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1
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Huong TT, Thong NV, The TM, Tram LH, Thuy LT, My NTT, Dung DV, Huong DTM, Van Cuong P, Ta V, Bach NV, Van Thanh B. Anti-Inflammatory Activity and In Silico Approach of Phenolics From the Roots of Aganonerion polymorphum. Chem Biodivers 2025:e202500185. [PMID: 40235136 DOI: 10.1002/cbdv.202500185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 04/17/2025]
Abstract
A study on the chemical components from the roots of Aganonerion polymorphum resulted in the isolation of a new and six first isolated compounds. The structure of the new compound was definitively determined by the employment of multiple spectroscopic techniques, hydrolysis reaction, followed by high-performance liquid chromatography-mass spectrometry analysis in comparison with those reported in the literature. All compounds were evaluated for inhibitory effect in lipopolysaccharide (LPS)-induced nitric oxide (NO) production on RAW264.7 cells. Compounds 1, 4, 6, and 7 demonstrated IC50 values of 4.71 ± 0.08, 7.89 ± 0.42, 7.51 ± 0.70, and 9.63 ± 0.40 µM, respectively, which considerably decreased NO generation generated by LPS-activated RAW264.7 cells. This is the first investigation of the anti-inflammatory capacity of A. polymorphum. Molecular docking offers proof of their anti-inflammatory properties by how well these compounds bind to the proteins that target inflammation. Our findings either highlight chemical or pharmacology investigation from this plant for utilizing the development of functional products to manage inflammatory diseases.
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Affiliation(s)
- Tran Thu Huong
- Hanoi University of Science and Technology, Hanoi, Vietnam
| | | | - Tran Minh The
- Hanoi University of Science and Technology, Hanoi, Vietnam
- Public Security Institute of Science and Technology, Hanoi, Vietnam
| | - Le Huyen Tram
- Hanoi University of Science and Technology, Hanoi, Vietnam
| | - Le Thi Thuy
- Hanoi University of Science and Technology, Hanoi, Vietnam
| | | | | | | | | | | | | | - Bui Van Thanh
- Institute of Ecology and Biological Resources (IEBR), Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
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2
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Gergues M, Bari R, Koppisetti S, Gosiewska A, Kang L, Hariri RJ. Senescence, NK cells, and cancer: navigating the crossroads of aging and disease. Front Immunol 2025; 16:1565278. [PMID: 40255394 PMCID: PMC12006071 DOI: 10.3389/fimmu.2025.1565278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/18/2025] [Indexed: 04/22/2025] Open
Abstract
Cellular senescence, a state of stable cell cycle arrest, acts as a double-edged sword in cancer biology. In young organisms, it acts as a barrier against tumorigenesis, but in the aging population, it may facilitate tumor growth and metastasis through the senescence-associated secretory phenotype (SASP). Natural killer (NK) cells play a critical role in the immune system, particularly in the surveillance, targeting, and elimination of malignant and senescent cells. However, age-related immunosenescence is characterized by declining NK cell function resulting in diminished ability to fight infection, eliminate senescent cells and suppress tumor development. This implies that preserving or augmenting NK cell function may be central to defense against age-related degenerative and malignant diseases. This review explores the underlying mechanisms behind these interactions, focusing on how aging influences the battle between the immune system and cancer, the implications of senescent NK cells in disease progression, and the potential of adoptive NK cell therapy as a countermeasure to these age-related immunological challenges.
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Affiliation(s)
| | | | | | | | - Lin Kang
- Research and Development, Celularity Inc., Florham Park, NJ, United States
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3
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Basu S, Ulbricht Y, Rossol M. Healthy and premature aging of monocytes and macrophages. Front Immunol 2025; 16:1506165. [PMID: 40165963 PMCID: PMC11955604 DOI: 10.3389/fimmu.2025.1506165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 02/28/2025] [Indexed: 04/02/2025] Open
Abstract
Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.
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Affiliation(s)
- Syamantak Basu
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
| | - Ying Ulbricht
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
| | - Manuela Rossol
- Molecular Immunology, Faculty of Health Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Environment and Natural Sciences, Brandenburg University of Technology (BTU) Cottbus-Senftenberg, Senftenberg, Germany
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4
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Xie Z, Lin M, Xing B, Wang H, Zhang H, Cai Z, Mei X, Zhu ZJ. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice. SCIENCE ADVANCES 2025; 11:eads4957. [PMID: 40053596 PMCID: PMC11887811 DOI: 10.1126/sciadv.ads4957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 01/31/2025] [Indexed: 03/09/2025]
Abstract
Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.
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Affiliation(s)
- Zhangdan Xie
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Moubin Lin
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, P.R. China
| | - Beizi Xing
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Hongmiao Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Haosong Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Zimu Cai
- College of Marine Life Sciences, Ocean University of China, Qingdao 266003, P. R. China
| | - Xinyu Mei
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, P.R. China
| | - Zheng-Jiang Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
- Shanghai Key Laboratory of Aging Studies, Shanghai 201210, P. R. China
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5
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Liu Z, Li Y, Ren Y, Chen J, Weng S, Zhou Z, Luo P, Chen Q, Xu H, Ba Y, Zuo A, Liu S, Zhang Y, Pan T, Han X. Efferocytosis: The Janus-Faced Gatekeeper of Aging and Tumor Fate. Aging Cell 2025; 24:e14467. [PMID: 39748782 PMCID: PMC11822654 DOI: 10.1111/acel.14467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 10/30/2024] [Accepted: 12/12/2024] [Indexed: 01/04/2025] Open
Abstract
From embryogenesis to aging, billions of cells perish daily in mammals. The multistep process by which phagocytes engulf these deceased cells without eliciting an inflammatory response is called efferocytosis. Despite significant insights into the fundamental mechanisms of efferocytosis, its implications in disorders such as aging and cancer remain elusive. Upon summarizing and analyzing existing studies on efferocytosis, it becomes evident that efferocytosis is our friend in resolving inflammation, yet it transforms into our foe by facilitating tumor development and metastasis. This review illuminates recent discoveries regarding the emerging mechanisms of efferocytosis in clearing apoptotic cells, explores its connections with aging, examines its influence on tumor development and metastasis, and identifies the regulatory factors of efferocytosis within the tumor microenvironment. A comprehensive understanding of these efferocytosis facets offers insights into crucial physiological and pathophysiological processes, paving the way for innovative therapeutic approaches to combat aging and cancer.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Interventional Institute of Zhengzhou UniversityZhengzhouHenanChina
- Interventional Treatment and Clinical Research Center of Henan ProvinceZhengzhouHenanChina
- Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yan Li
- Medical School of Zhengzhou UniversityZhengzhouHenanChina
| | - Yuqing Ren
- Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Jingqi Chen
- Medical School of Zhengzhou UniversityZhengzhouHenanChina
| | - Siyuan Weng
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Zhaokai Zhou
- Department of UrologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Peng Luo
- The Department of Oncology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Quan Chen
- Department of Neurosurgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Hui Xu
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Yuhao Ba
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Anning Zuo
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Shutong Liu
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Yuyuan Zhang
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Teng Pan
- Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College)ShenzhenGuangdongChina
| | - Xinwei Han
- Department of Interventional RadiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Interventional Institute of Zhengzhou UniversityZhengzhouHenanChina
- Interventional Treatment and Clinical Research Center of Henan ProvinceZhengzhouHenanChina
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6
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Reusswig F, An O, Deppermann C. Platelet life cycle during aging: function, production and clearance. Platelets 2024; 35:2433750. [PMID: 39618096 DOI: 10.1080/09537104.2024.2433750] [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: 09/04/2024] [Revised: 10/10/2024] [Accepted: 11/15/2024] [Indexed: 12/13/2024]
Abstract
Platelets are important players in hemostasis. Alterations in platelet number and/or function lead to life-threatening conditions like thrombosis, myocardial infarction and stroke. During aging, changes at the cellular, organ and systemic level occur that affect platelet counts, platelet functionality, the expression of platelet surface receptors, clearance markers as well as their interactions with immune cells. Understanding how these changes influence platelets can help to prevent the alterations of hemostasis and thrombosis we observe in the elderly. In this review, we highlight the respective changes at important sites of the platelet life cycle: bone marrow, liver and spleen, but also show how alterations in immunity contribute. We point out the necessity for further research on age-related systemic alterations in these systems and their interplay with platelets to better understand the complex processes that cause alterations in the platelet life cycle during aging.
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Affiliation(s)
- Friedrich Reusswig
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Olga An
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Research Center for Immune Therapy, Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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7
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Rice MC, Imun M, Jung SW, Park CY, Kim JS, Lai RW, Barr CR, Son JM, Tor K, Kim E, Lu RJ, Cohen I, Benayoun BA, Lee C. The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.02.530691. [PMID: 39553971 PMCID: PMC11565950 DOI: 10.1101/2023.03.02.530691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFNγ, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.
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8
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Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: Mechanisms and role in diseases. Ageing Res Rev 2024; 101:102540. [PMID: 39395575 DOI: 10.1016/j.arr.2024.102540] [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: 04/28/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/14/2024]
Abstract
Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechanisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.
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Affiliation(s)
- Amir Ajoolabady
- Department of Biomedical Engineering, University of Alabama at Birmingham, AL 35294, USA
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Shuqin Zhou
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Claudio Franceschi
- IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy; Department of Applied Mathematics and Laboratory of Systems Biology of Aging, Lobachevsky University, Nizhny Novgorod, Russia.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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9
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Ji RC. The emerging importance of lymphangiogenesis in aging and aging-associated diseases. Mech Ageing Dev 2024; 221:111975. [PMID: 39089499 DOI: 10.1016/j.mad.2024.111975] [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: 05/15/2024] [Revised: 07/17/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.
