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Shinde U, Balasinor NH, Ravichandran V, Kumar AS, Gunasekaran VP. "Extracellular Vesicle DNA: Advances and Applications as a Non-Invasive Biomarker in Disease Diagnosis and Treatment". Clin Chim Acta 2025; 568:120125. [PMID: 39793847 DOI: 10.1016/j.cca.2025.120125] [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: 11/19/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 01/13/2025]
Abstract
Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures released by cells into the extracellular milieu. These vesicles encapsulate a diverse array of molecular constituents, including nucleic acids, proteins, and lipids, which provide insights into the physiological or pathological conditions of their parent cells. Despite their potential, the study of EV-derived DNA (EV-DNA) has gathered relatively limited attention. This review aims to present a thorough examination of the emerging knowledge surrounding the utility of EV-DNA as a non-invasive biomarker across a spectrum of diseases. The review delves into various mechanisms underlying DNA packaging within EVs and the prevalent methodologies employed for extraction of EV-DNA. The relevance of EV-DNA is assessed across numerous health conditions, notably cancer, cardiovascular diseases, neurodegenerative disorders, infectious diseases, and pregnancy-related complications. The use of EV-DNA for cancer mutation detection has demonstrated remarkable sensitivity and specificity, thereby enhancing both diagnostic accuracy and therapeutic monitoring. In the context of cardiovascular diseases, EV-DNA serves as a predictive marker for events such as myocardial infarctions and shows a correlation with the severity of the disease. With respect to neurodegenerative conditions, including Parkinson's and Alzheimer's, EV-DNA contributes to the understanding of disease mechanisms and progression. Additionally, it plays an essential role in modulating immune tolerance and facilitating communication between maternal and fetal systems. Although there is a pressing need for standardized protocols for EV isolation and DNA analysis to facilitate clinical implementation, the prospect of EV-DNA as a non-invasive biomarker for diagnostic and prognostic purposes across diverse pathological conditions is considerable.
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Affiliation(s)
- Uma Shinde
- Center for Drug Discovery and Development, Amity Institute of Biotechnology, Amity University Mumbai (AUM), Maharashtra, India
| | - Nafisa Huseni Balasinor
- ICMR-National Institute for Research in Reproductive and Child Health (ICMR- NIRRCH), Parel, Mumbai, India
| | - Vinothkannan Ravichandran
- Center for Drug Discovery and Development, Amity Institute of Biotechnology, Amity University Mumbai (AUM), Maharashtra, India
| | - Aw Santhosh Kumar
- Center for Drug Discovery and Development, Amity Institute of Biotechnology, Amity University Mumbai (AUM), Maharashtra, India; California University of Science & Medicine, CA, United States of America
| | - Vinoth Prasanna Gunasekaran
- Center for Drug Discovery and Development, Amity Institute of Biotechnology, Amity University Mumbai (AUM), Maharashtra, India.
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Moskovitch O, Anaki A, Caller T, Gilburd B, Segal O, Gendelman O, Watad A, Mehrian-Shai R, Mintz Y, Segev S, Shoenfeld Y, Popovtzer R, Amital H, Halpert G. The potential of autologous patient-derived circulating extracellular vesicles to improve drug delivery in rheumatoid arthritis. Clin Exp Immunol 2025; 219:uxae101. [PMID: 39756417 PMCID: PMC11754864 DOI: 10.1093/cei/uxae101] [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: 04/09/2024] [Revised: 10/07/2024] [Accepted: 01/03/2025] [Indexed: 01/07/2025] Open
Abstract
Recognizing the need for innovative therapeutic approaches in the management of autoimmune diseases, our current investigation explores the potential of autologous extracellular vesicles (EVs), derived from the blood of rheumatoid arthritis patients, to serve as therapeutic vectors to improve drug delivery. We found that circulating EVs derived from arthritic mice (collagen-induced arthritis model) express the joint/synovia homing receptor, αVβ3 integrin. Importantly, both autologous labeled EVs, derived from the blood of arthritic mice (collagen antibody-induced arthritis model) and healthy mice-derived EVs, exhibit targeted migration toward inflamed synovia without infiltrating healthy joints, as demonstrated by an in vivo imaging system. Furthermore, EVs derived from plasma of rheumatoid arthritis patients show an overexpression of αV integrin and are effectively taken up by lipopolysaccharides/tumor necrosis factor alpha (TNFα)-induced activated human synovial cell line in vitro, although interestingly the uptake of healthy EVs was found to be significantly increased. Notably, arthritic mice-derived circulating EVs, strongly express murine glucose transporter 1, which in turn can facilitate their binding to glucose-coated gold nanoparticles (previously shown to be conjugated with drugs for improved drug delivery). The significance of our results, lies in the identification of autologous tissue homing EVs as promising vectors, offering a novel avenue to enhance targeted delivery of anti-inflammatory/rheumatic drugs in rheumatoid arthritis treatment.
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Affiliation(s)
- Ori Moskovitch
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Anaki
- Bar-Ilan Institute for Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat Gan, Israel
| | - Tal Caller
- Faculty of Medicine, Neufeld Cardiovascular Research Institutes, Tel Aviv University, Tel-Aviv, Israel
- Tamman Cardiovascular Research Institutes, Sheba Medical Center, Tel-Hashomer, Israel
| | - Boris Gilburd
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
| | - Ori Segal
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Omer Gendelman
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Internal Medicine ‘B’, Sheba Medical Center, Ramat Gan, Israel
| | - Abdulla Watad
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Internal Medicine ‘B’, Sheba Medical Center, Ramat Gan, Israel
| | - Ruty Mehrian-Shai
- Department of Pediatric Hemato-Oncology, The Cancer Research Center, Sheba Medical Center, Ramat Gan, Israel
| | - Yael Mintz
- Institute for Medical Screening, Sheba Medical Center, Ramat Gan, Israel
| | - Shlomo Segev
- The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute for Medical Screening, Sheba Medical Center, Ramat Gan, Israel
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Dina Recanati School of Medicine, Reichman University, Herzliya, Israel
| | - Rachela Popovtzer
- Bar-Ilan Institute for Nanotechnology and Advanced Materials (BINA), Bar-Ilan University, Ramat Gan, Israel
| | - Howard Amital
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Internal Medicine ‘B’, Sheba Medical Center, Ramat Gan, Israel
| | - Gilad Halpert
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel
- The Dina Recanati School of Medicine, Reichman University, Herzliya, Israel
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Duan L, Lin W, Zhang Y, Jin L, Xiao J, Wang H, Pang S, Wang H, Sun D, Gong Y, Li H. Exosomes in Autoimmune Diseases: A Review of Mechanisms and Diagnostic Applications. Clin Rev Allergy Immunol 2025; 68:5. [PMID: 39820756 DOI: 10.1007/s12016-024-09013-2] [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] [Accepted: 12/13/2024] [Indexed: 01/19/2025]
Abstract
Exosomes, small extracellular vesicles secreted by various cell types, have emerged as key players in the pathophysiology of autoimmune diseases. These vesicles serve as mediators of intercellular communication, facilitating the transfer of bioactive molecules such as proteins, lipids, and nucleotide. In autoimmune diseases, exosomes have been implicated in modulating immune responses, oxidative stress, autophagy, gut microbes, and the cell cycle, contributing to disease initiation, progression, and immune dysregulation. Recent advancements in exosome isolation techniques and their molecular characterization have paved the way for exploring their clinical potential as biomarkers and therapeutic targets. This review focuses on the mechanisms by which exosomes influence autoimmune disease development and their potential clinical applications, particularly in diagnosis. The role of exosomes in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), inflammatory bowel disease (IBD), and Sjögren's syndrome (SS), is discussed in relation to their involvements in antigen presentation, T-cell activation, and the induction of inflammatory pathways. Additionally, exosome-based biomarkers offer promising non-invasive diagnostic tools for early diagnostic, disease monitoring, and therapeutic response assessment. However, challenges such as standardization of exosome isolation protocols and validation of their clinical significance remain. This review highlights the potential of exosomes as both diagnostic biomarkers and therapeutic targets in autoimmune diseases, emphasizing the need for further research to overcome current limitations and fully harness their clinical value.
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Affiliation(s)
- Lina Duan
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Wanying Lin
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Yi Zhang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Lingyue Jin
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Jie Xiao
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Haifang Wang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Shuyin Pang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Hongxia Wang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Dehua Sun
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
| | - Ying Gong
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
| | - Haixia Li
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
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Chen T, Zhan X, Zhu J, Zhou C, Huang C, Wu S, Yao Y, Zhang B, Feng S, Chen J, Xue J, Yang Z, Liu C. Integrating multiomics and Single-Cell communication analysis to uncover Ankylosing spondylitis mechanisms. Int Immunopharmacol 2024; 143:113276. [PMID: 39357209 DOI: 10.1016/j.intimp.2024.113276] [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: 04/11/2024] [Revised: 09/13/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND Ankylosing spondylitis (AS) is a chronic inflammatory joint disorder, necessitating early diagnosis and effective treatment. The specific mechanism of action of Cassia twigs in the treatment of AS is not fully understood. METHODS Blood samples and clinical data from 28,458 individuals (6,101 with AS, 22,357 without AS) were collected. To construct a predictive model, we utilized logistic regressions and machine learning techniques to create a dynamic nomogram. Immune cell infiltration was evaluated using the GSE73754 dataset. Subsequently, we obtained vertebral bone marrow blood from AS patients for 10X single-cell sequencing. We also extracted and purified total RNA from hip joint ligament tissue samples from six AS patients and six non-AS patients. The genes related to the expression of AS and Cassia twigs were analyzed comprehensively, and the specific drug targets were identified by molecular docking. The interactions between immune cells through cell communication analysis were elucidated. RESULTS We developed a dynamic nomogram incorporating the neutrophil count (NEUT) and other variables. Neutrophil immune responses were confirmed through immune infiltration analysis utilizing GSE73754. We observed the early involvement of neutrophils in the pathology of AS. The CAT-expressing Cassia twigs gene could be used as a drug target for the treatment of AS. Moreover, comprehensive RNA analysis revealed notable CAT expression in neutrophils and various other immune cells. CONCLUSIONS Neutrophils play dual roles in AS, regulating inflammation and initiating differentiation signals to other cells. The CAT gene, which is expressed in Cassia twigs, has emerged as a potential therapeutic target for AS treatment.
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Affiliation(s)
- Tianyou Chen
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Xinli Zhan
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Jichong Zhu
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Chenxing Zhou
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Chengqian Huang
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Shaofeng Wu
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Yuanlin Yao
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Bin Zhang
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Sitan Feng
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Jiarui Chen
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Jiang Xue
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Zhenwei Yang
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
| | - Chong Liu
- The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi, 530021, P.R. China.
