDCs or yDCs+Pg. The SASP of DCs, consisting of secreted exosomes and inflammasome-related cytokines was further analyzed. Exosomes of DCs cocultured with P. gingivalis (PgDCexo) were purified, quantitated and characterized. Though typical in terms of size, shape and phenotype, PgDCexo were 2-fold greater in number than control DCs, with several important distinctions. Namely, PgDCexo were enriched in age-related miRNAs, and miRNAs reported to disrupt immune homeostasis through negative regulation of apoptosis and autophagy functions. We further show that PgDCexo were enriched in P. gingivalis fimbrial adhesin protein mfa1 and in inflammasome related cytokines IL-1β, TNFα and IL-6. Functionally PgDCexo were readily endocytosed by recipient yDCs, amplifying functional impairment in maturation and ability to promote Ova-driven proliferation of OTII CD4+ T cells from young mice. In conclusion P. gingivalis induces premature (autocrine) senescence in DCs by direct cellular invasion and greatly amplifies senescence, in paracrine, of bystander DCs by secretion of inflammatory exosomes. The implications of this pathological pathway for periodontal disease in vivo is under investigation in mouse models.
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Affiliation(s)
- Ranya Elsayed
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - Mahmoud Elashiry
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - Yutao Liu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, United States
| | - Ahmed El-Awady
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - Mark Hamrick
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, United States
| | - Christopher W. Cutler
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States,*Correspondence: Christopher W. Cutler,
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Bocheva GS, Slominski RM, Slominski AT. Immunological Aspects of Skin Aging in Atopic Dermatitis. Int J Mol Sci 2021; 22:ijms22115729. [PMID: 34072076 PMCID: PMC8198400 DOI: 10.3390/ijms22115729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
The cutaneous immune response is important for the regulation of skin aging well as for the development of immune-mediated skin diseases. Aging of the human skin undergoes immunosenescence with immunological alterations and can be affected by environmental stressors and internal factors, thus leading to various epidermal barrier abnormalities. The dysfunctional epidermal barrier, immune dysregulation, and skin dysbiosis in the advanced age, together with the genetic factors, facilitate the late onset of atopic dermatitis (AD) in the elderly, whose cases have recently been on the rise. Controversial to the healthy aged skin, where overproduction of many cytokines is found, the levels of Th2/Th22 related cytokines inversely correlated with age in the skin of older AD patients. As opposed to an endogenously aged skin, the expression of the terminal differentiation markers significantly increases with age in AD. Despite the atenuated barrier disturbances in older AD patients, the aged skin carries an impairment associated with the aging process, which reflects the persistence of AD. The chronicity of AD in older patients might not directly affect skin aging but does not allow spontaneous remission. Thus, adult- and elderly subtypes of AD are considered as a lifelong disease.
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Affiliation(s)
- Georgeta St. Bocheva
- Department of Pharmacology and Toxicology, Medical University of Sofia, 1431 Sofia, Bulgaria
- Correspondence: (G.S.B.); (A.T.S.)
| | - Radomir M. Slominski
- Division of Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Veteran Administration Medical Center, Birmingham, AL 35294, USA
- Correspondence: (G.S.B.); (A.T.S.)
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26
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Andryukov BG, Besednova NN. Older adults: panoramic view on the COVID-19 vaccination. AIMS Public Health 2021; 8:388-415. [PMID: 34395690 PMCID: PMC8334630 DOI: 10.3934/publichealth.2021030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022] Open
Abstract
In December 2020, COVID-19 vaccination started in many countries, with which the world community hopes to stop the further spread of the current pandemic. More than 90% of sick and deceased patients belong to the category of older adults (65 years and older). This category of the population is most vulnerable to infectious diseases, so vaccination is the most effective preventive strategy, the need for which for older adults is indisputable. Here we briefly summarize information about age-related changes in the immune system and present current data on their impact on the formation of the immune response to vaccination. Older age is accompanied by the process of biological aging accompanied by involution of the immune system with increased susceptibility to infections and a decrease in the effect of immunization. Therefore, in the ongoing mass COVID-19 vaccination, the older adults are a growing public health concern. The authors provide an overview of the various types of COVID-19 vaccines approved for mass immunization of the population by the end of 2020, including older adults, as well as an overview of strategies and platforms to improve the effectiveness of vaccination of this population. In the final part, the authors propose for discussion a system for assessing the safety and monitoring the effectiveness of COVID-19 vaccines for the older adults.
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Affiliation(s)
- Boris G Andryukov
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087, Vladivostok, Russia
- Far Eastern Federal University (FEFU), 690091, Vladivostok, Russia
| | - Natalya N Besednova
- G.P. Somov Institute of Epidemiology and Microbiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 690087, Vladivostok, Russia
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Stoy N. Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19. Front Immunol 2021; 12:638446. [PMID: 33936053 PMCID: PMC8085890 DOI: 10.3389/fimmu.2021.638446] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 02/24/2021] [Indexed: 12/15/2022] Open
Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the "cytokine storm" of COVID-19.