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Affiliation(s)
- Rui-Cheng Ji
- Faculty of Welfare and Health Science, Oita University, Oita 870-1192, Japan.
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10
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Stiel L, Gaudet A, Thietart S, Vallet H, Bastard P, Voiriot G, Oualha M, Sarton B, Kallel H, Brechot N, Kreitmann L, Benghanem S, Joffre J, Jouan Y. Innate immune response in acute critical illness: a narrative review. Ann Intensive Care 2024; 14:137. [PMID: 39227416 PMCID: PMC11371990 DOI: 10.1186/s13613-024-01355-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/23/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies. MAIN TEXT Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population. CONCLUSIONS Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.
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Affiliation(s)
- Laure Stiel
- Department of Intensive Care Medicine, Groupe Hospitalier de la Région Mulhouse Sud Alsace, Mulhouse, France.
- Lipness Team, INSERM Research Team, LNC UMR 1231 and LabEx LipSTIC, University of Burgundy, Dijon, France.
| | - Alexandre Gaudet
- CHU Lille, Department of Intensive Care Medicine, Critical Care Center, Univ. Lille, 59000, Lille, France
- CIIL (Centre d'Infection et d'Immunité de Lille), Institut Pasteur de Lille, U1019-UMR9017, 59000, Lille, France
| | - Sara Thietart
- Département de Gériatrie, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
- Inserm, PARCC U970, F75, Université Paris Cité, Paris, France
| | - Hélène Vallet
- Department of Geriatric Medicine, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Saint Antoine, Paris, France
- INSERM UMR1135, Centre d'immunologie et des Maladies Infectieuses, Sorbonne Université, Paris, France
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Imagine Institute, University of Paris, Paris, France
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Guillaume Voiriot
- Service de Médecine Intensive Réanimation, Hôpital Tenon, Hôpitaux de Paris, Paris, France
- Centre de Recherche, Saint-Antoine UMRS_938, INSERM, Sorbonne Université, Assistance Publique, Paris, France
| | - Mehdi Oualha
- Pediatric Intensive Care Unit, Necker Hospital, APHP, Centre-Paris University, Paris, France
| | - Benjamine Sarton
- Service de Réanimation Polyvalente Purpan, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- ToNIC Lab (Toulouse NeuroImaging Center) INSERM/UPS UMR 1214, 31300, Toulouse, France
| | - Hatem Kallel
- Service de Réanimation, Centre Hospitalier de Cayenne, Guyane, France
| | - Nicolas Brechot
- Service de Médecine Intensive Réanimation, Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière- Charles Foix, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Center for Interdisciplinary Research in Biology (CIRB)-UMRS, INSERM U1050-CNRS 7241, College de France, Paris, France
| | - Louis Kreitmann
- Centre for Antimicrobial Optimisation, Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, W12 0HS, UK
- ICU West, The Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK
| | - Sarah Benghanem
- Service de Médecine Intensive Réanimation, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Jérémie Joffre
- Service de Réanimation Médicale, Hôpital de Saint Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Centre de Recherche Saint Antoine INSERM, U938, Sorbonne University, Paris, France
| | - Youenn Jouan
- Service de Médecine Intensive Réanimation, CHRU Tours, Tours, France
- Services de Réanimation Chirurgicale Cardiovasculaire et de Chirurgie Cardiaque, CHRU Tours, Tours, France
- INSERM, U1100 Centre d'Etudes des Pathologies Respiratoires, Faculté de Médecine de Tours, Tours, France
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11
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Liao Y, Zhu L. At the heart of inflammation: Unravelling cardiac resident macrophage biology. J Cell Mol Med 2024; 28:e70050. [PMID: 39223947 PMCID: PMC11369210 DOI: 10.1111/jcmm.70050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Cardiovascular disease remains one of the leading causes of death globally. Recent advancements in sequencing technologies have led to the identification of a unique population of macrophages within the heart, termed cardiac resident macrophages (CRMs), which exhibit self-renewal capabilities and play crucial roles in regulating cardiac homeostasis, inflammation, as well as injury and repair processes. This literature review aims to elucidate the origin and phenotypic characteristics of CRMs, comprehensively outline their contributions to cardiac homeostasis and further summarize their functional roles and molecular mechanisms implicated in the onset and progression of cardiovascular diseases. These insights are poised to pave the way for novel therapeutic strategies centred on targeted interventions based on the distinctive properties of resident macrophages.
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Affiliation(s)
- Yingnan Liao
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
- Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026)Sichuan Academy of Medical Sciences and Sichuan Provincial People's HospitalChengduSichuanChina
| | - Liyuan Zhu
- Center of Clinical Pharmacology, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
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12
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Soraci L, Beccacece A, Princiotto M, Villalta Savedra E, Gambuzza ME, Aguennouz M, Corsonello A, Luciani F, Muglia L, Filicetti E, Greco GI, Volpentesta M, Biscetti L. The emerging links between immunosenescence in innate immune system and neurocryptococcosis. Front Immunol 2024; 15:1410090. [PMID: 39229268 PMCID: PMC11369721 DOI: 10.3389/fimmu.2024.1410090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 07/29/2024] [Indexed: 09/05/2024] Open
Abstract
Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.
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Affiliation(s)
- Luca Soraci
- Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
| | - Alessia Beccacece
- Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy
| | | | | | | | - M’Hammed Aguennouz
- Department of Clinical and Experimental Medicine, Unit of Neurology and Neuromuscular Diseases, University of Messina, Messina, Italy
| | - Andrea Corsonello
- Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
- Department of Pharmacy, Health and Nutritional Sciences, School of Medicine and Digital Technologies, University of Calabria, Arcavacata di Rende, Italy
| | | | - Lucia Muglia
- Centre for Biostatistics and Applied Geriatric Clinical Epidemiology, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
| | - Elvira Filicetti
- Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
| | - Giada Ida Greco
- Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
| | - Mara Volpentesta
- Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), Cosenza, Italy
| | - Leonardo Biscetti
- Section of Neurology, Italian National Research Center on Aging (IRCCS INRCA), Ancona, Italy
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13
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Roux S, Cherradi S, Duong HT. Exploiting the predictive power of educated spheroids to detect immune-mediated idiosyncratic drug-induced liver injury: the case of troglitazone. Front Pharmacol 2024; 15:1378371. [PMID: 38659594 PMCID: PMC11039894 DOI: 10.3389/fphar.2024.1378371] [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: 01/29/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024] Open
Abstract
Idiosyncratic drug-induced liver injury (iDILI) is a major concern in drug development because its occurrence is unpredictable. Presently, iDILI prediction is a challenge, and cell toxicity is observed only at concentrations that are much higher than the therapeutic doses in preclinical models. Applying a proprietary cell educating technology, we developed a person-dependent spheroid system that contains autologous educated immune cells that can detect iDILI risk at therapeutic concentrations. Integrating this system into a high-throughput screening platform will help pharmaceutical companies accurately detect the iDILI risk of new molecules de-risking drug development.
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Affiliation(s)
| | | | - Hong Tuan Duong
- PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France
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14
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Hager M, Chang P, Lee M, Burns CM, Endicott SJ, Miller RA, Li X. Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice. GeroScience 2024; 46:2653-2670. [PMID: 38114855 PMCID: PMC10828233 DOI: 10.1007/s11357-023-01025-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.
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Affiliation(s)
- Mary Hager
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Peter Chang
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Michael Lee
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Calvin M Burns
- Department of Pathology, University of Michigan School of Medicine, Room 3160, BSRB ,109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
| | - S Joseph Endicott
- Department of Pathology, University of Michigan School of Medicine, Room 3160, BSRB ,109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA
| | - Richard A Miller
- Department of Pathology, University of Michigan School of Medicine, Room 3160, BSRB ,109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA
| | - Xinna Li
- Department of Pathology, University of Michigan School of Medicine, Room 3160, BSRB ,109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA.
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15
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Hay Q, Grubb C, Minucci S, Valentine MS, Van Mullekom J, Heise RL, Reynolds AM. Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis. PLoS Comput Biol 2024; 20:e1011113. [PMID: 38386693 PMCID: PMC10914268 DOI: 10.1371/journal.pcbi.1011113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 03/05/2024] [Accepted: 01/23/2024] [Indexed: 02/24/2024] Open
Abstract
A variety of pulmonary insults can prompt the need for life-saving mechanical ventilation; however, misuse, prolonged use, or an excessive inflammatory response, can result in ventilator-induced lung injury. Past research has observed an increased instance of respiratory distress in older patients and differences in the inflammatory response. To address this, we performed high pressure ventilation on young (2-3 months) and old (20-25 months) mice for 2 hours and collected data for macrophage phenotypes and lung tissue integrity. Large differences in macrophage activation at baseline and airspace enlargement after ventilation were observed in the old mice. The experimental data was used to determine plausible trajectories for a mathematical model of the inflammatory response to lung injury which includes variables for the innate inflammatory cells and mediators, epithelial cells in varying states, and repair mediators. Classification methods were used to identify influential parameters separating the parameter sets associated with the young or old data and separating the response to ventilation, which was measured by changes in the epithelial state variables. Classification methods ranked parameters involved in repair and damage to the epithelial cells and those associated with classically activated macrophages to be influential. Sensitivity results were used to determine candidate in-silico interventions and these interventions were most impact for transients associated with the old data, specifically those with poorer lung health prior to ventilation. Model results identified dynamics involved in M1 macrophages as a focus for further research, potentially driving the age-dependent differences in all macrophage phenotypes. The model also supported the pro-inflammatory response as a potential indicator of age-dependent differences in response to ventilation. This mathematical model can serve as a baseline model for incorporating other pulmonary injuries.