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Li Y, Baniel A, Diaz D, Ogawa-Momohara M, Ricco C, Eldaboush A, Bashir M, Sharma M, Liu ML, Werth VP. Keratinocyte derived extracellular vesicles mediated crosstalk between epidermis and dermis in UVB-induced skin inflammation. Cell Commun Signal 2024; 22:461. [PMID: 39350252 PMCID: PMC11441254 DOI: 10.1186/s12964-024-01839-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND AND RATIONALE Ultraviolet-B (UVB) light induces dermal inflammation, although it is mostly absorbed in the epidermis. Recent reports suggest extracellular vesicles (EVs) act as a mediator of photodamage signaling. Melatonin is reported to be a protective factor against UV-induced damage. We hypothesized that EVs derived from UVB-irradiated keratinocytes might trigger proinflammatory responses in dermal cells and tested whether melatonin can ameliorate UVB-induced inflammation. METHODS We used UVB-irradiated HaCaT cells, primary keratinocytes and STING knock-out mice to model production of EVs under photodamaging conditions and performed immunoblotting and ELISA to measure their effect on dermal macrophages. RESULTS UVB-irradiated keratinocytes produce an increased number of EVs that contain higher concentrations of DNA and protein compared with controls. KC-derived EVs (KEVs) induced a STING- and inflammasome-mediated proinflammatory response in macrophages in vitro, and a pronounced inflammatory infiltrate in mouse dermis in vivo. Melatonin ameliorated KEVs inflammatory effect both in vitro and in vivo. CONCLUSIONS This data suggests EVs are mediators in a crosstalk that takes place between keratinocytes and their neighboring cells as a result of photodamage. Further studies exploring EVs induced by damaging doses of UVB, and their impact on other cells will provide insight into photodamage and may help develop targeted therapeutic approaches.
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Affiliation(s)
- Yubin Li
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Avital Baniel
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - DeAnna Diaz
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Mariko Ogawa-Momohara
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Cristina Ricco
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Ahmed Eldaboush
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Muhammad Bashir
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Meena Sharma
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Ming-Lin Liu
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Victoria P Werth
- Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
- Department of Dermatology, School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
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Shahsavari A, Liu F. Diagnostic and therapeutic potentials of extracellular vesicles for primary Sjögren's Syndrome: A review. DENTISTRY REVIEW 2024; 4:100150. [PMID: 39310092 PMCID: PMC11416744 DOI: 10.1016/j.dentre.2024.100150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Primary Sjögren syndrome (pSS) is a chronic autoimmune disease mainly affecting salivary and lacrimal glands. The current pSS biomarkers, serum autoantibodies, are negative in many pSS patients diagnosed with histopathology changes, indicating the need of novel biomarkers. The current therapies of pSS are merely short-term symptomatic relief and can't provide effective long-term remedy. Extracellular vehicles (EVs) are nano-sized lipid bilayer-delimited particles spontaneously released by almost all types of cells and carrying various bioactive molecules to mediate inter-cellular communications. Recent studies found that EVs from salivary gland epithelial cells and immune cells play essential roles in pSS pathogenesis. Correspondingly, EVs and their cargos in plasma and saliva are promising candidate biomarkers for pSS diagnosis. Moreover, EVs from mesenchymal stem cells have shown promises to improve pSS treatment by modulating immune responses. This review summarizes recent findings in roles of EVs in pSS pathogenesis, diagnosis, and treatment of pSS, as well as related challenges and future research directions.
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Affiliation(s)
- Arash Shahsavari
- Cell Biology and Genetics department, School of Medicine, Texas A&M University, College Station, TX, USA
| | - Fei Liu
- Cell Biology and Genetics department, School of Medicine, Texas A&M University, College Station, TX, USA
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Yan Q, Song C, Liu H, Li Y, Ma J, Zhao Y, Song Z, Chen Y, Zhu R, Zhang Z. Adipose-derived stem cell exosomes loaded with icariin attenuated M1 polarization of macrophages via inhibiting the TLR4/Myd88/NF-κB signaling pathway. Int Immunopharmacol 2024; 137:112448. [PMID: 38870883 DOI: 10.1016/j.intimp.2024.112448] [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: 02/07/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024]
Abstract
Abnormal macrophage polarization is one of the common pathological bases of various inflammatory diseases. The current research focus involves targeting macrophages to remodel their phenotype as a treatment approach for inflammatory diseases. Notably, exosomes can be delivered to specific types of cells or tissues or inflammatory area to realize targeted drug delivery. Although icariin (ICA) exhibits regulatory potential in macrophage polarization, the practical application of ICA is impeded by its water insolubility, poor permeability, and low bioavailability. Exploiting the inherent advantages of exosomes as natural drug carriers, we introduce a novel drug delivery system-adipose-derived stem cells-exosomes (ADSCs-EXO)-ICA. High-performance liquid chromatography analysis confirmed a loading rate of 92.7 ± 0.01 % for ADSCs-EXO-ICA, indicating the successful incorporation of ICA. As demonstrated by cell counting kit-8 assays, ADSCs-EXO exerted a significantly higher promotion effect on macrophage proliferation. The subsequent experimental results revealed the superior anti-inflammatory effect of ADSCs-EXO-ICA compared to individual treatments with EXO or ICA in the lipopolysaccharide + interferon-gamma-induced M1 inflammation model. Additionally, results from enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and western blot analyses revealed that ADSCs-EXO-ICA effectively inhibited macrophage polarization toward the M1-type and concurrently promoted polarization toward the M2-type. The underlying mechanism involved the modulation of macrophage polarization through inhibition of the Toll-like receptor 4/myeloid differentiation factor 88/nuclear transcription factor-kappa B signaling pathway, thereby mitigating inflammation. These findings underscore the potential therapeutic value of ADSCs-EXO-ICA as a novel intervention for inflammatory diseases.
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Affiliation(s)
- Qiqi Yan
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Changheng Song
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Haixia Liu
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yubo Li
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayi Ma
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yukun Zhao
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiqian Song
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yanjing Chen
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruyuan Zhu
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Zhiguo Zhang
- Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
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Su J, Song Y, Zhu Z, Huang X, Fan J, Qiao J, Mao F. Cell-cell communication: new insights and clinical implications. Signal Transduct Target Ther 2024; 9:196. [PMID: 39107318 PMCID: PMC11382761 DOI: 10.1038/s41392-024-01888-z] [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: 12/29/2023] [Revised: 05/09/2024] [Accepted: 06/02/2024] [Indexed: 09/11/2024] Open
Abstract
Multicellular organisms are composed of diverse cell types that must coordinate their behaviors through communication. Cell-cell communication (CCC) is essential for growth, development, differentiation, tissue and organ formation, maintenance, and physiological regulation. Cells communicate through direct contact or at a distance using ligand-receptor interactions. So cellular communication encompasses two essential processes: cell signal conduction for generation and intercellular transmission of signals, and cell signal transduction for reception and procession of signals. Deciphering intercellular communication networks is critical for understanding cell differentiation, development, and metabolism. First, we comprehensively review the historical milestones in CCC studies, followed by a detailed description of the mechanisms of signal molecule transmission and the importance of the main signaling pathways they mediate in maintaining biological functions. Then we systematically introduce a series of human diseases caused by abnormalities in cell communication and their progress in clinical applications. Finally, we summarize various methods for monitoring cell interactions, including cell imaging, proximity-based chemical labeling, mechanical force analysis, downstream analysis strategies, and single-cell technologies. These methods aim to illustrate how biological functions depend on these interactions and the complexity of their regulatory signaling pathways to regulate crucial physiological processes, including tissue homeostasis, cell development, and immune responses in diseases. In addition, this review enhances our understanding of the biological processes that occur after cell-cell binding, highlighting its application in discovering new therapeutic targets and biomarkers related to precision medicine. This collective understanding provides a foundation for developing new targeted drugs and personalized treatments.
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Affiliation(s)
- Jimeng Su
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu, China
| | - Ying Song
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
| | - Zhipeng Zhu
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Cancer Center, Peking University Third Hospital, Beijing, China
| | - Xinyue Huang
- Biomedical Research Institute, Shenzhen Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Jibiao Fan
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu, China
| | - Jie Qiao
- State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
- National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China.
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China.
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
| | - Fengbiao Mao
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
- Cancer Center, Peking University Third Hospital, Beijing, China.
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Young NA, Schwarz E, Zeno BM, Bruckner S, Mesa RA, Jablonski K, Wu LC, Roberson EDO, Jarjour WN. Inhibition of miRNA associated with a disease-specific signature and secreted via extracellular vesicles of systemic lupus erythematosus patients suppresses target organ inflammation in a humanized mouse model. Front Immunol 2024; 14:1090177. [PMID: 38939646 PMCID: PMC11208704 DOI: 10.3389/fimmu.2023.1090177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 04/17/2023] [Indexed: 06/29/2024] Open
Abstract
Introduction Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice. Methods Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination. Results EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3. Discussion These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.
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Affiliation(s)
- Nicholas A. Young
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Emily Schwarz
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Braden M. Zeno
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Shane Bruckner
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Rosana A. Mesa
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Kyle Jablonski
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Lai-Chu Wu
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, United States
| | - Elisha D. O. Roberson
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
- Department of Genetics, Washington University, St. Louis, MO, United States
| | - Wael N. Jarjour
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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10
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Li H, Dai J, Zhao C, Hu T, Zhao G, Wang Q, Zhang L. Gut Subdoligranulum variabile ameliorates rheumatoid arthritis by promoting TSG-6 synthesis from joint cells. Front Immunol 2024; 15:1418717. [PMID: 38979426 PMCID: PMC11229780 DOI: 10.3389/fimmu.2024.1418717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 05/27/2024] [Indexed: 07/10/2024] Open
Abstract
Background A burgeoning body of evidence has substantiated the association between alterations in the composition of the gut microbiota and rheumatoid arthritis (RA). Nevertheless, our understanding of the intricate mechanisms underpinning this association is limited. Methods To investigate whether the gut microbiota influences the pathogenesis of RA through metabolism or immunity, we performed rigorous synthesis analyses using aggregated statistics from published genome-wide association studies (GWAS) using two-sample Mendelian randomization (MR) and mediated MR techniques, including two-step MR and multivariate MR analyses. Subsequently, we conducted in vitro cellular validation of the analyzed Microbial-Cytokine-RA pathway. We determined the optimal culture conditions through co-culture experiments involving concentration and time. Cell Counting Kit-8 (CCK-8) assays were employed to assess cellular viability, and enzyme-linked immunosorbent assays (ELISA) were performed to assess tumor necrosis factor-inducible gene 6 protein (TSG-6) and tumor necrosis factor-α (TNF-α) levels. Results Our univariable MR results confirmed 15 microbial traits, 7 metabolites and 2 cytokines that may be causally associated with RA (P FDR < 0.05). Mediation analysis revealed that microbial traits influence the risk of RA through metabolite or cytokine (proportion mediated: 7.75% - 58.22%). In vitro experiments demonstrated that TSG-6 was highly expressed in the Subdoligranulum variabile treatment group and was correlated with decreased RA severity (reduced TNF-α expression). Silencing the TSG-6 gene significantly increased TNF-α expression, regardless of treatment with S. variabile. Additionally, S. variabile-secreted exosomes exhibited the same effect. Conclusion The results of this study suggest that S. variabile has the potential to promote TSG-6 secretion, thereby reducing RA inflammation.
