|
1
|
Lv X, Liu W, Zhou X, Yang Y, Zhao W, Meng L, Mu F, Zhang Z, Zhu S, Zhang S, Wang Y. Exosomes in Systemic Autoimmune Diseases: Recent Advances in Diagnostic Biomarkers and Therapeutic Applications. Int J Nanomedicine 2025; 20:5137-5160. [PMID: 40292402 PMCID: PMC12024484 DOI: 10.2147/ijn.s506221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/02/2025] [Indexed: 04/30/2025] Open
Abstract
Systemic autoimmune diseases (SADs) encompass a spectrum of organ involvement, clinical heterogeneity, and therapeutic challenges meriting significant research. These conditions involve the immune system mistakenly attacking and damaging multiple body tissues and organs, leading to chronic inflammation and damage. Exosomes are nanoscale extracellular vesicles secreted by cells that modulate intercellular communication and immunity. Accumulating evidence indicates that exosomes have multifaceted roles in the pathogenesis of SADs through processes like cellular signaling, immune modulation, antigen presentation, and inflammatory response. The cargo of exosomes, such as proteins, miRNAs, and lipids, are vital determinants of cellular and humoral immunity. This review examines key signaling pathways in four common SADs, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome, and explores exosome as non-invasive biomarkers for diagnosis, disease monitoring, and therapeutic response prediction. Additionally, the therapeutic potential of mesenchymal stromal cells (MSCs) or various type of mesenchymal stem cells derived exosomes as cell-free immunotherapies for SADs is highlighted. Engineered exosomes, with enhanced targeting, bioavailability, low toxicity, are emerging as promising drug delivery vehicles. However, challenges such as high production costs, technical complexity, and inefficiency, along with the lack of standardized protocols, limit clinical implementation in SADs. A deeper understanding of exosome roles in SADs pathogenesis and innovative immunotherapies may provide valuable theoretical support for the diagnosis and treatment of these challenging conditions.
Collapse
Affiliation(s)
- Xinchen Lv
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Wendong Liu
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Xue Zhou
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Yu Yang
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Wangqian Zhao
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Linfeng Meng
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Fenghuoyi Mu
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Zhixiang Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Shaohua Zhu
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Shuai Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| | - Ying Wang
- Department of Forensic Medicine, School of Basic Medical Sciences, Soochow University, Suzhou, 215123, People’s Republic of China
| |
Collapse
|
|
2
|
Grossini E, Bellan M, Venkatesan S, Ola Pour MM, Mennuni M, D’Amario D, Bruno S, Ferrante D, Capello D, Sainaghi PP, Pirisi M, Patti G. Characterization of Circulating Vesicles of Complicated and Uncomplicated Systemic Sclerosis Patients and Their Role in Vascular Dysfunction. Int J Mol Sci 2025; 26:2380. [PMID: 40141024 PMCID: PMC11942416 DOI: 10.3390/ijms26062380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
Extracellular vesicles (EVs) could be involved in the onset of systemic sclerosis (SSc) through the modulation of vascular function. Anyway, available data are contradictory, and further investigation would be necessary to clarify this aspect. Here, we characterized circulating EVs isolated from SSc patients and evaluated their effects on human vascular endothelial cells (HUVECs) and smooth muscle cells. In EVs from 13 complicated and 27 uncomplicated SSc patients and five healthy controls (HCs), we analyzed the size, concentration, and surface marker expression. In addition, EVs were used to stimulate HUVECs, and we evaluated cell viability, mitochondrial membrane potential, and nitric oxide (NO) and mitochondrial reactive oxygen species (MitoROS) release. In smooth muscle cells, the effects of EVs on calcium movement were examined. The results showed that the EVs of SSc patients expressed markers of T-lymphocyte/platelet/endothelial cell origin and were larger and more concentrated than those from HCs. In addition, the EVs of SSc patients reduced cell viability and mitochondrial membrane potential and increased NO and MitoROS release in HUVECs and intracellular calcium in smooth muscle cells. In conclusion, we found a specific pattern for EVs isolated from SSc patients, which could have a pathogenic role through direct actions on endothelial and smooth muscle cells.
Collapse
Affiliation(s)
- Elena Grossini
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Mattia Bellan
- Internal Medicine Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.B.); (P.P.S.); (M.P.)
- CAAD, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy
| | - Sakthipriyan Venkatesan
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Mohammad Mostafa Ola Pour
- Laboratory of Physiology, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (S.V.); (M.M.O.P.)
| | - Marco Mennuni
- Cardiology Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.M.); (D.D.); (G.P.)
| | - Domenico D’Amario
- Cardiology Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.M.); (D.D.); (G.P.)
| | - Stefania Bruno
- Laboratory of Translational Research, Department of Medical Sciences, University of Torino, 10126 Torino, Italy;
| | - Daniela Ferrante
- Statistic Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Daniela Capello
- Laboratory of Clinical Biochemistry, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
- UPO Biobank, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Internal Medicine Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.B.); (P.P.S.); (M.P.)
- CAAD, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy
| | - Mario Pirisi
- Internal Medicine Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.B.); (P.P.S.); (M.P.)
- CAAD, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy
| | - Giuseppe Patti
- Cardiology Unit, Department of Translational Medicine, Università del Piemonte Orientale, Azienda Ospedaliera Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.M.); (D.D.); (G.P.)
| |
Collapse
|
|
3
|
Mohseni Meybodi MA, Nilforoushzadeh MA, KhandanDezfully N, Mansouri P. The safety and efficacy of adipose tissue-derived exosomes in treating mild to moderate plaque psoriasis: A clinical study. Life Sci 2024; 353:122915. [PMID: 39013528 DOI: 10.1016/j.lfs.2024.122915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/18/2024]
Abstract
AIM This study evaluates the safety and efficacy of autologous adipose-derived mesenchymal stem cell-derived exosomes as a treatment for Psoriasis, a chronic immune-related skin and joint disorder, compared to current treatments like topicals, phototherapy, and systemic. MATERIALS AND METHODS The study isolated exosomes from Mesenchymal Stem Cells(MSCs) of healthy adipose tissue using ultracentrifugation. 12 patients with plaque psoriasis were divided into three groups and given single doses of exosomes. Tissue samples were collected pre- and post-treatment and examined for inflammatory(TNFα, IL23, IL17, IFNγ, CD3) and anti-inflammatory (FOXP3, IL10) markers. The severity of the lesion was also evaluated. KEY FINDINGS In this study, it was found that erythema and induration (P < 0.05) decreased significantly in patients receiving 200 μg. Still, this reduction in scaling was not significant, the thickness was significantly reduced in patients receiving 100 and 200 μg doses (P < 0.05). H&E evaluation showed that the decreasing trend in these patients was not significant (P > 0.05). IHC evaluation in patients receiving doses of 100 and 200 μg showed a decrease in the presence of IL17 (P < 0.05, <0.001) & CD3(P < 0.001, <0.05) and a considerable increase in FOXP3(P ≤ 0.001), in the tissue samples of the patients. Examining the expression of inflammatory factors also shows that dose 200 μg decreased the expression of IL17(P > 0.05), IFNγ(P > 0.05), IL23(P < 0.05), & TNFα(P ≤ 0.05) and increased the expression of the anti-inflammatory factor IL10(P < 0.05). SIGNIFICANCE The study indicates that a 200 μg dose is optimal for patients, but a larger patient population is needed for more reliable results. Additionally, higher doses or multiple injections with specific intervals can increase confidence.