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Affiliation(s)
- Quintessa Hay
- Department of Mathematics & Applied Mathematics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Christopher Grubb
- Department of Statistics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Sarah Minucci
- Department of Mathematics & Applied Mathematics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Michael S. Valentine
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Jennifer Van Mullekom
- Department of Statistics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Rebecca L. Heise
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Angela M. Reynolds
- Department of Mathematics & Applied Mathematics, Virginia Commonwealth University, Richmond, Virginia, United States of America
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16
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Minucci SB, Heise RL, Reynolds AM. Agent-based vs. equation-based multi-scale modeling for macrophage polarization. PLoS One 2024; 19:e0270779. [PMID: 38271449 PMCID: PMC10810539 DOI: 10.1371/journal.pone.0270779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 09/29/2023] [Indexed: 01/27/2024] Open
Abstract
Macrophages show high plasticity and result in heterogenic subpopulations or polarized states identified by specific cellular markers. These immune cells are typically characterized as pro-inflammatory, or classically activated M1, and anti-inflammatory, or alternatively activated M2. However, a more precise definition places them along a spectrum of activation where they may exhibit a number of pro- or anti-inflammatory roles. To understand M1-M2 dynamics in the context of a localized response and explore the results of different mathematical modeling approaches based on the same biology, we utilized two different modeling techniques, ordinary differential equation (ODE) modeling and agent-based modeling (ABM), to simulate the spectrum of macrophage activation to general pro- and anti-inflammatory stimuli on an individual and multi-cell level. The ODE model includes two hallmark pro- and anti-inflammatory signaling pathways and the ABM incorporates similar M1-M2 dynamics but in a spatio-temporal platform. Both models link molecular signaling with cellular-level dynamics. We then performed simulations with various initial conditions to replicate different experimental setups. Similar results were observed in both models after tuning to a common calibrating experiment. Comparing the two models' results sheds light on the important features of each modeling approach. When more data is available these features can be considered when choosing techniques to best fit the needs of the modeler and application.
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Affiliation(s)
- Sarah B. Minucci
- Department of Mathematics & Applied Mathematics, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Rebecca L. Heise
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Angela M. Reynolds
- Department of Mathematics & Applied Mathematics, Virginia Commonwealth University, Richmond, VA, United States of America
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17
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Li J, Xin Y, Wang Z, Li J, Li W, Li H. The role of cardiac resident macrophage in cardiac aging. Aging Cell 2023; 22:e14008. [PMID: 37817547 PMCID: PMC10726886 DOI: 10.1111/acel.14008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/12/2023] Open
Abstract
Advancements in longevity research have provided insights into the impact of cardiac aging on the structural and functional aspects of the heart. Notable changes include the gradual remodeling of the myocardium, the occurrence of left ventricular hypertrophy, and the decline in both systolic and diastolic functions. Macrophages, a type of immune cell, play a pivotal role in innate immunity by serving as vigilant agents against pathogens, facilitating wound healing, and orchestrating the development of targeted acquired immune responses. Distinct subsets of macrophages are present within the cardiac tissue and demonstrate varied functions in response to myocardial injury. The differentiation of cardiac macrophages according to their developmental origin has proven to be a valuable strategy in identifying reparative macrophage populations, which originate from embryonic cells and reside within the tissue, as well as inflammatory macrophages, which are derived from monocytes and recruited to the heart. These subsets of macrophages possess unique characteristics and perform distinct functions. This review aims to summarize the current understanding of the roles and phenotypes of cardiac macrophages in various conditions, including the steady state, aging, and other pathological conditions. Additionally, it will highlight areas that require further investigation to expand our knowledge in this field.
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Affiliation(s)
- Jiayu Li
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
- Laboratory for Clinical MedicineBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Yanguo Xin
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
- Laboratory for Clinical MedicineBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Zhaojia Wang
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
- Laboratory for Clinical MedicineBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Jingye Li
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
| | - Weiping Li
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
- Laboratory for Clinical MedicineBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
| | - Hongwei Li
- Department of Cardiology, Cardiovascular Center, Beijing Friendship HospitalCapital Medical UniversityBeijingChina
- Laboratory for Clinical MedicineBeijing Friendship Hospital, Capital Medical UniversityBeijingChina
- Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular DiseaseBeijingChina
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18
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Lauzier DC, Chiang SN, Moran CJ. Etiologies of Brain Arteriovenous Malformation Recurrence: A Focus on Pediatric Disease. Pediatr Neurol 2023; 148:94-100. [PMID: 37690270 DOI: 10.1016/j.pediatrneurol.2023.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 09/12/2023]
Abstract
Pediatric brain arteriovenous malformations are a major cause of morbidity and mortality, with the harmful effects of this disease compounded by the additional disability-years experienced by children with ruptured or other symptomatic arteriovenous malformations. In addition to the risks shared with their adult counterparts, pediatric patients frequently experience recurrence following radiographic cure, which presents an additional source of morbidity and mortality. Therefore, there is a need to synthesize potential mechanisms contributing to the elevated recurrence risk in the pediatric population and discuss how these translate to practical considerations for managing these patients.
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Affiliation(s)
- David C Lauzier
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
| | - Sarah N Chiang
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Christopher J Moran
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
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19
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Asghari F, Asghary A, Majidi Zolbanin N, Faraji F, Jafari R. Immunosenescence and Inflammaging in COVID-19. Viral Immunol 2023; 36:579-592. [PMID: 37797216 DOI: 10.1089/vim.2023.0045] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023] Open
Abstract
Despite knowledge gaps in understanding the full spectrum of the hyperinflammatory phase caused by SARS-CoV-2, according to the World Health Organization (WHO), COVID-19 is still the leading cause of death worldwide. Susceptible people to severe COVID-19 are those with underlying medical conditions or those with dysregulated and senescence-associated immune responses. As the immune system undergoes aging in the elderly, such drastic changes predispose them to various diseases and affect their responsiveness to infections, as seen in COVID-19. At-risk groups experience poor prognosis in terms of disease recovery. Changes in the quantity and quality of immune cell function have been described in numerous literature sites. Impaired immune cell function along with age-related metabolic changes can lead to features such as hyperinflammatory response, immunosenescence, and inflammaging in COVID-19. Inflammaging is related to the increased activity of the most inflammatory factors and is the main cause of age-related diseases and tissue failure in the elderly. Since hyperinflammation is a common feature of most severe cases of COVID-19, this pathway, which is not fully understood, leads to immunosenescence and inflammaging in some individuals, especially in the elderly and those with comorbidities. In this review, we shed some light on the age-related abnormalities of innate and adaptive immune cells and how hyperinflammatory immune responses contribute to the inflammaging process, leading to clinical deterioration. Further, we provide insights into immunomodulation-based therapeutic approaches, which are potentially important considerations in vaccine design for elderly populations.
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Affiliation(s)
- Faezeh Asghari
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Amir Asghary
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Naime Majidi Zolbanin
- Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Fatemeh Faraji
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Jafari
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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20
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Ontiveros CO, Murray CE, Crossland G, Curiel TJ. Considerations and Approaches for Cancer Immunotherapy in the Aging Host. Cancer Immunol Res 2023; 11:1449-1461. [PMID: 37769157 PMCID: PMC11287796 DOI: 10.1158/2326-6066.cir-23-0121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/16/2023] [Accepted: 08/22/2023] [Indexed: 09/30/2023]
Abstract
Advances in cancer immunotherapy are improving treatment successes in many distinct cancer types. Nonetheless, most tumors fail to respond. Age is the biggest risk for most cancers, and the median population age is rising worldwide. Advancing age is associated with manifold alterations in immune cell types, abundance, and functions, rather than simple declines in these metrics, the consequences of which remain incompletely defined. Our understanding of the effects of host age on immunotherapy mechanisms, efficacy, and adverse events remains incomplete. A deeper understanding of age effects in all these areas is required. Most cancer immunotherapy preclinical studies examine young subjects and fail to assess age contributions, a remarkable deficit given the known importance of age effects on immune cells and factors mediating cancer immune surveillance and immunotherapy efficacy. Notably, some cancer immunotherapies are more effective in aged versus young hosts, while others fail despite efficacy in the young. Here, we review our current understanding of age effects on immunity and associated nonimmune cells, the tumor microenvironment, cancer immunotherapy, and related adverse effects. We highlight important knowledge gaps and suggest areas for deeper enquiries, including in cancer immune surveillance, treatment response, adverse event outcomes, and their mitigation.