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Affiliation(s)
- Nicholas Stoy
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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28
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Stavropoulou E, Kantartzi K, Tsigalou C, Aftzoglou K, Voidarou C, Konstantinidis T, Chifiriuc MC, Thodis E, Bezirtzoglou E. Microbiome, Immunosenescence, and Chronic Kidney Disease. Front Med (Lausanne) 2021; 8:661203. [PMID: 33816535 PMCID: PMC8017168 DOI: 10.3389/fmed.2021.661203] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 02/23/2021] [Indexed: 01/10/2023] Open
Abstract
The gut microbiome is known as an important predictive tool for perceiving characteristic shifts in disease states. Multiple renal diseases and pathologies seem to be associated with gut dysbiosis which directly affects host homeostasis. The gastrointestinal-kidney dialogue confers interesting information about the pathogenesis of multiple kidney diseases. Moreover, aging is followed by specific shifts in the human microbiome, and gradual elimination of physiological functions predisposes the microbiome to inflammaging, sarcopenia, and disease. Aging is characterized by a microbiota with an abundance of disease-associated pathobionts. Multiple factors such as the immune system, environment, medication, diet, and genetic endowment are involved in determining the age of the microbiome in health and disease. Our present review promotes recently acquired knowledge and is expected to inspire researchers to advance studies and investigations on the involved pathways of the gut microbiota and kidney axis.
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Affiliation(s)
- Elisavet Stavropoulou
- CHUV (Centre Hospitalier Universitaire Vaudois), Rue du Bugnon, Lausanne, Switzerland.,Department of Infectious Diseases, Central Institute, Valais Hospital, Sion, Switzerland
| | - Konstantia Kantartzi
- Nephrology Clinic, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece
| | - Christina Tsigalou
- Laboratory of Microbiology, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece
| | | | | | | | - Mariana Carmen Chifiriuc
- Laboratory of Microbiology, Faculty of Biology, The Research Institute of the University of Bucharest (ICUB), University of Bucharest, Bucharest, Romania
| | - Elias Thodis
- Nephrology Clinic, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece
| | - Eugenia Bezirtzoglou
- Laboratory of Hygiene and Environmental Protection, Department of Medicine, Democritus University of Thrace, Alexandroupoli, Greece
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29
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Feehan J, Tripodi N, Apostolopoulos V. The twilight of the immune system: The impact of immunosenescence in aging. Maturitas 2021; 147:7-13. [PMID: 33832647 DOI: 10.1016/j.maturitas.2021.02.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 12/22/2022]
Abstract
Cellular senescence is a critical part of human anti-tumor defence; however, the accumulation of senescent cells with age underpins a wide range of pathologies. Senescent change in immune cells, or immunosenescence, has a wide range of physiological effects and is at least partially responsible for many diseases associated with aging. Immunosenescence underpins inflammaging, increased vulnerability to infectious disease with age, malignant change in the elderly, and auto-immunity. Understanding the effects and mechanisms of immunosenescence will improve disease outcomes and prevention in older adults, and generate new treatments for common illnesses. In this review we summarize the key changes occurring in immunosenescence across each facet of the immune system, and identify their clinical correlates.
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Affiliation(s)
- Jack Feehan
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Melbourne, VIC, Australia; The Australian Institute for Musculoskeletal Science, The University of Melbourne, Victoria University and Western Health, Melbourne, VIC, Australia.
| | - Nicholas Tripodi
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia; The Australian Institute for Musculoskeletal Science, The University of Melbourne, Victoria University and Western Health, Melbourne, VIC, Australia
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30
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Honarpisheh P, Blixt FW, Blasco Conesa MP, Won W, d’Aigle J, Munshi Y, Hudobenko J, Furr JW, Mobley A, Lee J, Brannick KE, Zhu L, Hazen AL, Bryan RM, McCullough LD, Ganesh BP. Peripherally-sourced myeloid antigen presenting cells increase with advanced aging. Brain Behav Immun 2020; 90:235-247. [PMID: 32861719 PMCID: PMC8169202 DOI: 10.1016/j.bbi.2020.08.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/18/2020] [Accepted: 08/20/2020] [Indexed: 12/14/2022] Open
Abstract
Aging is associated with dysfunction of the gut microbiota-immune-brain axis, a major regulatory axis in both brain health and in central nervous system (CNS) diseases. Antigen presenting cells (APCs) play a major role in sensing changes in the gut microbiota and regulation of innate and adaptive immune responses. APCs have also been implicated in various chronic inflammatory conditions, including age-related neurodegenerative diseases. The increase in chronic low-level inflammation seen with aging has also been linked to behavioral decline. Despite their acknowledged importance along the gut microbiota-immune-brain axis, there is limited evidence on how APCs change with aging. In this study, we examined age-related changes in myeloid APCs in the gut, spleen, and brain as well as changes in the gut microbiota and behavioral phenotype in mice ranging in age from 2 months up to 32 months of both sexes. Our data show that the number of peripherally-sourced myeloid APCs significantly increases with advanced aging in the brain. In addition, our data showed that age-related changes in APCs are subset-specific in the gut and sexually dimorphic in the spleen. Our work highlights the importance of studying myeloid APCs in an age-, tissue-, and sex-specific manner.