Collapse
Affiliation(s)
| | | | | | - Parvin Mansouri
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran; Medical Laser Research Centers, Academic Center of Education - Culture and Research, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
4
|
Opriș-Belinski D, Cobilinschi CO, Caraiola S, Ungureanu R, Cotae AM, Grințescu IM, Cobilinschi C, Andrei AC, Țincu R, Ene R, Mirea L. Trace Element Deficiency in Systemic Sclerosis-Too Much Effort for Some Traces? Nutrients 2024; 16:2053. [PMID: 38999801 PMCID: PMC11242991 DOI: 10.3390/nu16132053] [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: 04/21/2024] [Revised: 06/06/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
Trace elements are essential for several physiological processes. To date, various data have suggested that inadequate levels of trace elements may be involved in the pathogenesis of different chronic diseases, including immune-mediated ones, or may develop during their course. Systemic sclerosis (SSc) is a complex autoimmune multisystemic disease, primarily characterized by microvascular dysregulation, the widespread activation of the immune system and tissue fibrosis. According to the latest reports regarding the pathogenesis of SSc, the main pathophysiological processes-inflammation, vasculopathy and fibrosis-may include various trace element derangements. The present literature review aims to update the available data regarding iron, zinc, copper and selenium status in SSc as well as to underline the possible implications of these trace elements in the complexity of the pathogenic process of the disease. We observe that the status of trace elements in SSc plays a crucial role in numerous pathogenic processes, emphasizing the necessity for proper monitoring and supplementation. The reported data are heterogenous and scarce, and future studies are needed in order to draw clearer conclusions about their complete spectrum.
Collapse
Affiliation(s)
- Daniela Opriș-Belinski
- Department of Internal Medicine Rheumatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Rheumatology and Internal Medicine, Sfânta Maria Clinical Hospital, 011172 Bucharest, Romania
| | - Claudia Oana Cobilinschi
- Department of Internal Medicine Rheumatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Rheumatology and Internal Medicine, Sfânta Maria Clinical Hospital, 011172 Bucharest, Romania
| | - Simona Caraiola
- Department of Internal Medicine Rheumatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Rheumatology and Internal Medicine, Colentina Clinical Hospital, 020125 Bucharest, Romania
| | - Raluca Ungureanu
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| | - Ana-Maria Cotae
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| | - Ioana Marina Grințescu
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| | - Cristian Cobilinschi
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| | - Andrei Cosmin Andrei
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| | - Radu Țincu
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
- Department of Clinical Toxicology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Răzvan Ene
- Department of Orthopedics, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Liliana Mirea
- Department of Anesthesiology and Intensive Care II, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Anesthesiology and Intensive Care, Clinical Emergency Hospital Bucharest, 014461 Bucharest, Romania
| |
Collapse
|
|
5
|
Ji Y, Mi L, Zhao M, He X, Hu Y, Gao Y, Yin C, Xu K. Innovative Diagnosis and Therapeutic Modalities: Engineered Exosomes in Autoimmune Disease. Int J Nanomedicine 2024; 19:3943-3956. [PMID: 38708179 PMCID: PMC11070165 DOI: 10.2147/ijn.s452184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/19/2024] [Indexed: 05/07/2024] Open
Abstract
Autoimmune diseases refer to a group of conditions where the immune system produces an immune response against self-antigens, resulting in tissue damage. These diseases have profound impacts on the health of patients. In recent years, with the rapid development in the field of biomedicine, engineered exosomes have emerged as a noteworthy class of biogenic nanoparticles. By precisely manipulating the cargo and surface markers of exosomes, engineered exosomes have gained enhanced anti-inflammatory, immunomodulatory, and tissue reparative abilities, providing new prospects for the treatment of autoimmune diseases. Engineered exosomes not only facilitate the efficient delivery of bioactive molecules including nucleic acids, proteins, and cytokines, but also possess the capability to modulate immune cell functions, suppress inflammation, and restore immune homeostasis. This review mainly focuses on the applications of engineered exosomes in several typical autoimmune diseases. Additionally, this article comprehensively summarizes the current approaches for modification and engineering of exosomes and outlines their prospects in clinical applications. In conclusion, engineered exosomes, as an innovative therapeutic approach, hold promise for the management of autoimmune diseases. However, while significant progress has been made, further rigorous research is still needed to address the challenges that engineered exosomes may encounter in the therapeutic intervention process, in order to facilitate their successful translation into clinical practice and ultimately benefit a broader population of patients.
Collapse
Affiliation(s)
- Yuli Ji
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Liangyu Mi
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Miaomiao Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Xiaoyao He
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Yuting Hu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Yanan Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Chengliang Yin
- Faculty of Medicine, Macau University of Science and Technology, Macau, People’s Republic of China
| | - Ke Xu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| |
Collapse
|
|
6
|
He Q, Xu C, Guo J, Chen Y, Huang N, Chen J. Bisphenol A exposure stimulates prostatic fibrosis via exosome-triggered epithelium changes. Food Chem Toxicol 2024; 185:114450. [PMID: 38215961 DOI: 10.1016/j.fct.2024.114450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/14/2024]
Abstract
Fibrosis is the pathological basis for the clinical progression of benign prostatic hyperplasia (BPH). Prostatic fibrosis is an important risk factor in patients with BPH who experience lower urinary tract symptoms. Bisphenol A (BPA) is an environmental endocrine disruptor (EED) that causes prostate defects. The effects of BPA on the prostate were investigated in this study using mouse and human prostate cell models. BPA-induced mouse prostatic fibrosis is characterized by collagen deposition and an increase in hydroxyproline concentration. Furthermore, BPA-exposed prostatic stromal fibroblasts exosomes promote the epithelial-mesenchymal transition of epithelial cells. High-throughput RNA sequencing and functional enrichment analyses show that substantially altered mRNAs, lncRNAs and circRNAs play roles in cellular interactions and the hypoxia-inducible factor-1 signaling pathway. The results showed that exosomes participated in the pro-fibrogenic effects of BPA on the prostate by mediating communication between stromal and epithelial cells and triggering epithelial changes.
Collapse
Affiliation(s)
- Qingqin He
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, Hubei Province, China
| | - Congyue Xu
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, Hubei Province, China
| | - Jing Guo
- Department of Basic Medicine, School of Medicine, Jianghan University, Wuhan, Hubei Province, China
| | - Yao Chen
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, Hubei Province, China
| | - Nianfang Huang
- Experimental Center, School of Medicine, Jianghan University, Wuhan, Hubei Province, China
| | - Jinglou Chen
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, Hubei Province, China.
| |
Collapse
|
|
7
|
Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
Collapse
Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| |
Collapse
|
|
8
|
de Almeida AR, Dantas AT, de Oliveira Gonçalves ME, Chêne C, Jeljeli M, Chouzenoux S, Thomas M, Cunha EGC, de Azevedo Valadares LD, de Melo Gomes JV, de Paula SKS, da Rocha Pitta MG, da Rocha Pitta I, de Melo Rêgo MJB, Pereira MC, Duarte ALBP, Abdalla DSP, Nicco C, Batteux F, da Rocha Pitta MG. PPARγ partial agonist LPSF/GQ-16 prevents dermal and pulmonary fibrosis in HOCl-induced systemic sclerosis (SSc) and modulates cytokine production in PBMC of SSc patients. Inflammopharmacology 2024; 32:433-446. [PMID: 37477795 DOI: 10.1007/s10787-023-01296-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/08/2023] [Indexed: 07/22/2023]
Abstract
Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfβ1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc.