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Affiliation(s)
- Carlos O. Ontiveros
- UT Health San Antonio Long School of Medicine and Graduate School of Biomedical Sciences, San Antonio, TX 78229
| | - Clare E. Murray
- UT Health San Antonio Long School of Medicine and Graduate School of Biomedical Sciences, San Antonio, TX 78229
| | - Grace Crossland
- Graduate School of Microbiology and Immunology, Dartmouth, Hanover, NH 03755
- The Geisel School of Medicine at Dartmouth, Hanover, NH 03755
| | - Tyler J. Curiel
- UT Health San Antonio Long School of Medicine and Graduate School of Biomedical Sciences, San Antonio, TX 78229
- Graduate School of Microbiology and Immunology, Dartmouth, Hanover, NH 03755
- The Geisel School of Medicine at Dartmouth, Hanover, NH 03755
- Dartmouth Health and Dartmouth Cancer Center, Lebanon, NH 03756
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21
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Chirumbolo S, Bertossi D, Magistretti P. Insights on the role of L-lactate as a signaling molecule in skin aging. Biogerontology 2023; 24:709-726. [PMID: 36708434 PMCID: PMC9883612 DOI: 10.1007/s10522-023-10018-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 01/17/2023] [Indexed: 01/29/2023]
Abstract
L-lactate is a catabolite from the anaerobic metabolism of glucose, which plays a paramount role as a signaling molecule in various steps of the cell survival. Its activity, as a master tuner of many mechanisms underlying the aging process, for example in the skin, is still presumptive, however its crucial position in the complex cross-talk between mitochondria and the process of cell survival, should suggest that L-lactate may be not a simple waste product but a fine regulator of the aging/survival machinery, probably via mito-hormesis. Actually, emerging evidence is highlighting that ROS are crucial in the signaling of skin health, including mechanisms underlying wound repair, renewal and aging. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Physiological ROS levels are essential for cutaneous health and the wound repair process. Aberrant redox signaling activity drives chronic skin disease in elderly. On the contrary, impaired redox modulation, due to enhanced ROS generation and/or reduced levels of antioxidant defense, suppresses wound healing via promoting lymphatic/vascular endothelial cell apoptosis and death. This review tries to elucidate this issue.
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Affiliation(s)
- Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, Unit of Human Anatomy, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.
| | - Dario Bertossi
- Department of Surgery, Dentistry, Paediatrics and Gynaecology-Unit of Maxillo-Facial Surgery, University of Verona, Verona, Italy
| | - Pierre Magistretti
- Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955, Saudi Arabia
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22
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Inamdar S, Suresh AP, Mangal JL, Ng ND, Sundem A, Behbahani HS, Rubino TE, Yaron JR, Khodaei T, Green M, Curtis M, Acharya AP. Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages. Biomaterials 2023; 301:122292. [PMID: 37643489 PMCID: PMC10544711 DOI: 10.1016/j.biomaterials.2023.122292] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023]
Abstract
Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
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Affiliation(s)
- Sahil Inamdar
- Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Abhirami P Suresh
- Biological Design, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Joslyn L Mangal
- Biological Design, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Nathan D Ng
- Molecular Biosciences and Biotechnology, The College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, 85281, USA
| | - Alison Sundem
- Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Hoda Shokrollahzadeh Behbahani
- Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Thomas E Rubino
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, 85259, USA; Department of Cancer Biology, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Jordan R Yaron
- Biological Design, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Taravat Khodaei
- Biomedical Engineering, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA
| | - Matthew Green
- Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA; Materials Science and Engineering, School for the Engineering of Matter, Transport, And Energy, Arizona State University, Tempe, AZ, 85281, USA
| | - Marion Curtis
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, 85259, USA; Department of Cancer Biology, Mayo Clinic, Scottsdale, AZ, 85259, USA; College of Medicine and Science, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Abhinav P Acharya
- Chemical Engineering, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA; Biological Design, School for the Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ, 85281, USA; Biomedical Engineering, School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA; Materials Science and Engineering, School for the Engineering of Matter, Transport, And Energy, Arizona State University, Tempe, AZ, 85281, USA; Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, 85281, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, United States.
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Li X, McPherson M, Hager M, Lee M, Chang P, Miller RA. Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice. GeroScience 2023; 45:2495-2510. [PMID: 36920743 PMCID: PMC10651632 DOI: 10.1007/s11357-023-00770-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.
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Affiliation(s)
- Xinna Li
- Department of Pathology, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, RoomAnn Arbor, MI, 316048109-2200, USA.
| | - Madaline McPherson
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Mary Hager
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Michael Lee
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Peter Chang
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Richard A Miller
- Department of Pathology, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, RoomAnn Arbor, MI, 316048109-2200, USA
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA
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Molinaro C, Scalise M, Leo I, Salerno L, Sabatino J, Salerno N, De Rosa S, Torella D, Cianflone E, Marino F. Polarizing Macrophage Functional Phenotype to Foster Cardiac Regeneration. Int J Mol Sci 2023; 24:10747. [PMID: 37445929 DOI: 10.3390/ijms241310747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
There is an increasing interest in understanding the connection between the immune and cardiovascular systems, which are highly integrated and communicate through finely regulated cross-talking mechanisms. Recent evidence has demonstrated that the immune system does indeed have a key role in the response to cardiac injury and in cardiac regeneration. Among the immune cells, macrophages appear to have a prominent role in this context, with different subtypes described so far that each have a specific influence on cardiac remodeling and repair. Similarly, there are significant differences in how the innate and adaptive immune systems affect the response to cardiac damage. Understanding all these mechanisms may have relevant clinical implications. Several studies have already demonstrated that stem cell-based therapies support myocardial repair. However, the exact role that cardiac macrophages and their modulation may have in this setting is still unclear. The current need to decipher the dual role of immunity in boosting both heart injury and repair is due, at least for a significant part, to unresolved questions related to the complexity of cardiac macrophage phenotypes. The aim of this review is to provide an overview on the role of the immune system, and of macrophages in particular, in the response to cardiac injury and to outline, through the modulation of the immune response, potential novel therapeutic strategies for cardiac regeneration.
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Affiliation(s)
- Claudia Molinaro
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Isabella Leo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Jolanda Sabatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Nadia Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
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Li X, Hager M, McPherson M, Lee M, Hagalwadi R, Skinner ME, Lombard D, Miller RA. Recapitulation of anti-aging phenotypes by global, but not by muscle-specific, deletion of PAPP-A in mice. GeroScience 2023; 45:931-948. [PMID: 36542300 PMCID: PMC9886707 DOI: 10.1007/s11357-022-00692-3] [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: 05/18/2022] [Accepted: 11/15/2022] [Indexed: 12/24/2022] Open
Abstract
Deletion of pregnancy-associated plasma protein-A (PAPP-A), a protease that cleaves some but not all IGF1 binding proteins, postpones late-life diseases and extends lifespan in mice, but the mechanism of this effect is unknown. Here we show that PAPP-A knockout (PKO) mice display a set of changes, in multiple tissues, that are characteristic of other varieties of slow-aging mice with alterations in GH production or GH responsiveness, including Ames dwarf, Snell dwarf, and GHRKO mice. PKO mice have elevated UCP1 in brown and white adipose tissues (WAT), and a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines. PKO mice also show increased levels of muscle FNDC5 and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation. PKO mice have elevated production of hepatic GPLD1 and plasma GPLD1, consistent with their elevation of hippocampal BDNF and DCX, used as indices of neurogenesis. In contrast, disruption of PAPP-A limited to muscle ("muPKO" mice) produces an unexpectedly complex set of changes, in most cases opposite in direction from those seen in PKO mice. These include declines in WAT UCP1, increases in inflammatory macrophages and cytokines in WAT, and a decline in muscle FNDC5 and plasma irisin. muPKO mice do, however, resemble global PKO mice in their elevation of hippocampal BDNF and DCX. The data for the PKO mice support the idea that these changes in fat, macrophages, liver, muscle, plasma, and brain are consistent and biologically significant features of the slow-aging phenotype in mice. The results on the muPKO mice provide a foundation for further investigation of the complex, local, and global circuits by which PAPP-A modulates signals ordinarily controlled by GH and/or IGF1.
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Affiliation(s)
- Xinna Li
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA.
- , Ann Arbor, USA.
| | - Mary Hager
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Madaline McPherson
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Michael Lee
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Riha Hagalwadi
- College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Mary E Skinner
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
| | - David Lombard
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
- Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Richard A Miller
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA
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Valentine MS, Weigel C, Kamga Gninzeko F, Tho C, Gräler MH, Reynolds AM, Spiegel S, Heise RL. S1P lyase inhibition prevents lung injury following high pressure-controlled mechanical ventilation in aging mice. Exp Gerontol 2023; 173:112074. [PMID: 36566871 PMCID: PMC9975034 DOI: 10.1016/j.exger.2022.112074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022]
Abstract
Ventilator-induced Lung Injury (VILI) is characterized by hypoxia, inflammatory cytokine influx, loss of alveolar barrier integrity, and decreased lung compliance. Aging influences lung structure and function and is a predictive factor in the severity of VILI; however, the mechanisms of aging that influence the progression or increased susceptibility remain unknown. Aging impacts immune system function and may increase inflammation in healthy individuals. Recent studies suggest that the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) and the enzyme that degrades it S1P lyase (SPL) may be involved in lung pathologies including acute lung injury. It is unknown whether aging influences S1P and SPL expression that have been implicated in lung inflammation, injury, and cell apoptosis. We hypothesized that aging and injurious mechanical ventilation synergistically impair S1P levels and enhance S1P lyase (SPL) expression that amplifies alveolar barrier damage and diminishes pulmonary function. Young (2-3 mo) and old (20-25 mo) C57BL/6 mice were mechanically ventilated for 2 h using pressure-controlled mechanical ventilation (PCMV) at 45 cmH2O and 35 cmH2O, respectively. We assessed the impact of aging and PCMV on several indications of acute lung injury, immune cell recruitment, S1P levels and SPL activity. Furthermore, we evaluated the protective effects of inhibiting SPL by tetrahydroxybutylimidazol (THI) administration on the negative outcomes associated with aging and mechanical injury. PCMV exacerbated lung injury in old mice and increased neutrophil influx that was further exacerbated due to aging. SPL expression increased in the young and old ventilated mice and the old nonventilated group. THI treatment reduced several of the indicators of lung injury and resulted in elevated S1P levels in lung tissue and plasma from mice that were injured from mechanical ventilation. CD80 and CD206 activation markers of alveolar and interstitial macrophages were also influenced by THI. SPL inhibition may be a viable therapeutic approach for patients requiring mechanical ventilation by preventing or regulating the exaggerated inflammatory response and reducing lung injury.