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Affiliation(s)
- Pedram Honarpisheh
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX, United States.
| | - Frank W. Blixt
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX
| | | | - William Won
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX, United States.
| | - John d’Aigle
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX
| | - Yashasvee Munshi
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX, United States.
| | - Jacob Hudobenko
- University of Connecticut School of Medicine, Farmington, CT, United States.
| | - J. Weldon Furr
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX
| | - Alexis Mobley
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX, United States.
| | - Juneyoung Lee
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX, United States.
| | - Katherine E. Brannick
- The University of Texas Health Science Center at Houston, Center for Laboratory Animal Medicine and Care, Houston, TX
| | - Liang Zhu
- University of Texas Health Science Center at Houston, Internal Medicine, The CCTS Biostatistics, Epidemiology & Research Design (BERD), Houston, TX, United States.
| | - Amy L. Hazen
- University of Texas McGovern Medical School, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, TX
| | - Robert M. Bryan
- Baylor College of Medicine, Department of Anesthesiology, Houston, TX
| | - Louise D. McCullough
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX
| | - Bhanu P. Ganesh
- University of Texas McGovern Medical School, Department of Neurology, Houston, TX
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31
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DNA Damage Response and Oxidative Stress in Systemic Autoimmunity. Int J Mol Sci 2019; 21:ijms21010055. [PMID: 31861764 PMCID: PMC6982230 DOI: 10.3390/ijms21010055] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/15/2019] [Accepted: 12/18/2019] [Indexed: 02/08/2023] Open
Abstract
The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.
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32
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Grudzinska FS, Brodlie M, Scholefield BR, Jackson T, Scott A, Thickett DR, Sapey E. Neutrophils in community-acquired pneumonia: parallels in dysfunction at the extremes of age. Thorax 2019; 75:164-171. [PMID: 31732687 PMCID: PMC7029227 DOI: 10.1136/thoraxjnl-2018-212826] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 09/16/2019] [Accepted: 09/25/2019] [Indexed: 12/15/2022]
Abstract
"Science means constantly walking a tight rope" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.
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Affiliation(s)
- Frances Susanna Grudzinska
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Malcolm Brodlie
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Barnaby R Scholefield
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Thomas Jackson
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Aaron Scott
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - David R Thickett
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
| | - Elizabeth Sapey
- Institute of Inflammation and Ageing, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
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33
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Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol 2019; 144:144-156. [DOI: 10.1016/j.jaci.2019.01.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 01/04/2019] [Accepted: 01/17/2019] [Indexed: 12/31/2022]
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34
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Soda K. Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism. Int J Mol Sci 2018; 19:E3106. [PMID: 30309036 PMCID: PMC6213949 DOI: 10.3390/ijms19103106] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/01/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.
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Affiliation(s)
- Kuniyasu Soda
- Cardiovascular Research Institute, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama-city, Saitama Prefecture 330-8503, Japan.
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35
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Jiang T, Li G, Xu J, Gao S, Chen X. The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit? Front Immunol 2018; 9:2047. [PMID: 30319601 PMCID: PMC6170625 DOI: 10.3389/fimmu.2018.02047] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/20/2018] [Indexed: 12/22/2022] Open
Abstract
The role of autoimmunity in Parkinson's disease (PD), as one of the most popular research subjects, has been intensively investigated in recent years. Although the ultimate cause of PD is unknown, one major area of interest remains identifying new therapeutic targets and options for patients suffering from PD. Herein, we present a comprehensive review of the impacts of autoimmunity in neurodegenerative diseases, especially PD, and we have composed a logical argument to substantiate that autoimmunity is actively involved in the pathogenesis of PD through several proteins, including α-synuclein, DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells. Furthermore, a detailed analysis of the relevance of autoimmunity to the clinical symptoms of PD provides strong evidence for the close correlation of autoimmunity with PD. In addition, the previously identified relationships between other autoimmune diseases and PD help us to better understand the disease pattern, laying the foundation for new therapeutic solutions to PD. In summary, this review aims to integrate and present currently available data to clarify the pathogenesis of PD and discuss some controversial but innovative research perspectives on the involvement of autoimmunity in PD, as well as possible novel diagnostic methods and treatments based on autoimmunity targets.