Collapse
Affiliation(s)
- Anderson Rodrigues de Almeida
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Andréa Tavares Dantas
- Serviço de Reumatologia, Hospital das Clínicas, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Maria Eduarda de Oliveira Gonçalves
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| | - Charlotte Chêne
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Mohamed Jeljeli
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Sandrine Chouzenoux
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Marine Thomas
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Eudes Gustavo Constantino Cunha
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| | | | - João Victor de Melo Gomes
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| | - Simão Kalebe Silva de Paula
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| | - Marina Galdino da Rocha Pitta
- Laboratório de Planejamento e Síntese de Fármacos, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Ivan da Rocha Pitta
- Laboratório de Planejamento e Síntese de Fármacos, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Moacyr Jesus Barreto de Melo Rêgo
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| | - Michelly Cristiny Pereira
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil.
| | | | - Dulcineia Saes Parra Abdalla
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Carole Nicco
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Frédéric Batteux
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Maira Galdino da Rocha Pitta
- Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Departamento de Fisiologia e Farmacologia, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT SG), Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil
| |
Collapse
|
|
9
|
Wang Y, Jiao L, Qiang C, Chen C, Shen Z, Ding F, Lv L, Zhu T, Lu Y, Cui X. The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms. Biomed Pharmacother 2024; 171:116116. [PMID: 38181715 DOI: 10.1016/j.biopha.2023.116116] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature is the massive deposition of extracellular matrix (mainly collagen), eventually leading to tissue dysfunction and organ failure. The progression of fibrotic diseases has put a significant strain on global health and the economy, and as a result, there is an urgent need to find some new therapies. Previous studies have identified that inflammation, oxidative stress, some cytokines, and remodeling play a crucial role in fibrotic diseases and are essential avenues for treating fibrotic diseases. Among them, matrix metalloproteinases (MMPs) are considered the main targets for the treatment of fibrotic diseases since they are the primary driver involved in ECM degradation, and tissue inhibitors of metalloproteinases (TIMPs) are natural endogenous inhibitors of MMPs. Through previous studies, we found that MMP-9 is an essential target for treating fibrotic diseases. However, it is worth noting that MMP-9 plays a bidirectional regulatory role in different fibrotic diseases or different stages of the same fibrotic disease. Previously identified MMP-9 inhibitors, such as pirfenidone and nintedanib, suffer from some rather pronounced side effects, and therefore, there is an urgent need to investigate new drugs. In this review, we explore the mechanism of action and signaling pathways of MMP-9 in different tissues and organs, hoping to provide some ideas for developing safer and more effective biologics.
Collapse
Affiliation(s)
- Yuling Wang
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Linke Jiao
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Caoxia Qiang
- Department of Traditional Chinese Medicine, Tumor Hospital Affiliated to Nantong University, Jiangsu, China
| | - Chen Chen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zihuan Shen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Fan Ding
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lifei Lv
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tingting Zhu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingdong Lu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Cui
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| |
Collapse
|
|
10
|
Argentino G, Olivieri B, Barbieri A, Beri R, Bason C, Friso S, Tinazzi E. Exploring the Utility of Circulating Endothelial Cell-Derived Extracellular Vesicles as Markers of Health and Damage of Vasal Endothelium in Systemic Sclerosis Patients Treated with Iloprost. Biomedicines 2024; 12:295. [PMID: 38397897 PMCID: PMC10886571 DOI: 10.3390/biomedicines12020295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
Endothelial cell-derived extracellular vesicles (eEVs) are released from endothelial cells, signifying endothelial integrity. Systemic Sclerosis (SSc) is a rare disease causing skin and organ fibrosis with early vascular damage. Iloprost, an SSc treatment, might affect eEV release, showing long-term benefits. We aimed to study eEVs in SSc, potentially serving as disease markers and linked to Iloprost's impact on organ involvement. We included 54 SSc patients and 15 healthy donors. Using flow cytometry on platelet-poor plasma (PPP) with specific antibodies (CD144, CD146, AnnexinV), we detected endothelial extracellular vesicles. Results showed fewer eEVs from apoptotic or normal cells in SSc patients than healthy controls. Specifically, patients with diffuse cutaneous SSc and lung issues had reduced eEVs from apoptotic endothelial cells (CD146+ AnnV+). No notable differences were seen in CD144 endothelial markers between patients and controls. After 1-day Iloprost infusion, there was an increase in eEVs, but not after 5 days. These findings suggest circulating eEVs reflect endothelial health/damage, crucial in early SSc stages. A 1-day Iloprost infusion seems effective in repairing endothelial damage, critical in scleroderma vasculopathy. Differences in marker outcomes may relate to CD146's surface expression and CD144's junctional location in endothelial cells.
Collapse
Affiliation(s)
- Giuseppe Argentino
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| | - Bianca Olivieri
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| | - Alessandro Barbieri
- Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Ruggero Beri
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| | - Caterina Bason
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| | - Simonetta Friso
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| | - Elisa Tinazzi
- Department of Medicine, University of Verona, 37134 Verona, Italy; (B.O.); (R.B.); (C.B.); (S.F.); (E.T.)
| |
Collapse
|
|
11
|
Ghorbani R, Hosseinzadeh S, Azari A, Taghipour N, Soleimani M, Rahimpour A, Abbaszadeh HA. The Current Status and Future Direction of Extracellular Nano-vesicles in the Alleviation of Skin Disorders. Curr Stem Cell Res Ther 2024; 19:351-366. [PMID: 37073662 DOI: 10.2174/1574888x18666230418121053] [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: 11/19/2022] [Revised: 02/21/2023] [Accepted: 03/06/2023] [Indexed: 04/20/2023]
Abstract
Exosomes are extracellular vesicles (EVs) that originate from endocytic membranes. The transfer of biomolecules and biological compounds such as enzymes, proteins, RNA, lipids, and cellular waste disposal through exosomes plays an essential function in cell-cell communication and regulation of pathological and physiological processes in skin disease. The skin is one of the vital organs that makes up about 8% of the total body mass. This organ consists of three layers, epidermis, dermis, and hypodermis that cover the outer surface of the body. Heterogeneity and endogeneity of exosomes is an advantage that distinguishes them from nanoparticles and liposomes and leads to their widespread usage in the remedy of dermal diseases. The biocompatible nature of these extracellular vesicles has attracted the attention of many health researchers. In this review article, we will first discuss the biogenesis of exosomes, their contents, separation methods, and the advantages and disadvantages of exosomes. Then we will highlight recent developments related to the therapeutic applications of exosomes in the treatment of common skin disorders like atopic dermatitis, alopecia, epidermolysis bullosa, keloid, melanoma, psoriasis, and systemic sclerosis.