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Affiliation(s)
- Hongfeng Li
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Health Inspection and Quarantine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Junhui Dai
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Changying Zhao
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianqi Hu
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guoping Zhao
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
- Chinese Academy of Sciences Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qinghua Wang
- School of Biological Science and Technology, University of Jinan, Jinan, China
| | - Lei Zhang
- Microbiome-X, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
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11
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Lin Y, Wang Z, Liu S, Liu J, Zhang Z, Ouyang Y, Su Z, Chen D, Guo L, Luo T. Roles of extracellular vesicles on macrophages in inflammatory bone diseases. Mol Cell Biochem 2024; 479:1401-1414. [PMID: 37436653 DOI: 10.1007/s11010-023-04809-w] [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: 04/02/2023] [Accepted: 07/02/2023] [Indexed: 07/13/2023]
Abstract
Inflammatory bone disease is a general term for a series of diseases caused by chronic inflammation, which leads to the destruction of bone homeostasis, that is, the osteolytic activity of osteoclasts increases, and the osteogenic activity of osteoblasts decreases, leading to osteolysis. Macrophages are innate immune cell with plasticity, and their polarization is related to inflammatory bone diseases. The dynamic balance of macrophages between the M1 phenotype and the M2 phenotype affects the occurrence and development of diseases. In recent years, an increasing number of studies have shown that extracellular vesicles existing in the extracellular environment can act on macrophages, affecting the progress of inflammatory diseases. This process is realized by influencing the physiological activity or functional activity of macrophages, inducing macrophages to secrete cytokines, and playing an anti-inflammatory or pro-inflammatory role. In addition, by modifying and editing extracellular vesicles, the potential of targeting macrophages can be used to provide new ideas for developing new drug carriers for inflammatory bone diseases.
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Affiliation(s)
- Yifan Lin
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziyan Wang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Shirong Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiaohong Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhiyi Zhang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuanting Ouyang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhikang Su
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ding Chen
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lvhua Guo
- Guangzhou Medical University, Guangzhou, Guangdong, China.
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Tao Luo
- Guangzhou Medical University, Guangzhou, Guangdong, China.
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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12
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Wang R, Shi Y, Lv Y, Xie C, Hu Y. The novel insights of epithelial-derived exosomes in various fibrotic diseases. Biomed Pharmacother 2024; 174:116591. [PMID: 38631144 DOI: 10.1016/j.biopha.2024.116591] [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: 01/14/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/19/2024] Open
Abstract
The characteristics of fibrosis include the abnormal accumulation of extracellular matrix proteins and abnormal tissue repair caused by injury, infection, and inflammation, leading to a significant increase in organ failure and mortality. Effective and precise treatments are urgently needed to halt and reverse the progression of fibrotic diseases. Exosomes are tiny vesicles derived from endosomes, spanning from 40 to 160 nanometers in diameter, which are expelled into the extracellular matrix environment by various cell types. They play a crucial role in facilitating cell-to-cell communication by transporting a variety of cargoes, including proteins, RNA, and DNA. Epithelial cells serve as the primary barrier against diverse external stimuli that precipitate fibrotic diseases. Numerous research suggests that exosomes from epithelial cells have a significant impact on several fibrotic diseases. An in-depth comprehension of the cellular and molecular mechanisms of epithelial cell-derived exosomes in fibrosis holds promise for advancing the exploration of novel diagnostic biomarkers and clinical drug targets. In this review, we expand upon the pathogenic mechanisms of epithelium-derived exosomes and highlight their role in the fibrotic process by inducing inflammation and activating fibroblasts. In addition, we are particularly interested in the bioactive molecules carried by epithelial-derived exosomes and their potential value in the diagnosis and treatment of fibrosis and delineate the clinical utility of exosomes as an emerging therapeutic modality, highlighting their potential application in addressing various medical conditions.
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Affiliation(s)
- Rifu Wang
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Yuxin Shi
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Yonglin Lv
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, Hunan, China
| | - Changqing Xie
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, Hunan, China; NHC Key Laboratory of Carcinogenesis, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China.
| | - Yanjia Hu
- Hunan Key Laboratory of Oral Health Research, Hunan 3D Printing Engineering Research Center of Oral Care, Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Hunan Clinical Research Center of Oral Major Diseases and Oral Health, Xiangya Stomatological Hospital, Xiangya School of Stomatology, Central South University, Changsha, Hunan, China.
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Anees F, Montoya DA, Pisetsky DS, Payne CK. DNA corona on nanoparticles leads to an enhanced immunostimulatory effect with implications for autoimmune diseases. Proc Natl Acad Sci U S A 2024; 121:e2319634121. [PMID: 38442162 PMCID: PMC10945806 DOI: 10.1073/pnas.2319634121] [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: 11/08/2023] [Accepted: 02/03/2024] [Indexed: 03/07/2024] Open
Abstract
Autoimmune and inflammatory diseases are highly complex, limiting treatment and the development of new therapies. Recent work has shown that cell-free DNA bound to biological microparticles is linked to systemic lupus erythematosus, a prototypic autoimmune disease. However, the heterogeneity and technical challenges associated with the study of biological particles have hindered a mechanistic understanding of their role. Our goal was to develop a well-controlled DNA-particle model system to understand how DNA-particle complexes affect cells. We first characterized the adsorption of DNA on the surface of polystyrene nanoparticles (200 nm and 2 µm) using transmission electron microscopy, dynamic light scattering, and colorimetric DNA concentration assays. We found that DNA adsorbed on the surface of nanoparticles was resistant to degradation by DNase 1. Macrophage cells incubated with the DNA-nanoparticle complexes had increased production of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). We probed two intracellular DNA sensing pathways, toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), to determine how cells sense the DNA-nanoparticle complexes. We found that the cGAS-STING pathway is the primary route for the interaction between DNA-nanoparticles and macrophages. These studies provide a molecular and cellular-level understanding of DNA-nanoparticle-macrophage interactions. In addition, this work provides the mechanistic information necessary for future in vivo experiments to elucidate the role of DNA-particle interactions in autoimmune diseases, providing a unique experimental framework to develop novel therapeutic approaches.
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Affiliation(s)
- Faisal Anees
- Thomas Lord Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC27708
| | - Diego A. Montoya
- Thomas Lord Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC27708
| | - David S. Pisetsky
- Division of Rheumatology and Immunology, Duke University Medical Center, and Medical Research Service, Durham VA Medical Center, Durham, NC27705
| | - Christine K. Payne
- Thomas Lord Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC27708
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Chen X, Yan X, Gingerich L, Chen QH, Bi L, Shan Z. Induction of Neuroinflammation and Brain Oxidative Stress by Brain-Derived Extracellular Vesicles from Hypertensive Rats. Antioxidants (Basel) 2024; 13:328. [PMID: 38539860 PMCID: PMC10967780 DOI: 10.3390/antiox13030328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 06/20/2024] Open
Abstract
Neuroinflammation and brain oxidative stress are recognized as significant contributors to hypertension including salt sensitive hypertension. Extracellular vesicles (EVs) play an essential role in intercellular communication in various situations, including physiological and pathological ones. Based on this evidence, we hypothesized that EVs derived from the brains of hypertensive rats with salt sensitivity could trigger neuroinflammation and oxidative stress during hypertension development. To test this hypothesis, we compared the impact of EVs isolated from the brains of hypertensive Dahl Salt-Sensitive rats (DSS) and normotensive Sprague Dawley (SD) rats on inflammatory factors and mitochondrial reactive oxygen species (mtROS) production in primary neuronal cultures and brain cardiovascular relevant regions, including the hypothalamic paraventricular nucleus (PVN) and lamina terminalis (LT). We found that brain-derived DSS-EVs significantly increased the mRNA levels of proinflammatory cytokines (PICs) and chemokines, including TNFα, IL1β, CCL2, CCL5, and CCL12, as well as the transcriptional factor NF-κB in neuronal cultures. DSS-EVs also induced oxidative stress in neuronal cultures, as evidenced by elevated NADPH oxidase subunit CYBA coding gene mRNA levels and persistent mtROS elevation. When DSS-EVs were injected into the brains of normal SD rats, the mRNA levels of PICs, chemokines, and the chronic neuronal activity marker FOSL1 were significantly increased in the PVN and LT. Furthermore, DSS-EVs caused mtROS elevation in brain PVN and LT, particularly in neurons. Our study reveals a novel role for brain-derived EVs from hypertensive rats in triggering neuroinflammation, upregulating chemokine expression, and inducing excessive ROS production. These findings provide insight into the complex interactions between EVs and hypertension-associated processes, offering potential therapeutic targets for hypertension-linked neurological complications.
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Affiliation(s)
- Xinqian Chen
- Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
| | - Xin Yan
- Department of Chemistry, Michigan Technological University, Houghton, MI 49931, USA
| | - Leah Gingerich
- Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA
| | - Qing-Hui Chen
- Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
| | - Lanrong Bi
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
- Department of Chemistry, Michigan Technological University, Houghton, MI 49931, USA
| | - Zhiying Shan
- Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA
- Health Research Institute, Michigan Technological University, Houghton, MI 49931, USA
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da Silva Lira Filho A, Lafleur A, Marcet-Palacios M, Olivier M. Identification of potential novel proteomic markers of Leishmania spp.-derived exosomes. Front Cell Infect Microbiol 2024; 14:1354636. [PMID: 38440791 PMCID: PMC10910114 DOI: 10.3389/fcimb.2024.1354636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/05/2024] [Indexed: 03/06/2024] Open
Abstract
Introduction Extracellular vesicles (EVs) are heterogenous cell-derived membrane-bound structures which can be subdivided into three distinct classes according to distinct morphological characteristics, cellular origins, and functions. Small EVs, or exosomes, can be produced by the protozoan parasite Leishmania through the evolutionarily conserved ESCRT pathway, and act as effectors of virulence and drivers of pathogenesis within mammalian hosts. Techniques for the identification of EVs of non-mammalian origin, however, remain inaccurate in comparison to their well-characterized mammalian counterparts. Thus, we still lack reliable and specific markers for Leishmania-derived exosomes, which poses a significant challenge to the field. Methods Herein, we utilized serial differential ultracentrifugation to separate Leishmania-derived EV populations into three distinct fractions. Nanoparticle tracking analysis and transmission electron microscopy were used to validate their morphological characteristics, and bioinformatic analysis of LC-MS/MS proteomics corroborated cellular origins and function. Discussion Proteomic data indicated potential novel proteic markers of Leishmania-derived exosomes, including proteins involved in endosomal machinery and the ESCRT pathway, as well as the parasitic phosphatase PRL-1. Further investigation is required to determine the specificity and sensitivity of these markers.