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Affiliation(s)
- Tianfang Jiang
- Department of Neurology, Shanghai Eighth People's Hospital Affiliated to Jiang Su University, Shanghai, China
| | - Gen Li
- Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Xu
- East Hospital, Tong Ji University School of Medicine, Shanghai, China
| | - Shane Gao
- East Hospital, Tong Ji University School of Medicine, Shanghai, China
| | - Xu Chen
- Department of Neurology, Shanghai Eighth People's Hospital Affiliated to Jiang Su University, Shanghai, China
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Gardner JK, Cornwall SMJ, Musk AW, Alvarez J, Mamotte CDS, Jackaman C, Nowak AK, Nelson DJ. Elderly dendritic cells respond to LPS/IFN-γ and CD40L stimulation despite incomplete maturation. PLoS One 2018; 13:e0195313. [PMID: 29652910 PMCID: PMC5898732 DOI: 10.1371/journal.pone.0195313] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 03/20/2018] [Indexed: 01/10/2023] Open
Abstract
There is evidence that dendritic cells (DCs) undergo age-related changes that modulate their function with their key role being priming antigen-specific effector T cells. This occurs once DCs develop into antigen-presenting cells in response to stimuli/danger signals. However, the effects of aging on DC responses to bacterial lipopolysaccharide (LPS), the pro-inflammatory cytokine interferon (IFN)-γ and CD40 ligand (CD40L) have not yet been systematically evaluated. We examined responses of blood myeloid (m)DC1s, mDC2s, plasmacytoid (p)DCs, and monocyte-derived DCs (MoDCs) from young (21–40 years) and elderly (60–84 years) healthy human volunteers to LPS/IFN-γ or CD40L stimulation. All elderly DC subsets demonstrated comparable up-regulation of co-stimulatory molecules (CD40, CD80 and/or CD86), intracellular pro-inflammatory cytokine levels (IFN-γ, tumour necrosis factor (TNF)-α, IL-6 and/or IL-12), and/or secreted cytokine levels (IFN-α, IFN-γ, TNF-α, and IL-12) to their younger counterparts. Furthermore, elderly-derived LPS/IFN-γ or CD40L-activated MoDCs induced similar or increased levels of CD8+ and CD4+ T cell proliferation, and similar T cell functional phenotypes, to their younger counterparts. However, elderly LPS/IFN-γ-activated MoDCs were unreliable in their ability to up-regulate chemokine (IL-8 and monocyte chemoattractant protein (MCP)-1) and IL-6 secretion, implying an inability to dependably induce an inflammatory response. A key age-related difference was that, unlike young-derived MoDCs that completely lost their ability to process antigen, elderly-derived MoDCs maintained their antigen processing ability after LPS/IFN-γ maturation, measured using the DQ-ovalbumin assay; this response implies incomplete maturation that may enable elderly DCs to continuously present antigen. These differences may impact on the efficacy of anti-pathogen and anti-tumour immune responses in the elderly.
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Affiliation(s)
- Joanne K. Gardner
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia (WA), Australia
- Curtin Health Innovation Research Institute, Bentley, WA, Australia
| | - Scott M. J. Cornwall
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia (WA), Australia
- Curtin Health Innovation Research Institute, Bentley, WA, Australia
| | - Arthur W. Musk
- Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | | | - Cyril D. S. Mamotte
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia (WA), Australia
- Curtin Health Innovation Research Institute, Bentley, WA, Australia
| | - Connie Jackaman
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia (WA), Australia
- Curtin Health Innovation Research Institute, Bentley, WA, Australia
| | - Anna K. Nowak
- School of Medicine, University of WA, Nedlands, Perth, WA, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Perth, WA, Australia
| | - Delia J. Nelson
- School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Western Australia (WA), Australia
- Curtin Health Innovation Research Institute, Bentley, WA, Australia
- * E-mail:
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Ray D, Yung R. Immune senescence, epigenetics and autoimmunity. Clin Immunol 2018; 196:59-63. [PMID: 29654845 DOI: 10.1016/j.clim.2018.04.002] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 04/05/2018] [Accepted: 04/05/2018] [Indexed: 12/17/2022]
Abstract
Aging of the immune system in humans and animals is characterized by a decline in both adaptive and innate immune responses. Paradoxically, aging is also associated with a state of chronic inflammation ("inflammaging") and an increased likelihood of developing autoimmune diseases. Epigenetic changes in non-dividing and dividing cells, including immune cells, due to environmental factors contribute to the inflammation and autoimmunity that characterize both the state and diseases of aging. Here, we review the epigenetic mechanisms involved in the development of immune senescence and autoimmunity in old age.
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Affiliation(s)
- Donna Ray
- Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - Raymond Yung
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
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Ebersole JL, Graves CL, Gonzalez OA, Dawson D, Morford LA, Huja PE, Hartsfield JK, Huja SS, Pandruvada S, Wallet SM. Aging, inflammation, immunity and periodontal disease. Periodontol 2000 2018; 72:54-75. [PMID: 27501491 DOI: 10.1111/prd.12135] [Citation(s) in RCA: 163] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2015] [Indexed: 12/29/2022]
Abstract
The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry.
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Gardner JK, Mamotte CD, Jackaman C, Nelson DJ. Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules. Ageing Res Rev 2017; 38:40-51. [PMID: 28736117 DOI: 10.1016/j.arr.2017.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/17/2017] [Accepted: 07/17/2017] [Indexed: 12/24/2022]
Abstract
Dendritic cells (DCs) undergo continuous changes throughout life, and there is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour immune responses in elderly people with cancer. Changes in checkpoint inhibitory molecules/pathways during aging may be one mechanism that impairs the ability of elderly DCs to activate T cells. However, little is currently known regarding the combined effects of aging and cancer on DC and T cell inhibitory molecules/pathways. In this review, we discuss our current understanding of the influence of aging and cancer on key DC and T cell inhibitory molecules/pathways, the potential underlying cellular and molecular mechanisms contributing to their modulation, and the possibility of therapeutically targeting inhibitory molecules in elderly cancer patients.