Collapse
Affiliation(s)
- Raziyeh Ghorbani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezo Azari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Niloofar Taghipour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azam Rahimpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hojjat Allah Abbaszadeh
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Assar S, Mohammadzadeh D, Norooznezhad AH, Payandeh M, Hassaninia D, Pournazari M, Soufivand P, Yarani R, Mansouri K. Improvement in the clinical manifestations of interstitial lung disease following treatment with placental mesenchymal stromal cell extracellular vesicles in a patient with systemic sclerosis: A case report. Respir Med Case Rep 2023; 46:101923. [PMID: 37928415 PMCID: PMC10622869 DOI: 10.1016/j.rmcr.2023.101923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/17/2023] [Accepted: 09/30/2023] [Indexed: 11/07/2023] Open
Abstract
Background Interstitial lung disease (ILD) is a severe systemic sclerosis (SSc) complication with no current approved or golden standard treatment. This report aims to investigate the effectiveness of treatment with placental mesenchymal stromal cell (MSC) extracellular vesicles (EVs) in a patient with ILD due to SSc. Case presentation The patient was a 55-year-old woman with a ten years history of SSc complicated by severe ILD. Over time, her lung disease progressed to interstitial fibrosis despite being treated with mycophenolate mofetil and monthly pulses of cyclophosphamide. Thus, she was treated with eight doses of placenta MSC-EVs. Four weeks after the third dose (Day 31 after the first dose), she reported marked improvement in her clinical symptoms, such as dyspnea and cough. Also, chest computed tomography (CT) scans demonstrated a significant reduction in ground glass consolidations and fibrotic changes. The patient was subsequently followed for twelve months, with findings showing significant improvement in exercise tolerance and reduced supplemental oxygen need. Conclusion In this single case, placental MSC-EVs were seen to provide a potentially efficient treatment for SSc-related ILD; however, further investigation and clinical trials are necessary.
Collapse
Affiliation(s)
- Shirin Assar
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Dena Mohammadzadeh
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Hossein Norooznezhad
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehrdad Payandeh
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Daryoush Hassaninia
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parviz Soufivand
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Yarani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| |
Collapse
|
|
13
|
Yu F, Deng X, Zhong Y, Guo B, Zhang X, Wu B. Hypoxic papillary thyroid carcinoma cells-secreted exosomes deliver miR-221-3p to normoxic tumor cells to elicit a pro-tumoral effect by regulating the ZFAND5. Exp Cell Res 2023; 431:113716. [PMID: 37488006 DOI: 10.1016/j.yexcr.2023.113716] [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: 03/27/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023]
Abstract
Papillary thyroid cancer (PTC) has seen a worldwide expansion in incidence in the past three decades. Tumor-derived exosomes have been associated with the metastasis of cancer cells and are present within the local hypoxic tumor microenvironment, where they mediate intercellular communication by transferring molecules including microRNAs (miRNAs) between cells. Although miRNAs have been shown to serve as non-invasive biomarkers for cancer diagnosis, the role of hypoxia-induced tumor-derived exosomes in PTC progression remains unclear. Herein, we investigated the differentially expressed miRNA expression profiles from GEO datasets (GSE191117 and GSE151180) by using the DESeq package in R and identified a novel role for miR-221-3p as an oncogene in PTC development. In vivo and in vitro loss and gain assays were used to clarify the mechanism of hypoxic PTC cells derived exosomal-miR-221-3p in PTC. miR-221-3p was upregulated in human PTC plasma exosomes, tissues and cell lines. We found that hypoxic PTC cells derived exosomal-miR-221-3p promoted normoxic PTC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, while inhibition of miR-221-3p limited PTC tumor growth in our PTC xenograft model in nude mice. We finally identified ZFAND5, to be a miR-221-3p target. Mechanistically, hypoxic PTC cell lines-derived exosomes carrying miR-221-3p promoted PTC tumorigenesis by regulating ZFAND5. Our findings further the understanding of the underlying mechanisms associated with PTC progression and identify exosomal-miR-221-3p as a potential biomarker for the diagnosis and prognosis of PTC patients. Our study also suggests that miR-221-3p inhibitors could be a potential treatment strategy for PTC.
Collapse
Affiliation(s)
- Fan Yu
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Xianzhao Deng
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Yong Zhong
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Bomin Guo
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Xiaoping Zhang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
| | - Bo Wu
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
| |
Collapse
|
|
14
|
Bobeica C, Niculet E, Craescu M, Parapiru EL, Corduneanu-Luca AM, Debita M, Pelin AM, Tiutiuca C, Vasile CI, Nicolescu AC, Miulescu M, Balan G, Tatu AL. Immunologic and nonimmunologic sclerodermal skin conditions - review. Front Immunol 2023; 14:1180221. [PMID: 37600771 PMCID: PMC10432860 DOI: 10.3389/fimmu.2023.1180221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/16/2023] [Indexed: 08/22/2023] Open
Abstract
Scleroderma-like cutaneous lesions have been found in many pathological conditions and they have the clinical appearance of sclerotic or scleroatrophic lesions. Affected skin biopsies described histopathological changes similar to those of scleroderma located strictly on the skin or those of systemic sclerosis. These skin lesions can be found in inflammatory diseases with autoimmune substrate (generalized morphea, chronic graft versus host disease, eosinophilic fasciitis), tissue storage diseases (scleredema, scleromyxedema, nephrogenyc systemic fibrosis, systemic amyloidosis), metabolic diseases (porphyrya cutanea tarda, phenylketonuria, hypothyroidism, scleredema diabeticorum), progeroid syndromes. Given the multiple etiologies of sclerodermal lesions, a correct differential diagnosis is necessary to establish the appropriate treatment.
Collapse
Affiliation(s)
- Carmen Bobeica
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Elena Niculet
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
- Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR (Centrul Integrat Multidisciplinar de Cercetare de Interfata Dermatologica - CIM-CID), “Dunărea de Jos” University, Galaţi, Romania
| | - Mihaela Craescu
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
- Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR (Centrul Integrat Multidisciplinar de Cercetare de Interfata Dermatologica - CIM-CID), “Dunărea de Jos” University, Galaţi, Romania
| | - Elena-Laura Parapiru
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | | | - Mihaela Debita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Ana Maria Pelin
- Department of Pharmaceutical Sciences, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Carmen Tiutiuca
- Clinical Surgical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Claudiu Ionut Vasile
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Alin Codrut Nicolescu
- Dermatology Department “Agrippa Ionescu” Emergency Clinical Hospital, Bucharest, Romania
| | - Magdalena Miulescu
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
| | - Gabriela Balan
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
- Research Center in the Field of Medical and Pharmaceutical Sciences, “Dunărea de Jos” University, Galaţi, Romania
| | - Alin Laurentiu Tatu
- Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR (Centrul Integrat Multidisciplinar de Cercetare de Interfata Dermatologica - CIM-CID), “Dunărea de Jos” University, Galaţi, Romania
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunărea de Jos” University, Galaţi, Romania
- Dermatology Department, “Sf. Cuvioasa Parascheva” Clinical Hospital of Infectious Diseases, Galaţi, Romania
| |
Collapse
|
|
15
|
Jimenez SA, Piera-Velazquez S. Probable role of exosomes in the extension of fibrotic alterations from affected to normal cells in systemic sclerosis. Rheumatology (Oxford) 2023; 62:999-1008. [PMID: 35944210 PMCID: PMC9977136 DOI: 10.1093/rheumatology/keac451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/14/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
SSc is a systemic autoimmune disease of unknown etiology characterized by frequently progressive cutaneous and internal organ fibrosis causing severe disability, organ failure and high mortality. A remarkable feature of SSc is the extension of the fibrotic alterations to nonaffected tissues. The mechanisms involved in the extension of fibrosis have remained elusive. We propose that this process is mediated by exosome microvesicles released from SSc-affected cells that induce an activated profibrotic phenotype in normal or nonaffected cells. Exosomes are secreted microvesicles involved in an intercellular communication system. Exosomes can transfer their macromolecular content to distant target cells and induce paracrine effects in the recipient cells, changing their molecular pathways and gene expression. Confirmation of this hypothesis may identify the molecular mechanisms responsible for extension of the SSc fibrotic process from affected cells to nonaffected cells and may allow the development of novel therapeutic approaches for the disease.