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Affiliation(s)
- Alonso da Silva Lira Filho
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Andrea Lafleur
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Marcelo Marcet-Palacios
- Department of Medicine, Alberta Respiratory Centre, University of Alberta, Edmonton, AB, Canada
- Department of Biological Sciences Technology, Laboratory Research and Biotechnology, Northern Alberta Institute of Technology, Edmonton, AB, Canada
| | - Martin Olivier
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
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Caño-Carrillo S, Castillo-Casas JM, Franco D, Lozano-Velasco E. Unraveling the Signaling Dynamics of Small Extracellular Vesicles in Cardiac Diseases. Cells 2024; 13:265. [PMID: 38334657 PMCID: PMC10854837 DOI: 10.3390/cells13030265] [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: 12/29/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024] Open
Abstract
Effective intercellular communication is essential for cellular and tissue balance maintenance and response to challenges. Cellular communication methods involve direct cell contact or the release of biological molecules to cover short and long distances. However, a recent discovery in this communication network is the involvement of extracellular vesicles that host biological contents such as proteins, nucleic acids, and lipids, influencing neighboring cells. These extracellular vesicles are found in body fluids; thus, they are considered as potential disease biomarkers. Cardiovascular diseases are significant contributors to global morbidity and mortality, encompassing conditions such as ischemic heart disease, cardiomyopathies, electrical heart diseases, and heart failure. Recent studies reveal the release of extracellular vesicles by cardiovascular cells, influencing normal cardiac function and structure. However, under pathological conditions, extracellular vesicles composition changes, contributing to the development of cardiovascular diseases. Investigating the loading of molecular cargo in these extracellular vesicles is essential for understanding their role in disease development. This review consolidates the latest insights into the role of extracellular vesicles in diagnosis and prognosis of cardiovascular diseases, exploring the potential applications of extracellular vesicles in personalized therapies, shedding light on the evolving landscape of cardiovascular medicine.
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Affiliation(s)
| | | | | | - Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (S.C.-C.); (J.M.C.-C.); (D.F.)
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Zhang R, Wei Y, Wang T, Nie X, Shi Z, Deng Y, Li D. Exosomal miRNAs in autoimmune skin diseases. Front Immunol 2023; 14:1307455. [PMID: 38106405 PMCID: PMC10722155 DOI: 10.3389/fimmu.2023.1307455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
Exosomes, bilaterally phospholipid-coated small vesicles, are produced and released by nearly all cells, which comprise diverse biological macromolecules, including proteins, DNA, RNA, and others, that participate in the regulation of their biological functions. An increasing number of studies have revealed that the contents of exosomes, particularly microRNA(miRNA), play a significant role in the pathogenesis of various diseases, including autoimmune skin diseases. MiRNA is a class of single-stranded non-coding RNA molecules that possess approximately 22 nucleotides in length with the capability of binding to the untranslated as well as coding regions of target mRNA to regulate gene expression precisely at the post-transcriptional level. Various exosomal miRNAs have been found to be significantly expressed in some autoimmune skin diseases and involved in the pathogenesis of conditions via regulating the secretion of crucial pathogenic cytokines and the direction of immune cell differentiation. Thus, exosomal miRNAs might be promising biomarkers for monitoring disease progression, relapse and reflection to treatment based on their functions and changes. This review summarized the current studies on exosomal miRNAs in several common autoimmune skin diseases, aiming to dissect the underlying mechanism from a new perspective, seek novel biomarkers for disease monitoring and lay the foundation for developing innovative target therapy in the future.
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Affiliation(s)
- Ri Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yujia Wei
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingmei Wang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqi Nie
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeqi Shi
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunhua Deng
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Li
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Becker MW, Peters LD, Myint T, Smurlick D, Powell A, Brusko TM, Phelps EA. Immune engineered extracellular vesicles to modulate T cell activation in the context of type 1 diabetes. SCIENCE ADVANCES 2023; 9:eadg1082. [PMID: 37267353 PMCID: PMC10765990 DOI: 10.1126/sciadv.adg1082] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/27/2023] [Indexed: 06/04/2023]
Abstract
Extracellular vesicles (EVs) can affect immune responses through antigen presentation and costimulation or coinhibition. We generated designer EVs to modulate T cells in the context of type 1 diabetes, a T cell-mediated autoimmune disease, by engineering a lymphoblast cell line, K562, to express HLA-A*02 (HLA-A2) alongside costimulatory CD80 and/or coinhibitory programmed death ligand 1 (PD-L1). EVs presenting HLA-A2 and CD80 activated CD8+ T cells in a dose, antigen, and HLA-specific manner. Adding PD-L1 to these EVs produced an immunoregulatory response, reducing CD8+ T cell activation and cytotoxicity in vitro. EVs alone could not stimulate T cells without antigen-presenting cells. EVs lacking CD80 were ineffective at modulating CD8+ T cell activation, suggesting that both peptide-HLA complex and costimulation are required for EV-mediated immune modulation. These results provide mechanistic insight into the rational design of EVs as a cell-free approach to immunotherapy that can be tailored to promote inflammatory or tolerogenic immune responses.
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Affiliation(s)
- Matthew W. Becker
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Leeana D. Peters
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Thinzar Myint
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Dylan Smurlick
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Andrece Powell
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Todd M. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Edward A. Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, University of Florida, Gainesville, FL, USA
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19
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Zhang E, Phan P, Zhao Z. Cellular nanovesicles for therapeutic immunomodulation: A perspective on engineering strategies and new advances. Acta Pharm Sin B 2023; 13:1789-1827. [PMID: 37250173 PMCID: PMC10213819 DOI: 10.1016/j.apsb.2022.08.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 02/08/2023] Open
Abstract
Cellular nanovesicles which are referred to as cell-derived, nanosized lipid bilayer structures, have emerged as a promising platform for regulating immune responses. Owing to their outstanding advantages such as high biocompatibility, prominent structural stability, and high loading capacity, cellular nanovesicles are suitable for delivering various immunomodulatory molecules, such as small molecules, nucleic acids, peptides, and proteins. Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors, which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases. Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses, with the aim to explicate their applications for immunomodulation. We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities. We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases.
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Affiliation(s)
- Endong Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Philana Phan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Zongmin Zhao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL 60612, USA
- Translational Oncology Program, University of Illinois Cancer Center, Chicago, IL 60612, USA
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20
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Yang X, Xia H, Liu C, Wu Y, Liu X, Cheng Y, Wang Y, Xia Y, Yue Y, Cheng X, Jia R. The novel delivery-exosome application for diagnosis and treatment of rheumatoid arthritis. Pathol Res Pract 2023; 242:154332. [PMID: 36696804 DOI: 10.1016/j.prp.2023.154332] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/15/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic degenerative disease characterized by persistent systemic synovitis, with a high risk of stiffness, pain, and swelling. It may affect the other extra-articular tissues. There is no ideal treatment for this disease at present, and it can only be controlled by medication to alleviate the prognosis. Exosomes are small vesicles secreted by various cells in the organism under normal or pathological conditions, and play a role in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and so on. Due to the adverse effects of conventional drugs and treatments in the treatment of RA, exosomes, as a nanocarrier with many advantages, can have a great impact on the loading of drugs for the treatment of RA. This article reviews the role of exosomes in the pathogenesis of RA and the progress of exosome-based therapy for RA.
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Affiliation(s)
- Xinying Yang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Hongmei Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China.
| | - Chang Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yifang Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xinyi Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yongfeng Cheng
- Clinical College of Anhui Medical University, Hefei 230031, People's Republic of China; School of Life Science, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Yu Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ying Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yan Yue
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xiaoman Cheng
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ruoyang Jia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
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21
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Ntostis P, Swanson G, Kokkali G, Iles D, Huntriss J, Pantou A, Tzetis M, Pantos K, Picton HM, Krawetz SA, Miller D. Trophectoderm non-coding RNAs reflect the higher metabolic and more invasive properties of young maternal age blastocysts. Syst Biol Reprod Med 2023; 69:3-19. [PMID: 36576378 DOI: 10.1080/19396368.2022.2153636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Increasing female age is accompanied by a corresponding fall in her fertility. This decline is influenced by a variety of factors over an individual's life course including background genetics, local environment and diet. Studying both coding and non-coding RNAs of the embryo could aid our understanding of the causes and/or effects of the physiological processes accompanying the decline including the differential expression of sub-cellular biomarkers indicative of various diseases. The current study is a post-hoc analysis of the expression of trophectoderm RNA data derived from a previous high throughput study. Its main aim is to determine the characteristics and potential functionalities that characterize long non-coding RNAs. As reported previously, a maternal age-related component is potentially implicated in implantation success. Trophectoderm samples representing the full range of maternal reproductive ages were considered in relation to embryonic implantation potential, trophectoderm transcriptome dynamics and reproductive maternal age. The long non-coding RNA (lncRNA) biomarkers identified here are consistent with the activities of embryo-endometrial crosstalk, developmental competency and implantation and share common characteristics with markers of neoplasia/cancer invasion. Corresponding genes for expressed lncRNAs were more active in the blastocysts of younger women are associated with metabolic pathways including cholesterol biosynthesis and steroidogenesis.
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Affiliation(s)
- Panagiotis Ntostis
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
- Department of Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Grace Swanson
- Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Georgia Kokkali
- Genesis Athens Clinic, Reproductive Medicine Unit, Athens, Greece
| | - David Iles
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - John Huntriss
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Agni Pantou
- Genesis Athens Clinic, Reproductive Medicine Unit, Athens, Greece
| | - Maria Tzetis
- Department of Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Helen M Picton
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Stephen A Krawetz
- Department of Obstetrics and Gynecology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - David Miller
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
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22
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Byappanahalli AM, Noren Hooten N, Vannoy M, Mode NA, Ezike N, Zonderman AB, Evans MK. Mitochondrial DNA and inflammatory proteins are higher in extracellular vesicles from frail individuals. Immun Ageing 2023; 20:6. [PMID: 36710345 PMCID: PMC9885591 DOI: 10.1186/s12979-023-00330-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/23/2023] [Indexed: 01/31/2023]
Abstract
BACKGROUND Frailty, a clinical syndrome commencing at midlife, is a risk for morbidity and mortality. Little is known about the factors that contribute to the chronic inflammatory state associated with frailty. Extracellular vesicles (EVs) are small, membrane-bound vesicles that are released into the circulation and are mediators of intercellular communication. We examined whether mitochondrial DNA (mtDNA) and inflammatory proteins in EVs may act as damage-associated molecular pattern (DAMP) molecules in frailty. RESULTS To address whether EVs and their associated mtDNA and inflammatory protein cargo are altered with frailty, EVs were isolated from non-frail (n = 90) and frail (n = 87) middle-aged (45-55 years) participants from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. EV concentration was highest in frail White participants. EV mtDNA levels were significantly higher in frail individuals compared to non-frail individuals. The presence of six inflammatory proteins in EVs (FGF-21, HGF, IL-12B, PD-L1, PRDX3, and STAMBP) were significantly associated with frailty. EV inflammatory proteins were significantly altered by frailty status, race, sex, and poverty status. Notably, frail White participants had higher levels of EV-associated CD5, CD8A, CD244, CXCL1, CXCL6, CXCL11, LAP-TGF-beta-1 and MCP-4 compared to frail and non-frail African American participants. Frail White participants living below poverty had higher levels of EV-associated uPA. EV-associated CCL28 levels were highest in non-frail women and CXCL1 were highest in non-frail men. Men living below poverty had higher levels of CD5, CD8A, CXCL1, LAP-TGF-beta-1, and uPA. CXCL6 levels were significantly higher in individuals living above poverty. There was a significant correlation between EV mtDNA levels and the presence of inflammatory proteins. CONCLUSIONS These data suggest that mtDNA within EVs may act as a DAMP molecule in frailty. Its association with chemokines and other inflammatory EV cargo proteins, may contribute to the frailty phenotype. In addition, the social determinant of health, poverty, influences the inflammatory cargo of EVs in midlife.