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Cao Dinh H, Beyer I, Mets T, Onyema OO, Njemini R, Renmans W, De Waele M, Jochmans K, Vander Meeren S, Bautmans I. Effects of Physical Exercise on Markers of Cellular Immunosenescence: A Systematic Review. Calcif Tissue Int 2017; 100:193-215. [PMID: 27866236 DOI: 10.1007/s00223-016-0212-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 11/07/2016] [Indexed: 12/31/2022]
Abstract
Aging affects negatively the immune system, defined as immunosenescence, which increases the susceptibility of elderly persons to infection, autoimmune disease, and cancer. There are strong indications that physical exercise in elderly persons may prevent the age-related decline in immune response without significant side effects. Consequently, exercise is being considered as a safe mode of intervention to reduce immunosenescence. The aim of this review was to appraise the existing evidence regarding the impact of exercise on surface markers of cellular immunosenescence in either young and old humans or animals. PubMed and Web of Science were systematically screened, and 28 relevant articles in humans or animals were retrieved. Most of the intervention studies demonstrated that an acute bout of exercise induced increases in senescent, naïve, memory CD4+ and CD8+ T-lymphocytes and significantly elevated apoptotic lymphocytes in peripheral blood. As regards long-term effects, exercise induced increased levels of T-lymphocytes expressing CD28+ in both young and elderly subjects. Few studies found an increase in natural killer cell activity following a period of training. We can conclude that exercise has considerable effects on markers of cellular aspects of the immune system. However, very few studies have been conducted so far to investigate the effects of exercise on markers of cellular immunosenescence in elderly persons. Implications for immunosenescence need further investigation.
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Affiliation(s)
- H Cao Dinh
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Gerontology Department, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - I Beyer
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Geriatrics Department, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - T Mets
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Gerontology Department, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Geriatrics Department, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - O O Onyema
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Gerontology Department, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - R Njemini
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Gerontology Department, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - W Renmans
- Laboratory of Hematology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - M De Waele
- Laboratory of Hematology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - K Jochmans
- Laboratory of Hematology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - S Vander Meeren
- Laboratory of Hematology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
| | - I Bautmans
- Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Gerontology Department, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Geriatrics Department, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
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Morii K, Nagano Y, Yamamoto T, Nakamura S, Okushin H. Increasing incidence of elderly-onset autoimmune hepatitis. Geriatr Gerontol Int 2016; 17:1722-1728. [PMID: 27531184 DOI: 10.1111/ggi.12874] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 12/24/2022]
Abstract
AIM Autoimmune hepatitis (AIH) commonly shows bimodal distribution of onset age: at young adulthood and at 50-60 years-of-age. However, in recent times, the incidence of elderly-onset AIH seems to be increasing. This study aimed to investigate whether the incidence of elderly-onset AIH is increasing, and whether these patients show any clinical features different from those observed in younger patients. METHODS Data about patients with newly diagnosed AIH visiting the Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan, were retrospectively collected for the period ranging from January 2010 to May 2016. A total of 71 patients (56 women and 15 men, age 18-88 years) were included in this study. Patients were divided into two cohorts: elderly (≥70 years; n = 28) and adult cohort (15-69 years; n = 43). Demographic and clinical characteristics, biochemical and serological markers, radiological and histological findings, and therapeutic courses were evaluated. RESULTS The median age of the patients was 65 years, the most frequent range being the 70s (37%), followed by the 60s (25%). The elderly cohort had significantly higher levels of serum immunoglobulin G and antinuclear antibody, lesser hepatitis activity scores, and lesser chance of developing other autoimmune diseases. They tended to have higher C-reactive protein levels and lower serum alanine aminotransferase levels. All patients achieved clinical remission after treatment. CONCLUSIONS This study clearly showed an increase in the incidence of elderly-onset AIH. These patients had some unique characteristics, showing that the development of elderly-onset AIH is influenced by age-associated immune dysfunction called immunosenescence. Geriatr Gerontol Int 2017; 17: 1722-1728.
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Affiliation(s)
- Kazuhiko Morii
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Yuh Nagano
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Takeharu Yamamoto
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Shinichiro Nakamura
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Kitaku, Okayama, Japan
| | - Hiroaki Okushin
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
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CD3(+)CD8(+)CD28(-) T Lymphocytes in Patients with Lupus Nephritis. J Immunol Res 2016; 2016:1058165. [PMID: 27446964 PMCID: PMC4944066 DOI: 10.1155/2016/1058165] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/28/2016] [Accepted: 06/01/2016] [Indexed: 01/10/2023] Open
Abstract
The results of studies on the CD3+CD8+CD28− cells in SLE are inconsistent since several analyses describe CD3+CD8+CD28− as either immunosuppressive or cytotoxic. The aim of this study is to inquire whether the quantitative changes of CD3+CD8+CD28− T lymphocytes subpopulation are related to the clinical status of patients with lupus nephritis. Evaluation of Foxp3 expression on CD3+CD8+CD28− cells may shed some light on functional properties of these cells. 54 adult SLE patients and 19 sex and age matched healthy volunteers were enrolled in the study. There were 15 patients in inactive (SLEDAI ≤ 5) and 39 in active (SLEDAI > 5) phase of disease. We determined absolute count of CD3+CD8+CD28− and CD3+CD8+CD28−Foxp3+ subpopulations by flow cytometry. We observed a statistically significant increase in absolute count and percentage of CD3+CD8+CD28− in SLE patients compared to HC (p < 0.001). Moreover there was significant positive correlation between increasing absolute count of CD3+CD8+CD28− cells and disease activity measured by SLEDAI (rs = 0.281, p = 0.038). Active LN patients had increased absolute count of CD3+CD8+CD28− cells compared to HC. Positive correlation of CD3+CD8+CD28− number with disease activity, and lack of Foxp3 expression on these cells, suggests that CD3+CD8+CD28− lymphocytes might be responsible for an increased proinflammatory response in the exacerbation of SLE.