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Affiliation(s)
- M S Valentine
- Department of Biomedical Engineering, Virginia Commonwealth University, United States of America
| | - C Weigel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, United States of America
| | - F Kamga Gninzeko
- Department of Biomedical Engineering, Virginia Commonwealth University, United States of America
| | - C Tho
- Department of Biomedical Engineering, Virginia Commonwealth University, United States of America
| | - M H Gräler
- Department of Anesthesiology and Intensive Care Medicine, Center for Molecular Biomedicine (CMB) and Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany
| | - A M Reynolds
- Department of Mathematics and Applied Mathematics, Virginia Commonwealth University, United States of America
| | - S Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, United States of America
| | - R L Heise
- Department of Biomedical Engineering, Virginia Commonwealth University, United States of America.
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Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions. J Clin Med 2023; 12:jcm12051914. [PMID: 36902701 PMCID: PMC10004236 DOI: 10.3390/jcm12051914] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/09/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169+ osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80+CD38+ M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.
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Zhang D, Dang Y, Deng R, Ma Y, Wang J, Ao J, Wang X. Research Progress of Macrophages in Bone Regeneration. J Tissue Eng Regen Med 2023; 2023:1512966. [PMID: 40226416 PMCID: PMC11919137 DOI: 10.1155/2023/1512966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/07/2022] [Accepted: 12/17/2022] [Indexed: 04/15/2025]
Abstract
Bone tissue regeneration plays an increasingly important role in contemporary clinical treatment. The reconstruction of bone defects remains a huge challenge for clinicians. Bone regeneration is regulated by the immune system, in which inflammation is an important regulating factor in bone formation and remodeling. As the main cells involved in inflammation, macrophages play a key role in osteogenesis by polarizing into different phenotypes during different stages of bone regeneration. Considering this, this review mainly summarizes the function of macrophage in bone regeneration based on mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, and vascular cells. In conclusion, anti-inflammatory macrophages (M2) have a greater potentiality to promote bone regeneration than M0 and classically activated proinflammatory macrophages (M1). In the fracture and bone defect models, tissue engineering materials can induce the transition from M1 to M2, alter the bone microenvironment, and promote bone regeneration through interactions with bone-related cells and blood vessels. The review provides a further understanding of macrophage polarization behavior in the evolving field of bone immunology.
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Affiliation(s)
- Dingmei Zhang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yi Dang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Renli Deng
- Nurse Department, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Yaping Ma
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jing Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Jun Ao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
| | - Xin Wang
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, China
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Wang Z, Zhang X, Cheng X, Ren T, Xu W, Li J, Wang H, Zhang J. Inflammation produced by senescent osteocytes mediates age-related bone loss. Front Immunol 2023; 14:1114006. [PMID: 36814916 PMCID: PMC9940315 DOI: 10.3389/fimmu.2023.1114006] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 01/11/2023] [Indexed: 02/08/2023] Open
Abstract
Purpose The molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs. Methods We collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR. Results The GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4. Conclusion With age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.
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Affiliation(s)
- Zixuan Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofei Zhang
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing Cheng
- Health Care Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianxing Ren
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weihua Xu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Li
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Wang
- Department of Medical Genetics, Basic School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Jinxiang Zhang, ; Hui Wang,
| | - Jinxiang Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Jinxiang Zhang, ; Hui Wang,
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Saul D, Khosla S. Fracture Healing in the Setting of Endocrine Diseases, Aging, and Cellular Senescence. Endocr Rev 2022; 43:984-1002. [PMID: 35182420 PMCID: PMC9695115 DOI: 10.1210/endrev/bnac008] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Indexed: 11/19/2022]
Abstract
More than 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes, and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of "inflammaging" results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
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Affiliation(s)
- Dominik Saul
- Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, Minnesota 55905, USA.,Department of Trauma, Orthopedics and Reconstructive Surgery, Georg-August-University of Goettingen, 37073 Goettingen, Germany
| | - Sundeep Khosla
- Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Park HE, Lee W, Choi S, Jung M, Shin MK, Shin SJ. Modulating macrophage function to reinforce host innate resistance against Mycobacterium avium complex infection. Front Immunol 2022; 13:931876. [PMID: 36505429 PMCID: PMC9730288 DOI: 10.3389/fimmu.2022.931876] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/21/2022] [Indexed: 11/25/2022] Open
Abstract
Mycobacterium avium complex (MAC) is the main causative agent of infectious diseases in humans among nontuberculous mycobacteria (NTM) that are ubiquitous organisms found in environmental media such as soil as well as in domestic and natural waters. MAC is a primary causative agent of NTM-lung disease that threaten immunocompromised or structural lung disease patients. The incidence and the prevalence of M. tuberculosis infection have been reduced, while MAC infections and mortality rates have increased, making it a cause of global health concern. The emergence of drug resistance and the side effects of long-term drug use have led to a poor outcome of treatment regimens against MAC infections. Therefore, the development of host-directed therapy (HDT) has recently gained interest, aiming to accelerate mycobacterial clearance and reversing lung damage by employing the immune system using a novel adjuvant strategy to improve the clinical outcome of MAC infection. Therefore, in this review, we discuss the innate immune responses that contribute to MAC infection focusing on macrophages, chief innate immune cells, and host susceptibility factors in patients. We also discuss potential HDTs that can act on the signaling pathway of macrophages, thereby contributing to antimycobacterial activity as a part of the innate immune response during MAC infection. Furthermore, this review provides new insights into MAC infection control that modulates and enhances macrophage function, promoting host antimicrobial activity in response to potential HDTs and thus presenting a deeper understanding of the interactions between macrophages and MACs during infection.
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Affiliation(s)
- Hyun-Eui Park
- Department of Microbiology and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Wonsik Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Sangwon Choi
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Myunghwan Jung
- Department of Microbiology and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, South Korea
| | - Min-Kyoung Shin
- Department of Microbiology and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, South Korea,*Correspondence: Min-Kyoung Shin, ; Sung Jae Shin,
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Disease, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea,*Correspondence: Min-Kyoung Shin, ; Sung Jae Shin,
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Stoff R, Grynberg S, Asher N, Laks S, Steinberg Y, Schachter J, Shapira-Frommer R, Ben-Betzalel G. Efficacy and toxicity of Ipilimumab-Nivolumab combination therapy in elderly metastatic melanoma patients. Front Oncol 2022; 12:1020058. [PMID: 36419899 PMCID: PMC9676931 DOI: 10.3389/fonc.2022.1020058] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Immunotherapy has revolutionized metastatic Melanoma therapy. The most active regimen is combination therapy of Ipilimumab-Nivolumab (Ipi-Nivo) with response rates (RR) of ~60% and median overall survival (OS) of ~6 years. Immune-related adverse events (irAE) are common (~60% develop grade 3-4) and pose a challenge when treating frail patients. We sought to examine whether Ipi-Nivo therapy is feasible in elderly metastatic melanoma patients. Methods Electronic records of patients treated at the Ella Lemelbaum Institute with Ipi-Nivo between the years 2017-2021 were screened for age. Elderly patients were defined as age 75 and older (group A) and were matched with records of patients age <75 (group B). Records were analyzed for baseline parameters, immunotherapy regimen, RR, toxicity and progression-free survival (PFS). Results Twenty-six relevant patients age >75 (median 77) were identified and were matched to 34 younger patients (median age 57). No statistically significant differences were noted in terms of baseline parameters except for BRAF mutation status (group A 15%, group B 47%, p=0.008). Response rate in group A was 38% and is consistent with previously published data. Median PFS was the same for both groups (A = 5.5 months, B= 7.5 months, p=NS). Treatment was similarly tolerated: 35% of group A patients completed 4 cycles of therapy compared to 28% for group B (p=NS). Grade 2-4 irAE were the same (A=58%, B=66%, p=NS) and there was no difference in the need for hospitalization for G3-4 events between the groups. (A=63%, B=69%, p=NS). Further division into 4 age groups (>80 vs 75-79 in group A and 65-74 vs <65 in group B) found no difference in terms of response rate or G3-4 toxicity. Conclusion Ipilimumab-Nivolumab combination therapy in elderly metastatic Melanoma patients seems to be well tolerated and efficient in selected elderly patients based on performance status and comorbidities, just as in younger patients. This regimen seems to be a feasible treatment option for this age group.