Collapse
Affiliation(s)
- Sergio A Jimenez
- Jefferson Institute of Molecular Medicine and The Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sonsoles Piera-Velazquez
- Jefferson Institute of Molecular Medicine and The Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, USA
| |
Collapse
|
|
16
|
Renaud L, Waldrep KM, da Silveira WA, Pilewski JM, Feghali-Bostwick CA. First Characterization of the Transcriptome of Lung Fibroblasts of SSc Patients and Healthy Donors of African Ancestry. Int J Mol Sci 2023; 24:3645. [PMID: 36835058 PMCID: PMC9966000 DOI: 10.3390/ijms24043645] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/25/2023] [Accepted: 02/04/2023] [Indexed: 02/16/2023] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in "AA-NL vs. EA-NL" and 384 DEGs in "AA-SScL vs. EA-SScL" analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a "pre-fibrosis" state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies.
Collapse
Affiliation(s)
- Ludivine Renaud
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Kristy M. Waldrep
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Willian A. da Silveira
- Department of Biological Sciences, School of Life Sciences and Education, Staffordshire University, Stoke-on-Trent ST4 2DF, UK
| | - Joseph M. Pilewski
- Department of Medicine, Pulmonary, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Carol A. Feghali-Bostwick
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
| |
Collapse
|
|
17
|
Bhandari R, Yang H, Kosarek NN, Smith AE, Garlick JA, Hinchcliff M, Whitfield ML, Pioli PA. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology (Oxford) 2023; 62:SI114-SI124. [PMID: 35946522 PMCID: PMC9910573 DOI: 10.1093/rheumatology/keac453] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 07/29/2022] [Accepted: 07/29/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Prior work demonstrates that co-cultured macrophages and fibroblasts from patients with SSc engage in reciprocal activation. However, the mechanism by which these cell types communicate and contribute to fibrosis and inflammation in SSc is unknown. METHODS Fibroblasts were isolated from skin biopsies obtained from 7 SSc patients or 6 healthy age and gender-matched control subjects following written informed consent. Human donor-derived macrophages were cultured with exosomes isolated from control or SSc fibroblasts for an additional 48 h. Macrophages were immunophenotyped using flow cytometry, qRT-PCR and multiplex. For mutual activation studies, exosome-activated macrophages were co-cultured with SSc or healthy fibroblasts using Transwells. RESULTS Macrophages activated with dermal fibroblast-derived exosomes from SSc patients upregulated surface expression of CD163, CD206, MHC Class II and CD16 and secreted increased levels of IL-6, IL-10, IL-12p40 and TNF compared with macrophages incubated with healthy control fibroblasts (n = 7, P < 0.05). Exosome-stimulated macrophages and SSc fibroblasts engaged in reciprocal activation, as production of collagen and fibronectin was significantly increased in SSc fibroblasts receiving signals from SSc exosome-stimulated macrophages (n = 7, P < 0.05). CONCLUSION In this work, we demonstrate for the first time that human SSc dermal fibroblasts mediate macrophage activation through exosomes. Our findings suggest that macrophages and fibroblasts engage in cross-talk in SSc skin, resulting in mutual activation, inflammation, and extracellular matrix (ECM) deposition. Collectively, these studies implicate macrophages and fibroblasts as cooperative mediators of fibrosis in SSc and suggest therapeutic targeting of both cell types may provide maximal benefit in ameliorating disease in SSc patients.
Collapse
Affiliation(s)
| | - Heetaek Yang
- Department of Microbiology and Immunology
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH
| | - Noelle N Kosarek
- Department of Microbiology and Immunology
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH
| | - Avi E Smith
- Department of Diagnostic Science, Tufts University School of Dental Medicine, Boston, MA
| | - Jonathan A Garlick
- Department of Diagnostic Science, Tufts University School of Dental Medicine, Boston, MA
| | - Monique Hinchcliff
- Division of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Michael L Whitfield
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH
| | | |
Collapse
|
|
18
|
Huang T, Chen J, Zhang Y, Chen Y, Xu C, Guo J, Ming H. Circ_0027470 promotes cadmium exposure-induced prostatic fibrosis via sponging miRNA-1236-3p and stimulating SHH signaling pathway. J Appl Toxicol 2023. [PMID: 36617218 DOI: 10.1002/jat.4436] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/19/2022] [Accepted: 01/05/2023] [Indexed: 01/09/2023]
Abstract
Cadmium (Cd) is a toxic heavy metal pollutant and serves as an important environmental endocrine-disrupting chemical. Cd exposure is believed to can enhance the risks of age-related disorders including benign prostatic hyperplasia (BPH). This study was to investigate the harms of Cd exposure on mice prostate and human nonmalignant prostate epithelial RWPE-1 cells. Mice prostate fibrosis was evaluated by visualizing the prostatic collagen deposition via Masson and Sirius red staining, and detecting the content of hydroxyproline. Additionally, the epithelial-mesenchymal transition (EMT), primary ciliogenesis and SHH signaling pathways in both mice prostate and RWPE-1 cells were evaluated. It was found that Cd exposure stimulated prostatic collagen deposition, EMT and primary ciliogenesis, as well as enhanced the circ_0027470 level and reduced the miRNA-1236-3p level. Circ_0027470 functioned as a sponge of miRNA-1236-3p, which had the inhibiting target of SHH. The whole results showed that circ_0027470 promoted Cd exposure-induced prostatic fibrosis via sponging miRNA-1236-3p and subsequently stimulating SHH signaling pathway. This study shed a light on a novel molecular mechanism involved in circRNA for Cd exposure-induced prostate deficits.