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do Nascimento MPP, Pinke KH, Penitenti M, Ikoma MRV, Lara VS. Aging does not affect the ability of human monocyte-derived dendritic cells to phagocytose Candida albicans. Aging Clin Exp Res 2015; 27:785-9. [PMID: 25783173 DOI: 10.1007/s40520-015-0344-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 02/24/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Dendritic cells (DCs) are the most potent antigen-presenting cells, playing a key role in induction of both innate and adaptive immunity. Immunosenescence refers to age-associated changes in the immune system, which may be associated with susceptibility to infections and their clinical complications. The precise effects of aging on DCs in immunity to infections are not well understood. Among the common pathogenic microorganisms, the fungus Candida albicans is an important pathogen for the development of invasive infections, especially in immunocompromised individuals, as well as during aging. AIMS To make a comparative in vitro evaluation of the immunomodulatory function of DCs challenged with C. albicans, by phagocytosis of the fungal cells, and determine the involvement of TLR2 and TLR4 receptors. For this purpose, DCs were generated with the use of peripheral blood monocytes from healthy young and aged subjects. RESULTS The phagocytosis of C. albicans is developed by DCs in TLR2- and TLR4-dependent way. This mechanism is not affected by aging. CONCLUSION Given the important role of the DCs in responses against the fungus, it is evident that if changes in phagocytosis occurred with aging, impairment in the elderly could develop. However, the evidence that phagocytosis of this fungus by DCs is not impaired with aging, brings us to the question of which are the mechanisms truly associated with the prevalence of certain diseases in the elderly.
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Affiliation(s)
- Magda Paula Pereira do Nascimento
- Department of Stomatology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, Bauru, SP, 17012-901, Brazil
| | - Karen Henriette Pinke
- Department of Stomatology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, Bauru, SP, 17012-901, Brazil
| | - Marcimara Penitenti
- Flow Cytometry Laboratory, Amaral Carvalho Foundation, R. Dona Silvéria, 150, Centro, Jau, SP, 17210-080, Brazil
| | - Maura Rosane Valério Ikoma
- Flow Cytometry Laboratory, Amaral Carvalho Foundation, R. Dona Silvéria, 150, Centro, Jau, SP, 17210-080, Brazil
| | - Vanessa Soares Lara
- Department of Stomatology, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisola, 9-75, Vila Universitária, Bauru, SP, 17012-901, Brazil.
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Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, Janssen EM. Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 195:2624-32. [PMID: 26246142 PMCID: PMC4561185 DOI: 10.4049/jimmunol.1501006] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 07/13/2015] [Indexed: 01/04/2023]
Abstract
Impaired functionality of dendritic cells (DCs) significantly contributes to decreased adaptive immune responses in aged hosts. The expression of MHC-peptide on the DC surface is the critical first step in T cell priming, but few studies have addressed the effect of aging on Ag acquisition, processing, and presentation by DCs. In this study, we show that aged murine DCs were less efficient in the cross-presentation of cell-associated Ag and subsequently in the cross-priming of CD8(+) T cells than were their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8α DCs and merocytic (CD8α(-)CD11b(-))DCs that could endocytose cell-associated Ag, as well as the number and the size of the endocytosed particles in the DC that did internalize cell-associated materials. Mechanistically, phagocytic capacity has been associated with mitochondrial activity and membrane potential (Δψm). Aged DCs exhibited profound signs of mitochondrial dysfunction, illustrated by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and reactive oxygen species (ROS) production. Mimicking the aged metabolic phenotype in young DCs by pharmacologic manipulation indicated that the reductions in Δψm and ATP impeded the phagocytic capacity whereas ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. Taken together, these data suggest that improvement of aged DC functionality might be feasible in the elderly by targeting metabolic dysfunction or its downstream sequelae, thereby opening new avenues for enhancing vaccine efficiency in this population.
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Affiliation(s)
- Claire A Chougnet
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Robert I Thacker
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Hesham M Shehata
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Cassandra M Hennies
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Maria A Lehn
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Celine S Lages
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
| | - Edith M Janssen
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
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The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3(+) lymphocyte-primed multipotent precursors. Cell Mol Immunol 2015; 13:593-604. [PMID: 26051474 DOI: 10.1038/cmi.2015.39] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 04/16/2015] [Accepted: 04/16/2015] [Indexed: 12/23/2022] Open
Abstract
The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a(-)CD8α(+)conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3(+) lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging.