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Affiliation(s)
- Anjali M. Byappanahalli
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
| | - Nicole Noren Hooten
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
| | - Mya Vannoy
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA ,grid.25879.310000 0004 1936 8972Present address: Perelman School of Medicine, University of Pennsylvania,3400 Civic Center Boulevard Philadelphia, Philadelphia, PA 19104 USA
| | - Nicolle A. Mode
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
| | - Ngozi Ezike
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
| | - Alan B. Zonderman
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
| | - Michele K. Evans
- grid.419475.a0000 0000 9372 4913Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224 USA
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23
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Zhao J, Zhang B, Meng W, Hu J. Elucidating a fresh perspective on the interplay between exosomes and rheumatoid arthritis. Front Cell Dev Biol 2023; 11:1177303. [PMID: 37187619 PMCID: PMC10175795 DOI: 10.3389/fcell.2023.1177303] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic synovitis and the destruction of bones and joints. Exosomes are nanoscale lipid membrane vesicles originating from multivesicular bodies and are used as a vital means of intercellular communication. Both exosomes and the microbial community are essential in RA pathogenesis. Multiple types of exosomes from different origins have been demonstrated to have effects on various immune cells through distinct mechanisms in RA, which depend on the specific cargo carried by the exosomes. Tens of thousands of microorganisms exist in the human intestinal system. Microorganisms exert various physiological and pathological effects on the host directly or through their metabolites. Gut microbe-derived exosomes are being studied in the field of liver disease; however, information on their role in the context of RA is still limited. Gut microbe-derived exosomes may enhance autoimmunity by altering intestinal permeability and transporting cargo to the extraintestinal system. Therefore, we performed a comprehensive literature review on the latest progress on exosomes in RA and provided an outlook on the potential role of microbe-derived exosomes as emerging players in clinical and translational research on RA. This review aimed to provide a theoretical basis for developing new clinical targets for RA therapy.
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Affiliation(s)
- Jianan Zhao
- Department of Nephropathy, The Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
| | - Binbin Zhang
- Zhejiang University of Traditional Chinese Medicine, Hangzhou, China
- Department of Translational Medicine Platform, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wanting Meng
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Hu
- Department of Nephropathy, The Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Jing Hu,
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24
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Meggiolaro A, Moccia V, Brun P, Pierno M, Mistura G, Zappulli V, Ferraro D. Microfluidic Strategies for Extracellular Vesicle Isolation: Towards Clinical Applications. BIOSENSORS 2022; 13:bios13010050. [PMID: 36671885 PMCID: PMC9855931 DOI: 10.3390/bios13010050] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 05/15/2023]
Abstract
Extracellular vesicles (EVs) are double-layered lipid membrane vesicles released by cells. Currently, EVs are attracting a lot of attention in the biological and medical fields due to their role as natural carriers of proteins, lipids, and nucleic acids. Thus, they can transport useful genomic information from their parental cell through body fluids, promoting cell-to-cell communication even between different organs. Due to their functionality as cargo carriers and their protein expression, they can play an important role as possible diagnostic and prognostic biomarkers in various types of diseases, e.g., cancers, neurodegenerative, and autoimmune diseases. Today, given the invaluable importance of EVs, there are some pivotal challenges to overcome in terms of their isolation. Conventional methods have some limitations: they are influenced by the starting sample, might present low throughput and low purity, and sometimes a lack of reproducibility, being operator dependent. During the past few years, several microfluidic approaches have been proposed to address these issues. In this review, we summarize the most important microfluidic-based devices for EV isolation, highlighting their advantages and disadvantages compared to existing technology, as well as the current state of the art from the perspective of the use of these devices in clinical applications.
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Affiliation(s)
- Alessio Meggiolaro
- Department of Physics and Astronomy, University of Padua, Via Marzolo 8, 35131 Padua, Italy
| | - Valentina Moccia
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, 35020 Legnaro, Italy
| | - Paola Brun
- Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy
| | - Matteo Pierno
- Department of Physics and Astronomy, University of Padua, Via Marzolo 8, 35131 Padua, Italy
| | - Giampaolo Mistura
- Department of Physics and Astronomy, University of Padua, Via Marzolo 8, 35131 Padua, Italy
| | - Valentina Zappulli
- Department of Comparative Biomedicine and Food Science, University of Padua, Viale dell’Università 16, 35020 Legnaro, Italy
| | - Davide Ferraro
- Department of Physics and Astronomy, University of Padua, Via Marzolo 8, 35131 Padua, Italy
- Correspondence:
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25
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Zhang HJ, Ding PP, Zhang XS, Wang XC, Sun DW, Bu QA, Li XQ. MAC mediates mammary duct epithelial cell injury in plasma cell mastitis and granulomatous mastitis. Int Immunopharmacol 2022; 113:109303. [DOI: 10.1016/j.intimp.2022.109303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/01/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
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26
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Kaisey M, Lashgari G, Fert-Bober J, Ontaneda D, Solomon AJ, Sicotte NL. An Update on Diagnostic Laboratory Biomarkers for Multiple Sclerosis. Curr Neurol Neurosci Rep 2022; 22:675-688. [PMID: 36269540 DOI: 10.1007/s11910-022-01227-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE For many patients, the multiple sclerosis (MS) diagnostic process can be lengthy, costly, and fraught with error. Recent research aims to address the unmet need for an accurate and simple diagnostic process through discovery of novel diagnostic biomarkers. This review summarizes recent studies on MS diagnostic fluid biomarkers, with a focus on blood biomarkers, and includes discussion of technical limitations and practical applicability. RECENT FINDINGS This line of research is in its early days. Accurate and easily obtainable biomarkers for MS have not yet been identified and validated, but several approaches to uncover them are underway. Continue efforts to define laboratory diagnostic biomarkers are likely to play an increasingly important role in defining MS at the earliest stages, leading to better long-term clinical outcomes.
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Affiliation(s)
- Marwa Kaisey
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA.
| | - Ghazal Lashgari
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
| | - Justyna Fert-Bober
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
| | - Daniel Ontaneda
- Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave. U10 Mellen Center, Cleveland, OH, 44106, USA
| | - Andrew J Solomon
- Department of Neurological Sciences, Larner College of Medicine at the University of Vermont University Health Center, Arnold 2, 1 South Prospect Street, Burlington, VT, 05401, USA
| | - Nancy L Sicotte
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
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27
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Gao Z, Feng Y, Xu J, Liang J. T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy. Front Immunol 2022; 13:977394. [PMID: 36211414 PMCID: PMC9538155 DOI: 10.3389/fimmu.2022.977394] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Immune-mediated inflammatory diseases(IMIDs) are referred to as highly disabling chronic diseases affecting different organs and systems. Inappropriate or excessive immune responses with chronic inflammation are typical manifestations. Usually in patients with chronic infection and cancer, due to long-term exposure to persistent antigens and inflammation microenvironment, T-cells are continuously stimulated and gradually differentiate into an exhausted state. Exhausted T-cells gradually lose effector function and characteristics of memory T-cells. However, existing studies have found that exhausted T-cells are not only present in the infection and tumor environment, but also in autoimmunity, and are associated with better prognosis of IMIDs. This suggests new prospects for the application of this reversible process of T-cell exhaustion in the treatment of IMID. This review will focus on the research progress of T-cell exhaustion in several IMIDs and its potential application for diagnosis and treatment in IMIDs.
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Affiliation(s)
- Zhanyan Gao
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yang Feng
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinhua Xu
- Shanghai Institute of Dermatology, Shanghai, China
- *Correspondence: Jun Liang, ; Jinhua Xu,
| | - Jun Liang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
- *Correspondence: Jun Liang, ; Jinhua Xu,
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28
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Garavelli S, Prattichizzo F, Ceriello A, Galgani M, de Candia P. Type 1 Diabetes and Associated Cardiovascular Damage: Contribution of Extracellular Vesicles in Tissue Crosstalk. Antioxid Redox Signal 2022; 36:631-651. [PMID: 34407376 DOI: 10.1089/ars.2021.0053] [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] [Indexed: 11/13/2022]
Abstract
Significance: Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin secreting β-cells, with consequent aberrant blood glucose levels. Hyperglycemia is the common denominator for most of the chronic diabetic vascular complications, which represent the main cause of life reduction in T1D patients. For this disease, three interlaced medical needs remain: understanding the underlying mechanisms involved in pancreatic β-cell loss; identifying biomarkers able to predict T1D progression and its related complications; recognizing novel therapeutic targets. Recent Advances: Extracellular vesicles (EVs), released by most cell types, were discovered to contain a plethora of different molecules (including microRNAs) with regulatory properties, which are emerging as mediators of cell-to-cell communication at the paracrine and endocrine level. Recent knowledge suggests that EVs may act as pathogenic factors, and be developed into disease biomarkers and therapeutic targets in the context of several human diseases. Critical Issues: EVs have been recently shown to sustain a dysregulated cellular crosstalk able to exacerbate the autoimmune response in the pancreatic islets of T1D; moreover, EVs were shown to be able to monitor and/or predict the progression of T1D and the insurgence of vasculopathies. Future Directions: More mechanistic studies are needed to investigate whether the dysregulation of EVs in T1D patients is solely reflecting the progression of diabetes and related complications, or EVs also directly participate in the disease process, thus pointing to a potential use of EVs as therapeutic targets/tools in T1D. Antioxid. Redox Signal. 36, 631-651.