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Affiliation(s)
- Ronen Stoff
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
- *Correspondence: Ronen Stoff, ; Shirly Grynberg,
| | - Shirly Grynberg
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
- *Correspondence: Ronen Stoff, ; Shirly Grynberg,
| | - Nethanel Asher
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
| | - Shachar Laks
- Surgical Division, Sheba Medical Center, Ramat Gan, Israel
| | - Yael Steinberg
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
| | - Jacob Schachter
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
| | | | - Guy Ben-Betzalel
- Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel
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Wang YH, Zhao CZ, Wang RY, Du QX, Liu JY, Pan J. The crosstalk between macrophages and bone marrow mesenchymal stem cells in bone healing. Stem Cell Res Ther 2022; 13:511. [PMID: 36333820 PMCID: PMC9636722 DOI: 10.1186/s13287-022-03199-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Bone injury plagues millions of patients worldwide every year, and it demands a heavy portion of expense from the public medical insurance system. At present, orthopedists think that autologous bone transplantation is the gold standard for treating large-scale bone defects. However, this method has significant limitations, which means that parts of patients cannot obtain a satisfactory prognosis. Therefore, a basic study on new therapeutic methods is urgently needed. The in-depth research on crosstalk between macrophages (Mϕs) and bone marrow mesenchymal stem cells (BMSCs) suggests that there is a close relationship between inflammation and regeneration. The in-depth understanding of the crosstalk between Mϕs and BMSCs is helpful to amplify the efficacy of stem cell-based treatment for bone injury. Only in the suitable inflammatory microenvironment can the damaged tissues containing stem cells obtain satisfactory healing outcomes. The excessive tissue inflammation and lack of stem cells make the transplantation of biomaterials necessary. We can expect that the crosstalk between Mϕs and BMSCs and biomaterials will become the mainstream to explore new methods for bone injury in the future. This review mainly summarizes the research on the crosstalk between Mϕs and BMSCs and also briefly describes the effects of biomaterials and aging on cell transplantation therapy.
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Affiliation(s)
- Yu-Hao Wang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Cheng-Zhi Zhao
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Ren-Yi Wang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Qian-Xin Du
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
| | - Ji-Yuan Liu
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China
| | - Jian Pan
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, #14 Third Section, Renmin Road South, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China ,grid.13291.380000 0001 0807 1581Chengdu Advanced Medical Science Center, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 Sichuan Province People’s Republic of China
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Van Avondt K, Strecker J, Tulotta C, Minnerup J, Schulz C, Soehnlein O. Neutrophils in aging and aging‐related pathologies. Immunol Rev 2022; 314:357-375. [PMID: 36315403 DOI: 10.1111/imr.13153] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Over the past millennia, life expectancy has drastically increased. While a mere 25 years during Bronze and Iron ages, life expectancy in many European countries and in Japan is currently above 80 years. Such an increase in life expectancy is a result of improved diet, life style, and medical care. Yet, increased life span and aging also represent the most important non-modifiable risk factors for several pathologies including cardiovascular disease, neurodegenerative diseases, and cancer. In recent years, neutrophils have been implicated in all of these pathologies. Hence, this review provides an overview of how aging impacts neutrophil production and function and conversely how neutrophils drive aging-associated pathologies. Finally, we provide a perspective on how processes of neutrophil-driven pathologies in the context of aging can be targeted therapeutically.
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Affiliation(s)
- Kristof Van Avondt
- Institute of Experimental Pathology (ExPat), Centre of Molecular Biology of Inflammation (ZMBE) University of Münster Münster Germany
| | - Jan‐Kolja Strecker
- Department of Neurology with Institute of Translational Neurology University Hospital Münster Münster Germany
| | - Claudia Tulotta
- Institute of Experimental Pathology (ExPat), Centre of Molecular Biology of Inflammation (ZMBE) University of Münster Münster Germany
| | - Jens Minnerup
- Department of Neurology with Institute of Translational Neurology University Hospital Münster Münster Germany
| | - Christian Schulz
- Department of Medicine I University Hospital, Ludwig Maximilian University Munich Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance Munich Germany
| | - Oliver Soehnlein
- Institute of Experimental Pathology (ExPat), Centre of Molecular Biology of Inflammation (ZMBE) University of Münster Münster Germany
- Department of Physiology and Pharmacology (FyFa) Karolinska Institute Stockholm Sweden
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Villalobos V, Garrido M, Reyes A, Fernández C, Diaz C, Torres VA, González PA, Cáceres M. Aging envisage imbalance of the periodontium: A keystone in oral disease and systemic health. Front Immunol 2022; 13:1044334. [PMID: 36341447 PMCID: PMC9630574 DOI: 10.3389/fimmu.2022.1044334] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/05/2022] [Indexed: 10/21/2023] Open
Abstract
Aging is a gradual and progressive deterioration of integrity across multiple organ systems that negatively affects gingival wound healing. The cellular responses associated with wound healing, such as collagen synthesis, cell migration, proliferation, and collagen contraction, have been shown to be lower in gingival fibroblasts (the most abundant cells from the connective gingival tissue) in aged donors than young donors. Cellular senescence is one of the hallmarks of aging, which is characterized by the acquisition of a senescence-associated secretory phenotype that is characterized by the release of pro-inflammatory cytokines, chemokines, growth factors, and proteases which have been implicated in the recruitment of immune cells such as neutrophils, T cells and monocytes. Moreover, during aging, macrophages show altered acquisition of functional phenotypes in response to the tissue microenvironment. Thus, inflammatory and resolution macrophage-mediated processes are impaired, impacting the progression of periodontal disease. Interestingly, salivary antimicrobial peptides, such as histatins, which are involved in various functions, such as antifungal, bactericidal, enamel-protecting, angiogenesis, and re-epithelization, have been shown to fluctuate with aging. Several studies have associated the presence of Porphyromonas gingivalis, a key pathogen related to periodontitis and apical periodontitis, with the progression of Alzheimer's disease, as well as gut, esophageal, and gastric cancers. Moreover, herpes simplex virus types 1 and 2 have been associated with the severity of periodontal disease, cardiovascular complications, and nervous system-related pathologies. This review encompasses the effects of aging on periodontal tissues, how P. gingivalis and HSV infections could favor periodontitis and their relationship with other pathologies.
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Affiliation(s)
- Verónica Villalobos
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Mauricio Garrido
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Antonia Reyes
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Christian Fernández
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Catalina Diaz
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Vicente A. Torres
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mónica Cáceres
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Chile, Santiago, Chile
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36
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Marrella V, Facoetti A, Cassani B. Cellular Senescence in Immunity against Infections. Int J Mol Sci 2022; 23:11845. [PMID: 36233146 PMCID: PMC9570409 DOI: 10.3390/ijms231911845] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Cellular senescence is characterized by irreversible cell cycle arrest in response to different triggers and an inflammatory secretome. Although originally described in fibroblasts and cell types of solid organs, cellular senescence affects most tissues with advancing age, including the lymphoid tissue, causing chronic inflammation and dysregulation of both innate and adaptive immune functions. Besides its normal occurrence, persistent microbial challenge or pathogenic microorganisms might also accelerate the activation of cellular aging, inducing the premature senescence of immune cells. Therapeutic strategies counteracting the detrimental effects of cellular senescence are being developed. Their application to target immune cells might have the potential to improve immune dysfunctions during aging and reduce the age-dependent susceptibility to infections. In this review, we discuss how immune senescence influences the host's ability to resolve more common infections in the elderly and detail the different markers proposed to identify such senescent cells; the mechanisms by which infectious agents increase the extent of immune senescence are also reviewed. Finally, available senescence therapeutics are discussed in the context of their effects on immunity and against infections.
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Affiliation(s)
- Veronica Marrella
- UOS Milan Unit, Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, 20138 Milan, Italy
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Amanda Facoetti
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy
| | - Barbara Cassani
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, Università Degli Studi di Milano, 20089 Milan, Italy
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Ferrara PJ, Yee EM, Petrocelli JJ, Fix DK, Hauser CT, de Hart NMMP, Mahmassani ZS, Reidy PT, O'Connell RM, Drummond MJ. Macrophage immunomodulation accelerates skeletal muscle functional recovery in aged mice following disuse atrophy. J Appl Physiol (1985) 2022; 133:919-931. [PMID: 36049060 PMCID: PMC9550586 DOI: 10.1152/japplphysiol.00374.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/30/2022] [Accepted: 08/30/2022] [Indexed: 11/22/2022] Open
Abstract
Poor recovery of muscle size and strength with aging coincides with a dysregulated macrophage response during the early stages of regrowth. Immunomodulation in the form of ex vivo cytokine (macrophage-colony stimulating factor) or polarized macrophage delivery has been demonstrated to improve skeletal muscle regeneration. However, it is unclear if these macrophage-promoting approaches would be effective to improve skeletal muscle recovery following disuse in aged animals. Here, we isolated bone marrow-derived macrophages from donor mice of different ages under various experimental conditions and polarized them into proinflammatory macrophages. Macrophages were delivered intramuscularly into young adult or aged recipient mice during the early recovery period following a period of hindlimb unloading (HU). Delivery of proinflammatory macrophages from donor young adults or aged mice was sufficient to increase muscle function of aged mice during the recovery period. Moreover, proinflammatory macrophages derived from aged donor mice collected during recovery were similarly able to increase muscle function of aged mice following disuse. In addition to the delivery of macrophages, we showed that the intramuscular injection of the cytokine, macrophage-colony stimulating factor, to the muscle of aged mice following HU was able to increase muscle macrophage content and muscle force production during recovery. Together, these results suggest that macrophage immunomodulation approaches in the form of ex vivo proinflammatory macrophage or macrophage-colony stimulating factor delivery during the early recovery phase following disuse atrophy were sufficient to restore the loss of aged skeletal muscle function.NEW & NOTEWORTHY A single intramuscular administration of polarized macrophages into muscles of aged mice following a bout of disuse atrophy was sufficient to improve functional recover similarly to young adults after disuse atrophy regardless of the age or experimental condition of the donor mice. Additionally, intramuscular delivery of macrophage-colony stimulating factor into aged mice was similarly effective. Targeting macrophage function early during the regrowth phase may be a novel tool to bolster muscle recovery in aging.