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Alyamkina EA, Nikolin VP, Popova NA, Minkevich AM, Kozel AV, Dolgova EV, Efremov YR, Bayborodin SI, Andrushkevich OM, Taranov OS, Omigov VV, Rogachev VA, Proskurina AS, Vereschagin EI, Kiseleva EV, Zhukova MV, Ostanin AA, Chernykh ER, Bogachev SS, Shurdov MA. Combination of cyclophosphamide and double-stranded DNA demonstrates synergistic toxicity against established xenografts. Cancer Cell Int 2015; 15:32. [PMID: 25798073 PMCID: PMC4369063 DOI: 10.1186/s12935-015-0180-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 02/24/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Extracellular double-stranded DNA participates in various processes in an organism. Here we report the suppressive effects of fragmented human double-stranded DNA along or in combination with cyclophosphamide on solid and ascites grafts of mouse Krebs-2 tumor cells and DNA preparation on human breast adenocarcinoma cell line MCF-7. METHODS Apoptosis and necrosis were assayed by electrophoretic analysis (DNA nucleosomal fragmentation) and by measurements of LDH levels in ascitic fluid, respectively. DNA internalization into MCF-7 was analyzed by flow cytometry and fluorescence microscopy. RESULTS Direct cytotoxic activity of double-stranded DNA (along or in combination with cyclophosphamide) on a solid transplant was demonstrated. This resulted in delayed solid tumor proliferation and partial tumor lysis due to necrosis of the tumor and adjacent tissues. In the case of ascites form of tumor, extensive apoptosis and secondary necrosis were observed. Similarly, MCF-7 cells showed induction of massive apoptosis (up to 45%) as a result of treatments with double-stranded DNA preparation. CONCLUSIONS Double-stranded DNA (along or in combination with cyclophosphamide) induces massive apoptosis of Krebs-2 ascite cells and MCF-7 cell line (DNA only). In treated mice it reduces the integrity of gut wall cells and contributes to the development of systemic inflammatory reaction.
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Affiliation(s)
- Ekaterina A Alyamkina
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Valeriy P Nikolin
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Nelly A Popova
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
- />Novosibirsk State University, Novosibirsk, 630090 Russia
| | - Alexandra M Minkevich
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Artem V Kozel
- />Novosibirsk State University, Novosibirsk, 630090 Russia
| | - Evgenia V Dolgova
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Yaroslav R Efremov
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
- />Novosibirsk State University, Novosibirsk, 630090 Russia
| | - Sergey I Bayborodin
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
- />Novosibirsk State University, Novosibirsk, 630090 Russia
| | - Oleg M Andrushkevich
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
- />Novosibirsk State University, Novosibirsk, 630090 Russia
| | - Oleg S Taranov
- />The State Research Center of Virology and Biotechnology VECTOR, Koltsovo, Novosibirsk region 630559 Russia
| | - Vladimir V Omigov
- />The State Research Center of Virology and Biotechnology VECTOR, Koltsovo, Novosibirsk region 630559 Russia
| | - Vladimir A Rogachev
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Anastasia S Proskurina
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | | | - Elena V Kiseleva
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Maria V Zhukova
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
| | - Alexandr A Ostanin
- />Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, 630099 Russia
| | - Elena R Chernykh
- />Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, 630099 Russia
| | - Sergey S Bogachev
- />Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, 630090 Novosibirsk, Russia
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Proskurina AS, Gvozdeva TS, Alyamkina EA, Dolgova EV, Orishchenko KE, Nikolin VP, Popova NA, Sidorov SV, Chernykh ER, Ostanin AA, Leplina OY, Dvornichenko VV, Ponomarenko DM, Soldatova GS, Varaksin NA, Ryabicheva TG, Uchakin PN, Zagrebelniy SN, Rogachev VA, Bogachev SS, Shurdov MA. Results of multicenter double-blind placebo-controlled phase II clinical trial of Panagen preparation to evaluate its leukostimulatory activity and formation of the adaptive immune response in patients with stage II-IV breast cancer. BMC Cancer 2015; 15:122. [PMID: 25886605 PMCID: PMC4365563 DOI: 10.1186/s12885-015-1142-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 02/27/2015] [Indexed: 12/20/2022] Open
Abstract
Background We performed a multicenter, double-blind, placebo-controlled, phase II clinical trial of human dsDNA-based preparation Panagen in a tablet form. In total, 80 female patients with stage II-IV breast cancer were recruited. Methods Patients received three consecutive FAC (5-fluorouracil, doxorubicin and cyclophosphamide) or AC (doxorubicin and cyclophosphamide) adjuvant chemotherapies (3 weeks per course) and 6 tablets of 5 mg Panagen or placebo daily (one tablet every 2–3 hours, 30 mg/day) for 18 days during each chemotherapy course. Statistical analysis was performed using Statistica 6.0 software, and non-parametric analyses, namely Wilcoxon-Mann–Whitney and paired Wilcoxon tests. To describe the results, the following parameters were used: number of observations (n), median, interquartile range, and minimum-maximum range. Results Panagen displayed pronounced leukostimulatory and leukoprotective effects when combined with chemotherapy. In an ancillary protocol, anticancer effects of a tablet form of Panagen were analyzed. We show that Panagen helps maintain the pre-therapeutic activity level of innate antitumor immunity and induces formation of a peripheral pool of cytotoxic CD8+ perforin + T-cells. Our 3-year follow-up analysis demonstrates that 24% of patients who received Panagen relapsed or died after the therapy, as compared to 45% in the placebo cohort. Conclusions The data collected in this trial set Panagen as a multi-faceted “all-in-one” medicine that is capable of simultaneously sustaining hematopoiesis, sparing the innate immune cells from adverse effects of three consecutive rounds of chemotherapy and boosting individual adaptive immunity. Its unique feature is that it is delivered via gastrointestinal tract and acts through the lymphoid system of intestinal mucosa. Taken together, maintenance of the initial levels of innate immunity, development of adaptive cytotoxic immune response and significantly reduced incidence of relapses 3 years after the therapy argue for the anticancer activity of Panagen. Trial registration ClinicalTrials.gov NCT02115984 from 04/07/2014. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1142-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anastasia S Proskurina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | | | - Ekaterina A Alyamkina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | - Evgenia V Dolgova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | - Konstantin E Orishchenko
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | - Valeriy P Nikolin
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | - Nelly A Popova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia. .,Novosibirsk State University, Novosibirsk, 630090, Russia.