Collapse
Affiliation(s)
- Tianqi Huang
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, China
| | - Jinglou Chen
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, China
| | - Yumiao Zhang
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, China
| | - Yao Chen
- Department of Pharmacy, School of Medicine, Jianghan University, Wuhan, China
| | - Congyue Xu
- Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Jing Guo
- Department of Basic Medicine, School of Medicine, Jianghan University, Wuhan, China
| | - Hao Ming
- Department of Traditional Chinese Medicine, School of Medicine, Jianghan University, Wuhan, China
| |
Collapse
|
|
19
|
Sun X, Ding T, Wang B, Chang Z, Fei H, Geng L, Wang Y. Identification of lncRNA-miRNA-mRNA networks in circulating exosomes as potential biomarkers for systemic sclerosis. Front Med (Lausanne) 2023; 10:1111812. [PMID: 36873898 PMCID: PMC9977830 DOI: 10.3389/fmed.2023.1111812] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/18/2023] [Indexed: 02/18/2023] Open
Abstract
Objective This study aimed to analyze potential biomarkers for systemic sclerosis (SSc) by constructing lncRNA-miRNA-mRNA networks in circulating exosomes (cirexos). Materials and methods Differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in SSc cirexos were screened using high-throughput sequencing and detected with real-time quantitative PCR (RT-qPCR). Differentially expressed genes (DEGs) were analyzed using the DisGeNET, GeneCards, GSEA4.2.3, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Receiver operating characteristic (ROC) curves, correlation analyses, and a double-luciferase reporter gene detection assay were used to analyze competing endogenous RNA (ceRNA) networks and clinical data. Results In this study, 286 DEmRNAs and 192 DElncRNAs were screened, of which 18 DEGs were the same as the SSc-related genes. The main SSc-related pathways included extracellular matrix (ECM) receptor interaction, local adhesion, platelet activation, and IgA production by the intestinal immune network. A hub gene, COL1A1, was obtained by a protein-protein interaction (PPI) network. Four ceRNA networks were predicted through Cytoscape. The relative expression levels of COL1A1, ENST0000313807, and NON-HSAT194388.1 were significantly higher in SSc, while the relative expression levels of hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were significantly lower in SSc (P < 0.05). The ROC curve showed that the ENST00000313807-hsa-miR-29a-3p-COL1A1 network as a combined biomarker of SSc is more valuable than independent diagnosis, and that it is correlated with high-resolution CT (HRCT), Scl-70, C-reactive protein (CRP), Ro-52, IL-10, IgM, lymphocyte percentage, neutrophil percentage, albumin divided by globulin, urea, and RDW-SD (P < 0.05). Double-luciferase reporter gene detection showed that ENST00000313807 interacts with hsa-miR-29a-3p, which interacts with COL1A1. Conclusion The ENST00000313807-hsa-miR-29a-3p-COL1A1 network in plasma cirexos represents a potential combined biomarker for the clinical diagnosis and treatment of SSc.
Collapse
Affiliation(s)
- Xiaolin Sun
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Tiantian Ding
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Baoyue Wang
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Zhifang Chang
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Hongchang Fei
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Lixia Geng
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Yongfu Wang
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| |
Collapse
|
|
20
|
Piera-Velazquez S, Dillon ST, Gu X, Libermann TA, Jimenez SA. Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis. PLoS One 2022; 17:e0279461. [PMID: 36548367 PMCID: PMC9779033 DOI: 10.1371/journal.pone.0279461] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc. OBJECTIVE To identify proteins contained within serum exosomes employing an aptamer proteomic analysis that may serve to reveal patients with Raynaud's Phenomenon at risk of developing SSc. METHODS Exosomes were isolated from serum samples from patients with Primary Raynaud's Phenomenon and from patients with Raynaud's Phenomenon harbouring serum antinuclear antibodies (ANA) who may be at high risk of evolving into SSc. The expression of 1,305 proteins was quantified using SOMAscan aptamer proteomics, and associations of the differentially elevated or reduced proteins with the clinical subsets of Raynaud's Phenomenon were assessed. RESULTS Twenty one differentially elevated and one differentially reduced (absolute fold change >|1.3|) proteins were identified. Principal component analysis using these 22 most differentially expressed proteins resulted in excellent separation of the two Raynaud's Phenomenon clinical subsets. Remarkably, the most differentially elevated proteins are involved in enhanced inflammatory responses, immune cell activation and cell migration, and abnormal vascular functions. CONCLUSION Aptamer proteomic analysis of circulating exosomes identified differentially elevated or reduced proteins between Raynaud's Phenomenon at high risk of evolving into SSc and Primary Raynaud's Phenomenon patients. Some of these proteins are involved in relevant biological pathways that may play a role in SSc pathogenesis including enhanced inflammatory responses, immune cell activation, and endothelial cell and vascular abnormalities.
Collapse
Affiliation(s)
- Sonsoles Piera-Velazquez
- Jefferson Institute of Molecular Medicine, Scleroderma Center of Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Simon T. Dillon
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Xuesong Gu
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Towia A. Libermann
- Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (SAJ); (TAL)
| | - Sergio A. Jimenez
- Jefferson Institute of Molecular Medicine, Scleroderma Center of Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail: (SAJ); (TAL)
| |
Collapse
|
|
21
|
Zhang Y, Zhu M, Xie L, Zhang H, Deng T. Identification and validation of key immune-related genes with promising diagnostic and predictive value in systemic sclerosis. Life Sci 2022; 312:121238. [PMID: 36460097 DOI: 10.1016/j.lfs.2022.121238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/30/2022]
Abstract
AIMS To screen and confirm key immune-related genes (IRGs) with diagnostic and predictive value in systemic sclerosis (SSc) and provide potential therapeutic targets for patients with SSc. MATERIALS AND METHODS In Gene Expression Omnibus database (GEO), four datasets of gene expression profiling related to SSc were downloaded and used for the analysis in this study. After differential analysis of SSc cases and controls in GSE130955, the differentially expressed genes (DEGs) were overlapped with IRGs to obtain the immune-related differentially expressed genes (IR-DEGs) in SSc. In addition, functional annotation and pathway enrichment of IR-DEGs were conducted. The protein-protein interaction network (PPI) was constructed to identify key IR-DEGs. Using GSE58095, GSE181549 and GSE130953, the diagnostic and predictive abilities for the key IR-DEGs in SSc were validated. Finally, the screened key genes were confirmed in skin derived bleomycin (BLM)-induced SSc mice by Real-time PCR. KEY FINDINGS NGFR, TNFSF13B, FCER1G, GIMAP5, TYROBP and CSF1R may have important or very high diagnostic value for SSc. TYROBP and TNFSF13B had moderate and mild predictive value respectively in SSc patients after treatment. Real-time PCR assay further confirmed that the expressions of Ngfr, Tyrobp, Csf1r, Fcer1g and Gimap5 were significantly higher in skin of BLM-induced SSc mice than that in controls. SIGNIFICANCE The key IR-DEGs, including NGFR, TNFSF13B, TYROBP, CSF1R, FCER1G and GIMAP5, may become auxiliary diagnostic indicators and potential biomarkers for SSc. Moreover, TNFSF13B and TYROBP could have good prospects as predictive indicators in SSc patients that accepted cyclophosphamide or transplantation therapy.