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Affiliation(s)
- Patrick J Ferrara
- Molecular Medicine Program, University of Utah, Salt Lake City, Utah
| | - Elena M Yee
- Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah
| | - Jonathan J Petrocelli
- Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah
| | - Dennis K Fix
- Molecular Medicine Program, University of Utah, Salt Lake City, Utah
| | - Carson T Hauser
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Naomi M M P de Hart
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Ziad S Mahmassani
- Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah
| | - Paul T Reidy
- Department of Kinesiology, Miami University, Oxford, Ohio
| | - Ryan M O'Connell
- Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah
| | - Micah J Drummond
- Molecular Medicine Program, University of Utah, Salt Lake City, Utah
- Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
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38
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Lu YN, Wang L, Zhang YZ. The promising roles of macrophages in geriatric hip fracture. Front Cell Dev Biol 2022; 10:962990. [PMID: 36092716 PMCID: PMC9458961 DOI: 10.3389/fcell.2022.962990] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
As aging becomes a global burden, the incidence of hip fracture (HF), which is the most common fracture in the elderly population and can be fatal, is rapidly increasing, and its extremely high fatality rate places significant medical and financial burdens on patients. Fractures trigger a complex set of immune responses, and recent studies have shown that with aging, the immune system shows decreased activity or malfunctions in a process known as immune senescence, leading to disease and death. These phenomena are the reasons why elderly individuals typically exhibit chronically low levels of inflammation and increased rates of infection and chronic disease. Macrophages, which are key players in the inflammatory response, are critical in initiating the inflammatory response, clearing pathogens, controlling the innate and adaptive immune responses and repairing damaged tissues. Tissue-resident macrophages (TRMs) are widely present in tissues and perform immune sentinel and homeostatic functions. TRMs are combinations of macrophages with different functions and phenotypes that can be directly influenced by neighboring cells and the microenvironment. They form a critical component of the first line of defense in all tissues of the body. Immune system disorders caused by aging could affect the biology of macrophages and thus the cascaded immune response after fracture in various ways. In this review, we outline recent studies and discuss the potential link between monocytes and macrophages and their potential roles in HF in elderly individuals.
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Affiliation(s)
- Yi-ning Lu
- Department of Orthopedic Research Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ling Wang
- Department of Orthopedic Research Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Orthopedic Oncology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Ying-ze Zhang, ; Ling Wang,
| | - Ying-ze Zhang
- Department of Orthopedic Research Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Ying-ze Zhang, ; Ling Wang,
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Abstract
PURPOSE OF REVIEW The cardiac immune landscape dynamically changes in response to aging, hemodynamic stress, and myocardial injury. Here, we highlight key cardiac immune cell types, their role in reshaping the cellular landscape and promoting tissue remodeling following cardiac insults, and how understanding of these processes uncovers novel disease mechanisms that contribute to cardiac pathology. RECENT FINDINGS Distinct subsets of cardiac macrophages reside within the heart and exhibit divergent functions in response to myocardial injury. Parsing cardiac macrophages based on developmental origin has served as a valuable approach to define functionally divergent populations of reparative (embryonic-derived, tissue resident) and inflammatory (monocyte-derived, recruited) cardiac macrophages. Single-cell transcriptomics and elucidation of the effector mechanisms that orchestrate macrophage functions has provided new and therapeutically tractable insights into the pathogenesis of numerous cardiac diseases. The immune landscape of the heart is dynamic and represents an important mediator of disease pathogenesis across an array of cardiac pathology. Elucidation of mechanisms that drive inflammatory monocyte/macrophage recruitment, activation, and effector responses may lead to the identification of new therapeutic targets.
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Affiliation(s)
- Jesus Jimenez
- Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 South Euclid Campus, Box 8086, St. Louis, MT, 63110, USA
| | - Kory J Lavine
- Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, 660 South Euclid Campus, Box 8086, St. Louis, MT, 63110, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
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40
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Wang XH, Guo W, Qiu W, Ao LQ, Yao MW, Xing W, Yu Y, Chen Q, Wu XF, Li Z, Hu XT, Xu X. Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution. Int J Biol Sci 2022; 18:4388-4399. [PMID: 35864974 PMCID: PMC9295062 DOI: 10.7150/ijbs.69890] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 06/13/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic non-healing wounds fail to progress beyond the inflammatory phase, characterized by a disorder of inflammation resolution. PD-1/PD-L1, a major co-inhibitory checkpoint signaling, plays critical roles in tumor immune surveillance and the occurrence of inflammatory or autoimmune diseases, but its roles in wound healing remains unclear. Here, we described a novel function of PD-L1 in fibroblast-like cells as a positive regulator of wound healing. PD-L1 dynamically expressed on the fibroblast-like cells in the granulation tissue during wound healing to form a wound immunosuppressive microenvironment, modulate macrophages polarization from M1-type to M2-type, and initiates resolution of inflammation, finally accelerate wound healing. Loss of PD-L1 delayed wound healing, especially in mice with LPS-induced severe inflammation. Furthermore, the mainly regulatory mechanism is that combination of FGF-2 and TGF-β1 promotes PD-L1 translation in fibroblasts through enhancing the eIF4E availability regulated by both PI3K-AKT-mTOR-4EBP1 and p38-ERK-MNK signaling pathways. Our results reveal the positive role of PD-L1 in wound healing, and provide a new strategy for the treatment of chronic wounds.
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Affiliation(s)
- Xiao-Hui Wang
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China.,College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Wei Guo
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Wei Qiu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China.,Department of Dermatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, P.R. China
| | - Luo-Quan Ao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Meng-Wei Yao
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Wei Xing
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Yang Yu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Quan Chen
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Xiao-Feng Wu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Xue-Ting Hu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China
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Sun H, Huang W, Ji F, Pan Y, Yang L. Comparisons of Metastatic Patterns, Survival Outcomes and Tumor Immune Microenvironment Between Young and Non-Young Breast Cancer Patients. Front Cell Dev Biol 2022; 10:923371. [PMID: 35912097 PMCID: PMC9329535 DOI: 10.3389/fcell.2022.923371] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/21/2022] [Indexed: 12/27/2022] Open
Abstract
Background: Metastases are the main cause of breast cancer-related deaths. Breast cancer has a more aggressive phenotype and less favorable prognosis in young females than in older females. In this study, we aimed to compare the metastatic patterns, survival outcomes and tumor immune microenvironment of young and non-young breast cancer patients.Methods: Patients with a diagnosis of breast cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. The significance of young age (≤40 years) in the metastatic profile and prognosis of breast cancer was investigated. The transciptome expression data were acquired from The Cancer Genome Atlas (TCGA) database. And the differentially expressed genes (DEGs) and primarily enriched function pathways were identified by comparing between young and non-young breast cancer samples, and tumor immune infiltrating cell types in the tumor microenvironment were compared.Results: A total of 281,829 female breast cancer patients were included in SEER: 18,331 young (6.5%) and 263,498 non-young (93.5%) women. The metastatic rates of bone, liver and distant lymph nodes (DLNs) in the young cohort were significantly higher than those in the non-young cohort. The most frequent two-site metastatic combination was bone and liver (0.61%) in the young cohort, whereas it was bone and lung (0.32%) in the non-young cohort. Breast cancer-specific survival (BCSS) was significantly shortened among those in the young cohort compared with those in the non-young cohort (p < 0.001). Young age was associated with significantly shorter BCSS only among patients with HR+/HER2- tumors (p < 0.001). The enriched biological pathways based on DEGs between two cohorts were related to the regulation of immune response and several metabolic processes. M2 macrophages were significantly abundant in non-young breast cancer than young breast cancer.Conclusion: Young and non-young breast cancer patients present with different metastatic patterns. Young age is a negative prognostic factor, particularly for HR+/HER2- breast cancer. The differences in metastatic patterns between young and non-young cohorts should be taken into account in the clinical management of metastatic breast cancer. The young breast cancer patients may gain better response to immunotherapy due to immune activated TME than non-young breast cancer.
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Affiliation(s)
- Hengwen Sun
- Department of Radiation Oncology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wei Huang
- Department of Radiation Oncology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fei Ji
- Cancer Center, Department of Breast Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yi Pan
- Department of Radiation Oncology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Lu Yang
- Department of Radiation Oncology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- *Correspondence: Lu Yang,
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Anti-inflammaging effects of black soybean and black rice mixture extract by reprogramming of mitochondrial respirations in murine macrophages. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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43
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Cellular Carcinogenesis: Role of Polarized Macrophages in Cancer Initiation. Cancers (Basel) 2022; 14:cancers14112811. [PMID: 35681791 PMCID: PMC9179569 DOI: 10.3390/cancers14112811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/26/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Inflammation is a hallmark of many cancers. Macrophages are key participants in innate immunity and important drivers of inflammation. When chronically polarized beyond normal homeostatic responses to infection, injury, or aging, macrophages can express several pro-carcinogenic phenotypes. In this review, evidence supporting polarized macrophages as endogenous sources of carcinogenesis is discussed. In addition, the depletion or modulation of macrophages by small molecule inhibitors and probiotics are reviewed as emerging strategies in cancer prevention. Abstract Inflammation is an essential hallmark of cancer. Macrophages are key innate immune effector cells in chronic inflammation, parainflammation, and inflammaging. Parainflammation is a form of subclinical inflammation associated with a persistent DNA damage response. Inflammaging represents low-grade inflammation due to the dysregulation of innate and adaptive immune responses that occur with aging. Whether induced by infection, injury, or aging, immune dysregulation and chronic macrophage polarization contributes to cancer initiation through the production of proinflammatory chemokines/cytokines and genotoxins and by modulating immune surveillance. This review presents pre-clinical and clinical evidence for polarized macrophages as endogenous cellular carcinogens in the context of chronic inflammation, parainflammation, and inflammaging. Emerging strategies for cancer prevention, including small molecule inhibitors and probiotic approaches, that target macrophage function and phenotype are also discussed.