| | - Sergey V Sidorov
- Novosibirsk State University, Novosibirsk, 630090, Russia. .,Oncology Department of Municipal Hospital No 1, Novosibirsk, 630047, Russia.
| | - Elena R Chernykh
- Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, 630099, Russia.
| | - Alexandr A Ostanin
- Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, 630099, Russia.
| | - Olga Y Leplina
- Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, 630099, Russia.
| | - Victoria V Dvornichenko
- Irkutsk State Medical Academy of Postgraduate Education, Irkutsk, 664049, Russia. .,Regional Oncology Dispensary, Irkutsk, 664035, Russia.
| | - Dmitriy M Ponomarenko
- Irkutsk State Medical Academy of Postgraduate Education, Irkutsk, 664049, Russia. .,Regional Oncology Dispensary, Irkutsk, 664035, Russia.
| | - Galina S Soldatova
- Novosibirsk State University, Novosibirsk, 630090, Russia. .,Clinic Department of the Central Clinical Hospital, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | | | | | | | | | - Vladimir A Rogachev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
| | - Sergey S Bogachev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 10 Lavrentieva ave, Novosibirsk, 630090, Russia.
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Choi W, Byun YJ, Jung E, Noh H, Hajrasouliha AR, Sadrai Z, Chang E, Lee JH, Lee HK. Chemokine decoy receptor D6 mimicking trap (D6MT) prevents allosensitization and immune rejection in murine corneal allograft model. J Leukoc Biol 2014; 97:413-24. [PMID: 25395300 DOI: 10.1189/jlb.5a0414-233rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Although corneal allotransplantation is performed in the immune-privileged cornea, many grafts are still rejected after transplantation. This study examined the role of chemokine receptor D6 expression in a corneal allograft rejection, investigated the modulation of D6 expression in cells, and determined the effect of D6 on graft survival. Interestingly, D6 was highly expressed in CD45 -: cells and the corneal epithelium of accepted corneal allografts. From the mouse corneal allograft model, TGF-β was found to play a key role in D6 up-regulation, leading to reduced CCL2, CCL5, and CCL3. To modulate D6 chemokine binding, a D6MT was developed and showed effective chemokine trapping through SPR and FACS assays. By treating corneal allografts with D6MT, the allograft survival rate was improved, and (lymph) angiogenesis was reduced. Direct allosensitization and DC LN homing was drastically reduced in the mouse corneal allograft model. These findings suggest that TGF-β is a positive regulator of D6 expression, and it is a potential therapeutic target to enhance the survival of corneal allografts.
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Affiliation(s)
- Wungrak Choi
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Yu Jeong Byun
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Eunae Jung
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Hyemi Noh
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Amir R Hajrasouliha
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Zahra Sadrai
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Eunju Chang
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Joon H Lee
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
| | - Hyung Keun Lee
- *Institute of Vision Research, Department of Ophthalmology, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea; Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, Kentucky, USA; Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; and Myunggok Eye Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea
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Boraschi D, Italiani P. Immunosenescence and vaccine failure in the elderly: Strategies for improving response. Immunol Lett 2014; 162:346-53. [DOI: 10.1016/j.imlet.2014.06.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/09/2014] [Accepted: 06/12/2014] [Indexed: 12/21/2022]
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Boraschi D, Aguado MT, Dutel C, Goronzy J, Louis J, Grubeck-Loebenstein B, Rappuoli R, Del Giudice G. The gracefully aging immune system. Sci Transl Med 2014; 5:185ps8. [PMID: 23677590 DOI: 10.1126/scitranslmed.3005624] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Prolonged life expectancy in the 20th century has been one of humankind's greatest triumphs. However, the substantial increase in the human life span has ushered in a new concern: healthy aging. Because infectious diseases prominently contribute to morbidity in the particularly vulnerable elderly population, strategies for preventing these diseases would have a clear impact on improving healthy aging. Thus, vaccines and immunization strategies tailored for the elderly population are needed, and vaccines should be developed to take into consideration the peculiar age-induced variations of immune responsiveness. The conference "Ageing and Immunity" recently held in Siena, Italy, has reviewed and discussed several possible causes of immune senescence, as well as strategies for counteracting this waning of immune responsiveness and for restoring immunocompetence. In addition, examples of diseases that should be targeted by vaccination in the senior population were considered.
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Affiliation(s)
- Diana Boraschi
- Institute of Biomedical Technologies, National Research Council, Pisa 56124, Italy
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