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Affiliation(s)
- Silvia Garavelli
- Institute for Endocrinology and Experimental Oncology "G. Salvatore," Consiglio Nazionale delle Ricerche (C.N.R.), Naples, Italy
| | | | | | - Mario Galgani
- Institute for Endocrinology and Experimental Oncology "G. Salvatore," Consiglio Nazionale delle Ricerche (C.N.R.), Naples, Italy.,Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II," Italy
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29
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Makhijani P, McGaha TL. Myeloid Responses to Extracellular Vesicles in Health and Disease. Front Immunol 2022; 13:818538. [PMID: 35320943 PMCID: PMC8934876 DOI: 10.3389/fimmu.2022.818538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/15/2022] [Indexed: 01/04/2023] Open
Abstract
Extracellular vesicles are mediators of cell-cell communication playing a key role in both steady-state and disease conditions. Extracellular vesicles carry diverse donor-derived cargos, including DNA, RNA, proteins, and lipids that induce a complex network of signals in recipient cells. Due to their ability to capture particulate matter and/or capacity to polarize and orchestrate tissue responses, myeloid immune cells (e.g., dendritic cells, macrophages, etc.) rapidly respond to extracellular vesicles, driving local and systemic effects. In cancer, myeloid-extracellular vesicle communication contributes to chronic inflammation, self-tolerance, and therapeutic resistance while in autoimmune disease, extracellular vesicles support inflammation and tissue destruction. Here, we review cellular mechanisms by which extracellular vesicles modulate myeloid immunity in cancer and autoimmune disease, highlighting some contradictory results and outstanding questions. We will also summarize how understanding of extracellular vesicle biology is being utilized for novel therapeutic and diagnostic applications.
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Affiliation(s)
- Priya Makhijani
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Tumor Immunotherapy Program, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
| | - Tracy L. McGaha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Tumor Immunotherapy Program, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada
- *Correspondence: Tracy L. McGaha,
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da Silva Lira Filho A, Fajardo EF, Chang KP, Clément P, Olivier M. Leishmania Exosomes/Extracellular Vesicles Containing GP63 Are Essential for Enhance Cutaneous Leishmaniasis Development Upon Co-Inoculation of Leishmania amazonensis and Its Exosomes. Front Cell Infect Microbiol 2022; 11:709258. [PMID: 35186777 PMCID: PMC8851419 DOI: 10.3389/fcimb.2021.709258] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
Protozoan parasites of the genus Leishmania are transmitted by the bite of infected sand flies leading to a wide range of diseases called leishmaniasis. Recently, we demonstrated that Leishmania spp.-derived exosomes/extracellular vesicles (EVs/LeishEXO) were released in the lumen of the sand fly midgut and to be co-egested with the parasite during the blood meal and that LeishEXO were found to stimulate an inflammatory response conducting to an exacerbated cutaneous leishmaniasis, also it was shown that these vesicles cargo important virulence factors like GP63. Thus, this study aimed to confirm through morphological and proteomic analysis a novel model specificity utilizing another set of GP63-altered Leishmania amazonensis parasite strains. Consequently, we proposed to further study the impact of different GP63 vesicle expression levels on their ability to modulate innate inflammatory cell responses, and finally to determine the importance of GP63 vesicle content on the exacerbation of the cutaneous Leishmania spp. pathology after their host co-inoculation. Our results revealed that the protein composition of extracted extracellular vesicles were similar to each other and that GP63 was the sole virulence factor changed in the exosomes composition confirming the specificity of the chosen novel model. We further demonstrated that vesicles with different GP63 EVs cargo displayed distinctive macrophage immunomodulatory capabilities at both gene and protein expression in vitro. Finally, we showed their diverse impact on the Leishmania spp. cutaneous pathology in an in vivo setting and confirmed GP63 as a primordial component of the ability of these EVs in augmenting the inflammatory cutaneous response in Leishmania spp. infection. Our findings provide new insight on the immune response happening in cutaneous leishmaniasis, shade light on the mechanism behind the host-pathogen interaction occurring in the initial moments of infection, thus creating the opportunity of using them as the target of new pharmacological treatments and vaccinations.
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Affiliation(s)
- Alonso da Silva Lira Filho
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, The Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Emanuella Francisco Fajardo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, The Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Kwang Poo Chang
- Department of Microbiology/Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Pauline Clément
- Infectious Diseases and Immunity in Global Health Program, The Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Martin Olivier
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunity in Global Health Program, The Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Martin Olivier,
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Nik Mohamed Kamal NNS, Shahidan WNS. Salivary Exosomes: From Waste to Promising Periodontitis Treatment. Front Physiol 2022; 12:798682. [PMID: 35069258 PMCID: PMC8766748 DOI: 10.3389/fphys.2021.798682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/30/2021] [Indexed: 12/17/2022] Open
Abstract
Periodontitis is a chronic inflammatory condition that causes tooth loss by destroying the supporting components of the teeth. In most cases, it is difficult to diagnose early and results in severe phases of the disease. Given their endogenous origins, exosomes, which are rich in peptides, lipids, and nucleic acids, have emerged as a cell-free therapeutic approach with low immunogenicity and increased safety. Because the constituents of exosomes can be reprogrammed depending on disease states, exosomes are increasingly being evaluated to act as potential diagnostic biomarkers for dental disease, including periodontitis. Exosomes also have been demonstrated to be involved in inflammatory signal transmission and periodontitis progression in vitro, indicating that they could be used as therapeutic targets for periodontal regeneration. Nevertheless, a review on the involvement of salivary exosomes in periodontitis in impacting the successful diagnosis and treatment of periodontitis is still lacking in the literature. Thus, this review is intended to scrutinize recent advancements of salivary exosomes in periodontitis treatment. We summarize recent research reports on the emerging roles and characteristics of salivary exosomes, emphasizing the different expressions and changed biological roles of exosomes in periodontitis.
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Ma X, Liu Y, Han Q, Han Y, Wang J, Zhang H. Transfusion‑related immunomodulation in patients with cancer: Focus on the impact of extracellular vesicles from stored red blood cells (Review). Int J Oncol 2021; 59:108. [PMID: 34841441 DOI: 10.3892/ijo.2021.5288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/05/2021] [Indexed: 01/28/2023] Open
Abstract
Red blood cell (RBC) transfusions may have a negative impact on the prognosis of patients with cancer, where transfusion‑related immunomodulation (TRIM) may be a significant contributing factor. A number of components have been indicated to be associated with TRIM. Among these, the impact of extracellular vesicles (EVs) has been garnering increasing attention from researchers. EVs are defined as nano‑scale, cell‑derived vesicles that carry a variety of bioactive molecules, including proteins, nucleic acids and lipids, to mediate cell‑to‑cell communication and exert immunoregulatory functions. RBCs in storage constitutively secrete EVs, which serve an important role in TRIM in patients with cancer receiving a blood transfusion. Therefore, the present review aimed to first summarize the available information on the biogenesis and characterization of EVs. Subsequently, the possible mechanisms of TRIM in patients with cancer and the impact of EVs on TRIM were discussed, aiming to provide an outlook for future studies, specifically for formulating recommendations for managing patients with cancer receiving RBC transfusions.
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Affiliation(s)
- Xingyu Ma
- Class 2018 Medical Inspection Technology, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yanxi Liu
- Class 2018 Medical Inspection Technology, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Qianlan Han
- Class 2018 Medical Inspection Technology, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yunwei Han
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Jing Wang
- Department of Blood Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Hongwei Zhang
- Department of Blood Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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Ashcroft J, Leighton P, Elliott TR, Hosgood SA, Nicholson ML, Kosmoliaptsis V. Extracellular vesicles in kidney transplantation: a state-of-the-art review. Kidney Int 2021; 101:485-497. [PMID: 34838864 DOI: 10.1016/j.kint.2021.10.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/11/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022]
Abstract
Kidney transplantation is the optimal treatment for patients with kidney failure; however, early detection and timely treatment of graft injury remain a challenge. Precise and noninvasive techniques of graft assessment and innovative therapeutics are required to improve kidney transplantation outcomes. Extracellular vesicles (EVs) are lipid bilayer-delimited particles with unique biosignatures and immunomodulatory potential, functioning as intermediaries of cell signalling. Promising evidence exists for the potential of EVs to develop precision diagnostics of graft dysfunction, and prognostic biomarkers for clinician decision making. The inherent targeting characteristics of EVs and their low immunogenic and toxicity profiles combined with their potential as vehicles for drug delivery make them ideal targets for development of therapeutics to improve kidney transplant outcomes. In this review, we summarize the current evidence for EVs in kidney transplantation, discuss common methodological principles of EV isolation and characterization, explore upcoming innovative approaches in EV research, and discuss challenges and opportunities to enable translation of research findings into clinical practice.
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Affiliation(s)
- James Ashcroft
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Philippa Leighton
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Tegwen R Elliott
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Sarah A Hosgood
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, UK
| | - Michael L Nicholson
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, UK
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK; NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge, UK.
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Yang N, Zhao Y, Wu X, Zhang N, Song H, Wei W, Liu ML. Recent advances in Extracellular Vesicles and their involvements in vasculitis. Free Radic Biol Med 2021; 171:203-218. [PMID: 33951487 PMCID: PMC9107955 DOI: 10.1016/j.freeradbiomed.2021.04.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 01/08/2023]
Abstract
Systemic vasculitis is a heterogeneous group of multisystem autoimmune disorders characterized by inflammation of blood vessels. Although many progresses in diagnosis and immunotherapies have been achieved over the past decades, there are still many unanswered questions about vasculitis from pathological understanding to more advanced therapies. Extracellular vesicles (EVs) are double-layer phospholipid membrane vesicles harboring various cargoes. EVs can be classified into exosomes, microvesicles (MVs), and apoptotic bodies depending on their size and origin of cellular compartment. EVs can be released by almost all cell types and may be involved in physical and pathological processes including inflammation and autoimmune responses. In systemic vasculitis, EVs may have pathogenic involvement in inflammation, autoimmune responses, thrombosis, endothelium injury, angiogenesis and intimal hyperplasia. EV-associated redox reaction may also be involved in vasculitis pathogenesis by inducing inflammation, endothelial injury and thrombosis. Additionally, EVs may serve as specific biomarkers for diagnosis or monitoring of disease activity and therapeutic efficacy, i.e. AAV-associated renal involvement. In this review, we have discussed the recent advances of EVs, especially their roles in pathogenesis and clinical involvements in vasculitis.
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Affiliation(s)
- Nan Yang
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Yin Zhao
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Xiuhua Wu
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Na Zhang
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Haoming Song
- Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, PR China
| | - Wei Wei
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China.
| | - Ming-Lin Liu
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Corporal Michael J. Crescenz VA Medical Center (Philadelphia), Philadelphia, PA, 19104, USA.
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35
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Grieco GE, Fignani D, Formichi C, Nigi L, Licata G, Maccora C, Brusco N, Sebastiani G, Dotta F. Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools. Front Immunol 2021; 12:682948. [PMID: 34177928 PMCID: PMC8219977 DOI: 10.3389/fimmu.2021.682948] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022] Open
Abstract
Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulin-producing pancreatic β cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic β cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers.
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Affiliation(s)
- Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Carla Maccora
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy.,Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
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Hwang HS, Kim H, Han G, Lee JW, Kim K, Kwon IC, Yang Y, Kim SH. Extracellular Vesicles as Potential Therapeutics for Inflammatory Diseases. Int J Mol Sci 2021; 22:5487. [PMID: 34067503 PMCID: PMC8196952 DOI: 10.3390/ijms22115487] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 05/17/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EV) deliver cargoes such as nucleic acids, proteins, and lipids between cells and serve as an intercellular communicator. As it is revealed that most of the functions associated to EVs are closely related to the immune response, the important role of EVs in inflammatory diseases is emerging. EVs can be functionalized through EV surface engineering and endow targeting moiety that allows for the target specificity for therapeutic applications in inflammatory diseases. Moreover, engineered EVs are considered as promising nanoparticles to develop personalized therapeutic carriers. In this review, we highlight the role of EVs in various inflammatory diseases, the application of EV as anti-inflammatory therapeutics, and the current state of the art in EV engineering techniques.