Collapse
Affiliation(s)
- Yajie Zhang
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, China.
| | - Mingxin Zhu
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, China.
| | - Limin Xie
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, China.
| | - Haowei Zhang
- The First Affiliated Hospital, Department of Orthopedics, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, China.
| |
Collapse
|
|
22
|
Wu F, Gao J, Kang J, Wang X, Niu Q, Liu J, Zhang L. Knowledge Mapping of Exosomes in Autoimmune Diseases: A Bibliometric Analysis (2002–2021). Front Immunol 2022; 13:939433. [PMID: 35935932 PMCID: PMC9353180 DOI: 10.3389/fimmu.2022.939433] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/24/2022] [Indexed: 12/14/2022] Open
Abstract
Background Autoimmune diseases (AIDs) are a class of chronic disabling diseases characterized by inflammation and damage to muscles, joints, bones, and internal organs. Recent studies have shown that much progress has been made in the research of exosomes in AIDs. However, there is no bibliometric analysis in this research field. This study aims to provide a comprehensive overview of the knowledge structure and research hotspots of exosomes in AIDs through bibliometrics. Method Publications related to exosomes in AIDs from 2002 to 2021 were searched on the web of science core collection (WoSCC) database. VOSviewers, CiteSpace and R package “bibliometrix” were used to conduct this bibliometric analysis. Results 312 articles from 48 countries led by China and the United States were included. The number of publications related to exosomes in AIDs is increasing year by year. Central South University, Sun Yat Sen University, Tianjin Medical University and University of Pennsylvania are the main research institutions. Frontiers in immunology is the most popular journal in this field, and Journal of Immunology is the most co-cited journal. These publications come from 473 authors among which Ilias Alevizos, Qianjin Lu, Wei Wei, Jim Xiang and Ming Zhao had published the most papers and Clotilde Théry was co-cited most often. Studying the mechanism of endogenous exosomes in the occurrence and development of AIDs and the therapeutic strategy of exogenous exosomes in AIDs are the main topics in this research field. “Mesenchymal stem cells”, “microRNA”, “biomarkers”, “immunomodulation”, and “therapy” are the primary keywords of emerging research hotspots. Conclusion This is the first bibliometric study that comprehensively summarizes the research trends and developments of exosomes in AIDs. This information identifies recent research frontiers and hot directions, which will provide a reference for scholars studying exosomes.
Collapse
Affiliation(s)
- Fengping Wu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Jinfang Gao
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Jie Kang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xuexue Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Qing Niu
- School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Jiaxi Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Liyun Zhang
- Department of Rheumatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Liyun Zhang,
| |
Collapse
|
|
23
|
Kose O, Botsali A, Caliskan E. Role of exosomes in skin diseases. J Cosmet Dermatol 2022; 21:3219-3225. [PMID: 35686395 DOI: 10.1111/jocd.15152] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 05/30/2022] [Accepted: 06/07/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Exosomes, as a family member of extracellular vesicles, are cell-secreted nanoscale structures that play pivotal roles in regulating physiological and pathophysiological processes of the skin. Exosomes induce communication between cells and are responsible for transporting cellular components such as microRNAs, mRNAs, DNA, lipids, metabolites, and cell-surface proteins. Numerous preclinical and clinical trials searched the contribution of exosomes to skin functions and disorders. Thus, exosomes are gaining increasing attention within investigational dermatology. In advance, stem-cell-derived exosomes were integrated into the functional cosmetics industry nominated as cell-free regenerative medicine. OBJECTIVE This review aims to demonstrate the roles of exosomes in inflammatory skin disorders, stem cell, and tumor biology through a comprehensive evaluation of the diagnostic, prognostic, and therapeutic perspectives. METHODS A comprehensive literature search was performed using electronic online databases "PubMed" and "Google Scholar" using key words ''exosomes'', ''skin'', ''wound healing''. CONCLUSION Exosomes are regarded as promising diagnostic and prognostic biomarkers for various skin diseases. Future prospects are repurposing exosomes to treat skin disorders, either as drug carriers or drugs themselves.
Collapse
Affiliation(s)
- Osman Kose
- Dermatologist, Private Practice, Ankara, Turkey
| | - Aysenur Botsali
- Department of Dermatology, Gülhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey
| | - Ercan Caliskan
- Department of Dermatology, Gülhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey
| |
Collapse
|
|
24
|
Chen J, Rong N, Liu M, Xu C, Guo J. The exosome-circ_0001359 derived from cigarette smoke exposed-prostate stromal cells promotes epithelial cells collagen deposition and primary ciliogenesis. Toxicol Appl Pharmacol 2021; 435:115850. [PMID: 34968637 DOI: 10.1016/j.taap.2021.115850] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 12/15/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023]
Abstract
Cigarettes consumption is continued to be popular. We found that cigarette smoke (CS) exposure promoted prostatic fibrosis. In this study, human prostate epithelial RWPE-1 cells were co-cultured with exosomes derived from CS exposed-WPMY-1 cells (CS-WPMY-1-exo). The collagen deposition, primary ciliogenesis, epithelial-mesenchymal transition (EMT) and transforming growth factor (TGF)-β1 level of RWPE-1 were evaluated. The circRNAs profiles of WPMY-1-exo were explored by high-throughput RNA sequencing. It was found that CS-WPMY-1-exo significantly promoted RWPE-1 collagen deposition, EMT and primary ciliogenesis. There were 17 differentially expressed (DE) circRNAs (including circ_0001359) between CS-WPMY-1-exo and the negative control. Functional enrichment analyses showed that the DE circRNAs played important roles in ciliary basal body, spindle microtubule and TGF-β signaling pathway. Circ_0001359 siRNA attenuated CS-WPMY-1 induced RWPE-1 cells collagen deposition, EMT and primary ciliogenesis, as well as inhibited the level of TGF-β1. The whole results showed that circ_0001359 derived from CS-WPMY-1-exo contributed to prostatic fibrosis via stimulating epithelial cells phenotypes changes and collagen deposition.
Collapse
Affiliation(s)
- Jinglou Chen
- School of Medical, Jianghan University, Wuhan, China; The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China.
| | - Nan Rong
- The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China
| | - Min Liu
- The Gerontology Research Center of Jianghan University, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Jianghan University, Wuhan, China
| | - Congyue Xu
- School of Medical, Jianghan University, Wuhan, China
| | - Jing Guo
- School of Medical, Jianghan University, Wuhan, China
| |
Collapse
|
|
25
|
Szabo I, Muntean L, Crisan T, Rednic V, Sirbe C, Rednic S. Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs. Biomedicines 2021; 9:biomedicines9101471. [PMID: 34680587 PMCID: PMC8533248 DOI: 10.3390/biomedicines9101471] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/03/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023] Open
Abstract
Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their differential response to external stimuli could explain the protean clinical manifestations of SSc while offering the opportunity of targeted drug development. Small, non-coding RNA sequences (miRNAs) have demonstrated complex interactions between vasculature, immune activation, and extracellular matrices. Distinct miRNA profiles were identified in SSc skin specimens and blood samples containing a wide variety of dysregulated miRNAs. Their target genes are mainly involved in profibrotic pathways, but new lines of evidence also confirm their participation in impaired angiogenesis and aberrant immune responses. Research approaches focusing on earlier stages of the disease and on differential miRNA expression in various tissues could bring novel insights into SSc pathogenesis and validate the clinical utility of miRNAs as biomarkers and therapeutic targets.
Collapse
Affiliation(s)
- Iulia Szabo
- Department of Rheumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.); (C.S.); (S.R.)
| | - Laura Muntean
- Department of Rheumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.); (C.S.); (S.R.)