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Songkiatisak P, Rahman SMT, Aqdas M, Sung MH. NF-κB, a culprit of both inflamm-ageing and declining immunity? Immun Ageing 2022; 19:20. [PMID: 35581646 PMCID: PMC9112493 DOI: 10.1186/s12979-022-00277-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/29/2022] [Indexed: 04/21/2023]
Abstract
NF-κB is generally recognized as an important regulator of ageing, through its roles in cellular senescence and inflammatory pathways. Activated in virtually all cell-cell communication networks of the immune system, NF-κB is thought to affect age-related defects of both innate and adaptive immune cells, relevant to inflamm-ageing and declining adaptive immunity, respectively. Moreover, the family of NF-κB proteins that exist as heterodimers and homodimers exert their function beyond the immune system. Given their involvement in diverse areas such as DNA damage to metabolism, NF-κB has the potential to serve as linkages between known hallmarks of ageing. However, the complexity of NF-κB dimer composition, dynamic signaling, and tissue-specific actions has received relatively little attention in ageing research. Here, we discuss some areas where further research may bear fruit in our understanding the impact of NF-κB in healthy ageing and longevity.
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Affiliation(s)
- Preeyaporn Songkiatisak
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 21224, Baltimore, MD, USA
| | - Shah Md Toufiqur Rahman
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 21224, Baltimore, MD, USA
| | - Mohammad Aqdas
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 21224, Baltimore, MD, USA
| | - Myong-Hee Sung
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 21224, Baltimore, MD, USA.
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Duong L, Pixley FJ, Nelson DJ, Jackaman C. Aging Leads to Increased Monocytes and Macrophages With Altered CSF-1 Receptor Expression and Earlier Tumor-Associated Macrophage Expansion in Murine Mesothelioma. FRONTIERS IN AGING 2022; 3:848925. [PMID: 35821822 PMCID: PMC9261395 DOI: 10.3389/fragi.2022.848925] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/12/2022] [Indexed: 11/15/2022]
Abstract
Increased cancer incidence occurs with the emergence of immunosenescence, highlighting the indispensability of the immune system in preventing cancer and its dysregulation with aging. Tumor-associated macrophages (TAMs) are often present in high numbers and are associated with poor clinical outcomes in solid cancers, including mesothelioma. Monocytes and macrophages from the bone marrow and spleen can respond to tumor-derived factors, such as CSF-1, and initiation of the CSF-1R signaling cascade results in their proliferation, differentiation, and migration to the tumor. Age-related changes occur in monocytes and macrophages in terms of numbers and function, which in turn can impact tumor initiation and progression. Whether this is due to changes in CSF-1R expression with aging is currently unknown and was investigated in this study. We examined monocytes and macrophages in the bone marrow and spleen during healthy aging in young (3–4 months) and elderly (20–24 months) female C57BL/6J mice. Additionally, changes to these tissues and in TAMs were examined during AE17 mesothelioma tumor growth. Healthy aging resulted in an expansion of Ly6Chigh monocytes and macrophages in the bone marrow and spleen. CSF-1R expression levels were reduced in elderly splenic macrophages only, suggesting differences in CSF-1R signaling between both cell type and tissue site. In tumor-bearing mice, Ly6Chigh monocytes increased with tumor growth in the spleen in the elderly and increased intracellular CSF-1R expression occurred in bone marrow Ly6Chigh monocytes in elderly mice bearing large tumors. Age-related changes to bone marrow and splenic Ly6Chigh monocytes were reflected in the tumor, where we observed increased Ly6Chigh TAMs earlier and expansion of Ly6Clow TAMs later during AE17 tumor growth in the elderly compared to young mice. F4/80high TAMs increased with tumor growth in both young and elderly mice and were the largest subset of TAMs in the tumor. Together, this suggests there may be a faster transition of Ly6Chigh towards F4/80high TAMs with aging. Amongst TAM subsets, expression of CSF-1R was lowest in F4/80high TAMs, however Ly6Clow TAMs had higher intracellular CSF-1R expression. This suggests downstream CSF-1R signaling may vary between macrophage subsets, which can have implications towards CSF-1R blockade therapies targeting macrophages in cancer.
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Affiliation(s)
- Lelinh Duong
- Curtin Medical School, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Fiona J. Pixley
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
| | - Delia J. Nelson
- Curtin Medical School, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Connie Jackaman
- Curtin Medical School, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
- *Correspondence: Connie Jackaman,
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Sheu KM, Hoffmann A. Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance. Annu Rev Immunol 2022; 40:295-321. [PMID: 35471841 PMCID: PMC10074967 DOI: 10.1146/annurev-immunol-101320-031555] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.
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Affiliation(s)
- Katherine M Sheu
- Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA;
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California, USA;
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Hofer S, Hofstätter N, Punz B, Hasenkopf I, Johnson L, Himly M. Immunotoxicity of nanomaterials in health and disease: Current challenges and emerging approaches for identifying immune modifiers in susceptible populations. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1804. [PMID: 36416020 PMCID: PMC9787548 DOI: 10.1002/wnan.1804] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/24/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022]
Abstract
Nanosafety assessment has experienced an intense era of research during the past decades driven by a vivid interest of regulators, industry, and society. Toxicological assays based on in vitro cellular models have undergone an evolution from experimentation using nanoparticulate systems on singular epithelial cell models to employing advanced complex models more realistically mimicking the respective body barriers for analyzing their capacity to alter the immune state of exposed individuals. During this phase, a number of lessons were learned. We have thus arrived at a state where the next chapters have to be opened, pursuing the following objectives: (1) to elucidate underlying mechanisms, (2) to address effects on vulnerable groups, (3) to test material mixtures, and (4) to use realistic doses on (5) sophisticated models. Moreover, data reproducibility has become a significant demand. In this context, we studied the emerging concept of adverse outcome pathways (AOPs) from the perspective of immune activation and modulation resulting in pro-inflammatory versus tolerogenic responses. When considering the interaction of nanomaterials with biological systems, protein corona formation represents the relevant molecular initiating event (e.g., by potential alterations of nanomaterial-adsorbed proteins). Using this as an example, we illustrate how integrated experimental-computational workflows combining in vitro assays with in silico models aid in data enrichment and upon comprehensive ontology-annotated (meta)data upload to online repositories assure FAIRness (Findability, Accessibility, Interoperability, Reusability). Such digital twinning may, in future, assist in early-stage decision-making during therapeutic development, and hence, promote safe-by-design innovation in nanomedicine. Moreover, it may, in combination with in silico-based exposure-relevant dose-finding, serve for risk monitoring in particularly loaded areas, for example, workplaces, taking into account pre-existing health conditions. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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Affiliation(s)
- Sabine Hofer
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
| | - Norbert Hofstätter
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
| | - Benjamin Punz
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
| | - Ingrid Hasenkopf
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
| | - Litty Johnson
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
| | - Martin Himly
- Division of Allergy & Immunology, Department of Biosciences & Medical BiologyParis Lodron University of SalzburgSalzburgAustria
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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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Kingren MS, Starr ME, Saito H. Divergent Sepsis Pathophysiology in Older Adults. Antioxid Redox Signal 2021; 35:1358-1375. [PMID: 34210173 PMCID: PMC8905233 DOI: 10.1089/ars.2021.0056] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022]
Abstract
Significance: Both incidence and mortality rates of sepsis significantly increase with advanced age, and the majority of sepsis patients are late middle-aged or older. With the proportion of older adults rapidly increasing in developed countries, age-dependent sepsis vulnerability is an urgent medical issue. Due to an increasing life expectancy, postsepsis complications and health care costs are expected to increase as well. Recent Advances: Older patients suffer from higher sepsis incidence and mortality rates, likely resulting from frequent comorbidities, increased coagulation, dysgylcemia, and altered immune responses. Critical Issues: Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy targeting older patients with severe sepsis. The disparity between clinical and basic studies is a problem, and this is largely due to the use of animal models lacking clinical relevance. Although the majority of sepsis cases occur in older adults, most laboratory animals used for sepsis research are very young. Further, despite the wide use of combination fluid and antibiotic treatment in intensive care unit (ICU) patients, most animal research does not include such treatment. Future Directions: Because sepsis is a systemic disease with multiple organ dysfunction, combined therapy approaches, not those targeting single pathways or single organs, are essential. As for preclinical research, it is critical to confirm new findings using aged animal models with clinically relevant ICU-like medical treatments. Antioxid. Redox Signal. 35, 1358-1375.
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Affiliation(s)
- Meagan S. Kingren
- Aging and Critical Care Research Laboratory, Departments of University of Kentucky, Lexington, Kentucky, USA
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Marlene E. Starr
- Aging and Critical Care Research Laboratory, Departments of University of Kentucky, Lexington, Kentucky, USA
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
- Surgery, University of Kentucky, Lexington, Kentucky, USA
| | - Hiroshi Saito
- Aging and Critical Care Research Laboratory, Departments of University of Kentucky, Lexington, Kentucky, USA
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
- Surgery, University of Kentucky, Lexington, Kentucky, USA
- Physiology, University of Kentucky, Lexington, Kentucky, USA
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Sharma R. Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology. Biogerontology 2021; 22:571-587. [PMID: 34490541 DOI: 10.1007/s10522-021-09936-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/30/2021] [Indexed: 01/10/2023]
Abstract
An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.
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Affiliation(s)
- Rohit Sharma
- Faculty of Applied Sciences & Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India.
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