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Affiliation(s)
- Hee Sook Hwang
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
- Department of Pharmaceutical Engineering, Dankook University, Cheonan 31116, Korea
| | - Hyosuk Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
| | - Geonhee Han
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
| | - Jong Won Lee
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
| | - Kwangmeyung Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
| | - Ick Chan Kwon
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea
- Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Yoosoo Yang
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
| | - Sun Hwa Kim
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; (H.S.H.); (H.K.); (G.H.); (J.W.L.); (K.K.); (I.C.K.)
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Li Y, Bax C, Patel J, Vazquez T, Ravishankar A, Bashir MM, Grinnell M, Diaz D, Werth VP. Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis. Am J Cancer Res 2021; 11:7144-7158. [PMID: 34158841 PMCID: PMC8210592 DOI: 10.7150/thno.59152] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/11/2021] [Indexed: 12/15/2022] Open
Abstract
Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-β, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.
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Zhang Y, Zhang R, Ge L, Wang L. Exosome-derived TXNDC5 is Required for the Inflammatory Progression of Rheumatoid Arthritis Fibroblast-like Synoviocytes. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021; 000:000-000. [DOI: 10.14218/erhm.2021.00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Role of Microenvironment in Non-Hodgkin Lymphoma: Understanding the Composition and Biology. ACTA ACUST UNITED AC 2021; 26:206-216. [PMID: 32496454 DOI: 10.1097/ppo.0000000000000446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Lymphoma microenvironment is a dynamic and well-orchestrated network of various immune and stromal cells that is indispensable for tumor cell survival, growth, migration, immune escape, and drug resistance. Recent progress has enhanced our knowledge of the pivotal role of microenvironment in lymphomagenesis. Understanding the characteristics, functions, and contributions of various components of the tumor niche, along with its bidirectional interactions with tumor cells, is paramount. It offers the potential to identify new therapeutic targets with the ability to restore antitumor immune surveillance and eliminate the protumoral factors contributed by the tumor niche.
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The Mystery of Red Blood Cells Extracellular Vesicles in Sleep Apnea with Metabolic Dysfunction. Int J Mol Sci 2021; 22:ijms22094301. [PMID: 33919065 PMCID: PMC8122484 DOI: 10.3390/ijms22094301] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Sleep is very important for overall health and quality of life, while sleep disorder has been associated with several human diseases, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. Obstructive sleep apnea (OSA) is the most common respiratory sleep-disordered breathing, which is caused by the recurrent collapse of the upper airway during sleep. OSA has emerged as a major public health problem and increasing evidence suggests that untreated OSA can lead to the development of various diseases including neurodegenerative diseases. In addition, OSA may lead to decreased blood oxygenation and fragmentation of the sleep cycle. The formation of free radicals or reactive oxygen species (ROS) can emerge and react with nitric oxide (NO) to produce peroxynitrite, thereby diminishing the bioavailability of NO. Hypoxia, the hallmark of OSA, refers to a decline of tissue oxygen saturation and affects several types of cells, playing cell-to-cell communication a vital role in the outcome of this interplay. Red blood cells (RBCs) are considered transporters of oxygen and nutrients to the tissues, and these RBCs are important interorgan communication systems with additional functions, including participation in the control of systemic NO metabolism, redox regulation, blood rheology, and viscosity. RBCs have been shown to induce endothelial dysfunction and increase cardiac injury. The mechanistic links between changes of RBC functional properties and cardiovascular are largely unknown. Extracellular vesicles (EVs) are secreted by most cell types and released in biological fluids both under physiological and pathological conditions. EVs are involved in intercellular communication by transferring complex cargoes including proteins, lipids, and nucleic acids from donor cells to recipient cells. Advancing our knowledge about mechanisms of RBC-EVs formation and their pathophysiological relevance may help to shed light on circulating EVs and to translate their application to clinical practice. We will focus on the potential use of RBC-EVs as valuable diagnostic and prognostic biomarkers and state-specific cargoes, and possibilities as therapeutic vehicles for drug and gene delivery. The use of RBC-EVs as a precision medicine for the diagnosis and treatment of the patient with sleep disorder will improve the prognosis and the quality of life in patients with cardiovascular disease (CVD).
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Mazzariol M, Camussi G, Brizzi MF. Extracellular Vesicles Tune the Immune System in Renal Disease: A Focus on Systemic Lupus Erythematosus, Antiphospholipid Syndrome, Thrombotic Microangiopathy and ANCA-Vasculitis. Int J Mol Sci 2021; 22:ijms22084194. [PMID: 33919576 PMCID: PMC8073859 DOI: 10.3390/ijms22084194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 01/02/2023] Open
Abstract
Extracellular vesicles (EV) are microparticles released in biological fluids by different cell types, both in physiological and pathological conditions. Owing to their ability to carry and transfer biomolecules, EV are mediators of cell-to-cell communication and are involved in the pathogenesis of several diseases. The ability of EV to modulate the immune system, the coagulation cascade, the angiogenetic process, and to drive endothelial dysfunction plays a crucial role in the pathophysiology of both autoimmune and renal diseases. Recent studies have demonstrated the involvement of EV in the control of renal homeostasis by acting as intercellular signaling molecules, mediators of inflammation and tissue regeneration. Moreover, circulating EV and urinary EV secreted by renal cells have been investigated as potential early biomarkers of renal injury. In the present review, we discuss the recent findings on the involvement of EV in autoimmunity and in renal intercellular communication. We focused on EV-mediated interaction between the immune system and the kidney in autoimmune diseases displaying common renal damage, such as antiphospholipid syndrome, systemic lupus erythematosus, thrombotic microangiopathy, and vasculitis. Although further studies are needed to extend our knowledge on EV in renal pathology, a deeper investigation of the impact of EV in kidney autoimmune diseases may also provide insight into renal biological processes. Furthermore, EV may represent promising biomarkers of renal diseases with potential future applications as diagnostic and therapeutic tools.
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42
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Han Y, Jones TW, Dutta S, Zhu Y, Wang X, Narayanan SP, Fagan SC, Zhang D. Overview and Update on Methods for Cargo Loading into Extracellular Vesicles. Processes (Basel) 2021; 9. [PMID: 33954091 PMCID: PMC8096148 DOI: 10.3390/pr9020356] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells. Growing evidence shows that EVs have great potential to serve as effective drug carriers. Since EVs can not only transfer biological information, but also effectively deliver hydrophobic drugs into cells, the application of EVs as a novel drug delivery system has attracted considerable scientific interest. Recently, EVs loaded with siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, or therapeutic drugs show improved delivery efficiency and drug effect. In this review, we summarize the methods used for the cargo loading into EVs, including siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, and therapeutic drugs. Furthermore, we also include the recent advance in engineered EVs for drug delivery. Finally, both advantages and challenges of EVs as a new drug delivery system are discussed. Here, we encourage researchers to further develop convenient and reliable loading methods for the potential clinical applications of EVs as drug carriers in the future.
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Affiliation(s)
- Yohan Han
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Timothy W. Jones
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Saugata Dutta
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Yin Zhu
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Xiaoyun Wang
- Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA
| | - S. Priya Narayanan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA
- James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA
| | - Susan C. Fagan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Duo Zhang
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA
- Correspondence: ; Tel.: +1-706-721-6491; Fax: +1-706-721-3994
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Rasmussen NS, Nielsen CT, Nielsen CH, Jacobsen S. Microvesicles in active lupus nephritis show Toll-like receptor 9-dependent co-expression of galectin-3 binding protein and double-stranded DNA. Clin Exp Immunol 2021; 204:64-77. [PMID: 33354779 DOI: 10.1111/cei.13569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 12/16/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Circulating microvesicles (MVs) from patients with systemic lupus erythematosus (SLE) express the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP), which may enhance their deposition in the glomerular basement membrane. The release of G3BP-expressing MVs from normal peripheral blood mononuclear cells (PBMCs) is induced by Toll-like receptor 9 (TLR-9) ligands, and these vesicles contain autoantibody-accessible double-stranded DNA (dsDNA). This study compares the release of MVs expressing G3BP and dsDNA from PBMCs derived from SLE patients with or without active lupus nephritis (LN) and from healthy donors, and taps further into the potential dependency on IFN-α for their generation and impacts of TLR-7/TLR-9 co-stimulation. PBMCs from 10 healthy donors and 12 SLE patients, six of whom had active LN at study inclusion, were stimulated in-vitro with recombinant human IFN-α and the TLR-9 agonists oligodeoxynucleotide (ODN)2216 or ODN2395 alone or in combination with the TLR-7 agonist gardiquimod. MVs in the supernatants were subsequently isolated by differential centrifugation and their expression of G3BP and dsDNA was quantified by flow cytometry. Stimulation with ODN2395 significantly increased the release of MVs co-expressing G3BP and dsDNA from PBMCs isolated from healthy donors and SLE patients. The expression of G3BP on individual MVs and the proportion of G3BP and dsDNA double-positive MVs released were increased in active LN patients. Neither co-stimulation with gardiquimod nor with the IFN-α inhibitor IN-1 had any effect on the MV release induced by ODN2395. In conclusion, the TLR-9-mediated inducibility of MVs co-expressing G3BP and dsDNA is increased in SLE patients with active LN.
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Affiliation(s)
- N S Rasmussen
- Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - C T Nielsen
- Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - C H Nielsen
- Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - S Jacobsen
- Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Therapeutic Application of Exosomes in Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22031144. [PMID: 33498928 PMCID: PMC7865921 DOI: 10.3390/ijms22031144] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses such as inflammation and autoimmune disease. Exosomes are emerging as a state-of-the-art therapeutic strategy for treating an overactive immune system. Thus, in this review, we will thoroughly review therapeutic applications of exosomes in various inflammatory and autoimmune diseases. Finally, issues for an outlook to the future of exosomal therapy will be introduced.
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Tsai CY, Shen CY, Liu CW, Hsieh SC, Liao HT, Li KJ, Lu CS, Lee HT, Lin CS, Wu CH, Kuo YM, Yu CL. Aberrant Non-Coding RNA Expression in Patients with Systemic Lupus Erythematosus: Consequences for Immune Dysfunctions and Tissue Damage. Biomolecules 2020; 10:biom10121641. [PMID: 33291347 PMCID: PMC7762297 DOI: 10.3390/biom10121641] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future.
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MESH Headings
- Adaptive Immunity/genetics
- Autoimmunity/genetics
- Chemokines/genetics
- Chemokines/immunology
- Dendritic Cells/immunology
- Dendritic Cells/pathology
- Gene Expression Regulation
- Humans
- Immunity, Innate/genetics
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/immunology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/pathology
- Lupus Erythematosus, Systemic/blood
- Lupus Erythematosus, Systemic/genetics
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/pathology
- MicroRNAs/genetics
- MicroRNAs/immunology
- Neutrophils/immunology
- Neutrophils/pathology
- RNA, Circular/genetics
- RNA, Circular/immunology
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/immunology
- RNA, Messenger/genetics
- RNA, Messenger/immunology
- T-Lymphocytes/immunology
- T-Lymphocytes/pathology
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Affiliation(s)
- Chang-Youh Tsai
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 11217, Taiwan; (C.-W.L.); (H.-T.L.)
- Correspondence: (C.-Y.T.); (C.-L.Y.)
| | - Chieh-Yu Shen
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
- Institute of Clinical Medicine, National Taiwan University School of Medicine, Taipei 10002, Taiwan
| | - Chih-Wei Liu
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 11217, Taiwan; (C.-W.L.); (H.-T.L.)
| | - Song-Chou Hsieh
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
| | - Hsien-Tzung Liao
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 11217, Taiwan; (C.-W.L.); (H.-T.L.)
| | - Ko-Jen Li
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
| | - Cheng-Shiun Lu
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
| | - Hui-Ting Lee
- Mackay Memorial Hospital and Mackay College of Medicine, Taipei 10449, Taiwan;
| | - Cheng-Sung Lin
- Department of Thoracic Surgery, Ministry of Health and Welfare Taipei Hospital, New Taipei City 24213, Taiwan;
| | - Cheng-Han Wu
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
| | - Yu-Min Kuo
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
| | - Chia-Li Yu
- Division of Rheumatology, Immunology, & Allergy, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-Y.S.); (S.-C.H.); (K.-J.L.); (C.-S.L.); (C.-H.W.); (Y.-M.K.)
- Correspondence: (C.-Y.T.); (C.-L.Y.)
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Xu K, Liu Q, Wu K, Liu L, Zhao M, Yang H, Wang X, Wang W. Extracellular vesicles as potential biomarkers and therapeutic approaches in autoimmune diseases. J Transl Med 2020; 18:432. [PMID: 33183315 PMCID: PMC7664085 DOI: 10.1186/s12967-020-02609-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles are heterogeneous populations of naturally occurring secreted small vesicles. EVs function as signaling platforms to facilitate intracellular communication, which indicates the physiological or pathophysiological conditions of cells or tissues. Considering that EVs can be isolated from most body fluids and that molecular constituents could be reprogrammed according to the physiological status of the secreting cells, EVs are regarded as novel diagnostic and prognostic biomarkers for many diseases. The ability to protect encapsulated molecules from degradation in body fluids suggests the potential of EVs as biological medicines or drug delivery systems. This article focuses on the EV-associated biomarkers and therapeutic approaches in autoimmune diseases.
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Affiliation(s)
- Kaiyuan Xu
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Qin Liu
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Kaihui Wu
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Liu Liu
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Maomao Zhao
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Hui Yang
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Xiang Wang
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China.
| | - Wenmei Wang
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China.
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Leleu D, Levionnois E, Laurent P, Lazaro E, Richez C, Duffau P, Blanco P, Sisirak V, Contin-Bordes C, Truchetet ME. Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis. Front Immunol 2020; 11:532177. [PMID: 33193304 PMCID: PMC7645042 DOI: 10.3389/fimmu.2020.532177] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 10/01/2020] [Indexed: 12/25/2022] Open
Abstract
Background Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis. Methods Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction. Results SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential. Conclusions In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients.
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Affiliation(s)
- Damien Leleu
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Immunology and Immunogenetic Department, Bordeaux University Hospital, Bordeaux, France
| | | | - Paoline Laurent
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
| | - Estibaliz Lazaro
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Internal Medicine Department, Bordeaux University Hospital, Bordeaux, France
- Centre national de reference des maladies auto-immunes systémiques rares de l’Est et du Sud-Ouest (RESO), Bordeaux, France
| | - Christophe Richez
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Centre national de reference des maladies auto-immunes systémiques rares de l’Est et du Sud-Ouest (RESO), Bordeaux, France
- Rheumatology Department, Bordeaux University Hospital, Bordeaux, France
| | - Pierre Duffau
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Internal Medicine Department, Bordeaux University Hospital, Bordeaux, France
| | - Patrick Blanco
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Immunology and Immunogenetic Department, Bordeaux University Hospital, Bordeaux, France
| | - Vanja Sisirak
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
| | - Cecile Contin-Bordes
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Immunology and Immunogenetic Department, Bordeaux University Hospital, Bordeaux, France
| | - Marie-Elise Truchetet
- University of Bordeaux, CNRS, ImmunoConcEpT, UMR 5164, Bordeaux, France
- Centre national de reference des maladies auto-immunes systémiques rares de l’Est et du Sud-Ouest (RESO), Bordeaux, France
- Rheumatology Department, Bordeaux University Hospital, Bordeaux, France
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48
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Baxter AA. Stoking the Fire: How Dying Cells Propagate Inflammatory Signalling through Extracellular Vesicle Trafficking. Int J Mol Sci 2020; 21:ijms21197256. [PMID: 33019535 PMCID: PMC7583891 DOI: 10.3390/ijms21197256] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/28/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
Communication between dying cells and their environment is a critical process that promotes tissue homeostasis during normal cellular turnover, whilst during disease settings, it can contribute to inflammation through the release of intracellular factors. Extracellular vesicles (EVs) are a heterogeneous class of membrane-bound cell-derived structures that can engage in intercellular communication via the trafficking of bioactive molecules between cells and tissues. In addition to the well-described functions of EVs derived from living cells, the ability of dying cells to release EVs capable of mediating functions on target cells or tissues is also of significant interest. In particular, during inflammatory settings such as acute tissue injury, infection and autoimmunity, the EV-mediated transfer of proinflammatory cargo from dying cells is an important process that can elicit profound proinflammatory effects in recipient cells and tissues. Furthermore, the biogenesis of EVs via unique cell-death-associated pathways has also been recently described, highlighting an emerging niche in EV biology. This review outlines the mechanisms and functions of dying-cell-derived EVs and their ability to drive inflammation during various modes of cell death, whilst reflecting on the challenges and knowledge gaps in investigating this subgenre of extracellular vesicles research.
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Affiliation(s)
- Amy A Baxter
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
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Giri KR, de Beaurepaire L, Jegou D, Lavy M, Mosser M, Dupont A, Fleurisson R, Dubreil L, Collot M, Van Endert P, Bach JM, Mignot G, Bosch S. Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome. Front Immunol 2020; 11:1814. [PMID: 33101266 PMCID: PMC7556286 DOI: 10.3389/fimmu.2020.01814] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
Beta cell failure and apoptosis following islet inflammation have been associated with autoimmune type 1 diabetes pathogenesis. As conveyors of biological active material, extracellular vesicles (EV) act as mediators in communication with immune effectors fostering the idea that EV from inflamed beta cells may contribute to autoimmunity. Evidence accumulates that beta exosomes promote diabetogenic responses, but relative contributions of larger vesicles as well as variations in the composition of the beta cell's vesiculome due to environmental changes have not been explored yet. Here, we made side-by-side comparisons of the phenotype and function of apoptotic bodies (AB), microvesicles (MV) and small EV (sEV) isolated from an equal amount of MIN6 beta cells exposed to inflammatory, hypoxic or genotoxic stressors. Under normal conditions, large vesicles represent 93% of the volume, but only 2% of the number of the vesicles. Our data reveal a consistently higher release of AB and sEV and to a lesser extent of MV, exclusively under inflammatory conditions commensurate with a 4-fold increase in the total volume of the vesiculome and enhanced export of immune-stimulatory material including the autoantigen insulin, microRNA, and cytokines. Whilst inflammation does not change the concentration of insulin inside the EV, specific Toll-like receptor-binding microRNA sequences preferentially partition into sEV. Exposure to inflammatory stress engenders drastic increases in the expression of monocyte chemoattractant protein 1 in all EV and of interleukin-27 solely in AB suggesting selective sorting toward EV subspecies. Functional in vitro assays in mouse dendritic cells and macrophages reveal further differences in the aptitude of EV to modulate expression of cytokines and maturation markers. These findings highlight the different quantitative and qualitative imprints of environmental changes in subpopulations of beta EV that may contribute to the spread of inflammation and sustained immune cell recruitment at the inception of the (auto-) immune response.
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Affiliation(s)
| | | | | | - Margot Lavy
- IECM, ONIRIS, INRAE, USC1383, Nantes, France
| | | | - Aurelien Dupont
- MRic, Biosit, UMS3480 CNRS, University of Rennes 1, Rennes, France
| | | | - Laurence Dubreil
- PAnTher, INRAE, Oniris, Université Bretagne Loire, Nantes, France
| | - Mayeul Collot
- Laboratoire de Biophotonique et Pharmacologie, UMR CNRS 7213, Université de Strasbourg, Illkirch, France
| | - Peter Van Endert
- Université Paris Descartes, Paris, France.,INSERM, U1151, Institut Necker-Enfants Malades, Paris, France
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50
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Wang JH, Liu XL, Sun JM, Yang JH, Xu DH, Yan SS. Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review. World J Stem Cells 2020; 12:879-896. [PMID: 32952864 PMCID: PMC7477661 DOI: 10.4252/wjsc.v12.i8.879] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/02/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been reported to possess immune regulatory effects in innate and adaptive immune reactions. MSCs can mediate intercellular communications by releasing extracellular vesicles (EVs), which deliver functional molecules to targeted cells. MSC derived EVs (MSC-EVs) confer altering effects on many immune cells, including T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages. A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases. This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases.
AIM To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases.
METHODS Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language. The keywords, such as “MSCs,” “EVs,” “exosome,” “autoimmunity,” “tumor immunity,” and “transplantation immunity,” and Boolean operator “AND” and “NOT” coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases. Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded.
RESULTS A total of 96 articles were chosen for final reference lists. After analyzing those publications, we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells, like T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages, to regulate immune responses in innate immunity and adaptive immunity. Many validated EVs-delivered molecules have been identified as key biomarkers, such as proteins, lipids, and nucleotides. Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease.
CONCLUSION MSC-EVs play an equally important part in the differentiation, activation, and proliferation of immune cells, and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.
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Affiliation(s)
- Jing-Hua Wang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Xiao-Ling Liu
- Department of Emergency Medicine, Yantai Shan Hospital, Yantai 264001, Shandong Province, China
| | - Jian-Mei Sun
- Department of Chemistry, School of Applied Chemistry, Food and Drug, Weifang Engineering Vocational College, Qingzhou 262500, Shandong Province, China
| | - Jing-Han Yang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Dong-Hua Xu
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Central Laboratory of the First Affiliated Hospital, Weifang 261000, Shandong Province, China
| | - Shu-Shan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
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