- Department of Rheumatology, County Emergency Hospital Cluj-Napoca, 400000 Cluj-Napoca, Romania
- Correspondence:
| | - Tania Crisan
- Department of Medical Genetics, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania;
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Voicu Rednic
- Department of Gastroenterology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania;
- Department of Gastroenterology II, “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, 400000 Cluj-Napoca, Romania
| | - Claudia Sirbe
- Department of Rheumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.); (C.S.); (S.R.)
| | - Simona Rednic
- Department of Rheumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.); (C.S.); (S.R.)
- Department of Rheumatology, County Emergency Hospital Cluj-Napoca, 400000 Cluj-Napoca, Romania
| |
Collapse
|
|
26
|
Antinozzi C, Sgrò P, Marampon F, Caporossi D, Del Galdo F, Dimauro I, Di Luigi L. Sildenafil Counteracts the In Vitro Activation of CXCL-9, CXCL-10 and CXCL-11/CXCR3 Axis Induced by Reactive Oxygen Species in Scleroderma Fibroblasts. BIOLOGY 2021; 10:491. [PMID: 34073032 PMCID: PMC8229934 DOI: 10.3390/biology10060491] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/26/2021] [Accepted: 05/29/2021] [Indexed: 02/06/2023]
Abstract
Oxidative stress plays a key role in systemic sclerosis (SSc) pathogenesis, and an altered redox homeostasis might be responsible for abnormal inflammatory status, fibrosis and tissue damage extension. In this study, we explored the effect of the phosphodiesterase type 5 inhibitor sildenafil in modulating the activation of the CXCL-9, -10, -11/CXCR3 axis, which is fundamental in the perpetuation of inflammation in different autoimmune diseases, in the cell culture of SSc human dermal fibroblasts exposed to a pro-oxidant environment. We observed that sildenafil significantly reduced gene expression and release of CXCL-9, -10 and -11, inhibited the CXCR3 action and suppressed the activation of STAT1-, JNK- and p38MAPK pathways. This in vitro study on dermal fibroblasts supports clinical studies to consider the efficacy of sildenafil in preventing tissue damage and fibrosis in SSc by targeting central biomarkers of disease progression, vascular injuries and fibrosis and reducing the pro-inflammatory activation induced by oxidative stress.
Collapse
Affiliation(s)
- Cristina Antinozzi
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (P.S.); (F.M.); (L.D.L.)
| | - Paolo Sgrò
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (P.S.); (F.M.); (L.D.L.)
| | - Francesco Marampon
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (P.S.); (F.M.); (L.D.L.)
- Department of Radiotherapy, Sapienza University of Rome, 00185 Rome, Italy
| | - Daniela Caporossi
- Unit of Biology and Genetic, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (D.C.); (I.D.)
| | - Francesco Del Galdo
- Leeds Institue of Rheumatic and Musculoskeletal Medicine and Diseases and NIHR Biomedical Research Centre, University of Leeds, Leeds LS2 9JT, UK;
| | - Ivan Dimauro
- Unit of Biology and Genetic, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (D.C.); (I.D.)
| | - Luigi Di Luigi
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy; (P.S.); (F.M.); (L.D.L.)
| |
Collapse
|
|
27
|
Rozier P, Maumus M, Maria ATJ, Toupet K, Lai-Kee-Him J, Jorgensen C, Guilpain P, Noël D. Mesenchymal stromal cells-derived extracellular vesicles alleviate systemic sclerosis via miR-29a-3p. J Autoimmun 2021; 121:102660. [PMID: 34020253 DOI: 10.1016/j.jaut.2021.102660] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/07/2021] [Accepted: 05/09/2021] [Indexed: 12/16/2022]
Abstract
Systemic sclerosis (SSc) is a potentially lethal disease with no curative treatment. Mesenchymal stromal cells (MSCs) have proved efficacy in SSc but no data is available on MSC-derived extracellular vesicles (EVs) in this multi-organ fibrosis disease. Small size (ssEVs) and large size EVs (lsEVs) were isolated from murine MSCs or human adipose tissue-derived MSCs (ASCs). Control antagomiR (Ct) or antagomiR-29a-3p (A29a) were transfected in MSCs and ASCs before EV production. EVs were injected in the HOCl-induced SSc model at day 21 and euthanasized at day 42. We found that both ssEVs and lsEVs were effective to slow-down the course of the disease. All disease parameters improved in skin and lungs. Interestingly, down-regulating miR-29a-3p in MSCs totally abolished therapeutic efficacy. Besides, we demonstrated a similar efficacy of human ASC-EVs and importantly, EVs from A29a-transfected ASCs failed to improve skin fibrosis. We identified Dnmt3a, Pdgfrbb, Bcl2, Bcl-xl as target genes of miR-29a-3p whose regulation was associated with skin fibrosis improvement. Our study highlights the therapeutic role of miR-29a-3p in SSc and the importance of regulating methylation and apoptosis.
Collapse
Affiliation(s)
- Pauline Rozier
- IRMB, University of Montpellier, INSERM, Montpellier, France
| | - Marie Maumus
- IRMB, University of Montpellier, INSERM, Montpellier, France
| | - Alexandre Thibault Jacques Maria
- IRMB, University of Montpellier, INSERM, Montpellier, France; Department of Internal Medicine, Multi-organic Diseases, CHU, Montpellier, France
| | - Karine Toupet
- IRMB, University of Montpellier, INSERM, Montpellier, France
| | - Joséphine Lai-Kee-Him
- Centre de Biochimie Structurale (CBS), University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Christian Jorgensen
- IRMB, University of Montpellier, INSERM, Montpellier, France; Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU, Montpellier, France
| | - Philippe Guilpain
- IRMB, University of Montpellier, INSERM, Montpellier, France; Department of Internal Medicine, Multi-organic Diseases, CHU, Montpellier, France
| | - Danièle Noël
- IRMB, University of Montpellier, INSERM, Montpellier, France; Clinical Immunology and Osteoarticular Disease Therapeutic Unit, Department of Rheumatology, CHU, Montpellier, France.
| |
Collapse
|
|
28
|
The emerging roles of exosomes in autoimmune diseases, with special emphasis on microRNAs in exosomes. Pharmacol Res 2021; 169:105680. [PMID: 34010670 DOI: 10.1016/j.phrs.2021.105680] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/29/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023]
Abstract
Autoimmune diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic vasculitis, dermatomyositis, systemic sclerosis (SSc), mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroiditis (AITD) and ulcerative colitis. Exosomes exist in body fluids, including blood, saliva, urine, cerebrospinal fluid and milk. They are mainly derived from the invagination of intracellular lysosomal particles, which are released into the extracellular matrix after fusion of the outer membrane of the exosomes with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying proteins, nucleic acids and lipids. Evidences show that exosomes are involved in the pathogenesis of various autoimmune diseases. In view of the important roles of exosomes in autoimmune diseases, this work systematically reviewed the effects of exosomes on the pathogenesis of autoimmune diseases, especially the regulatory roles of exosome derived microRNAs (miRNAs) in the pathogenesis of RA, SLE, dermatomyositis, SSc, AITD and ulcerative colitis. The review of the roles of exosomes in autoimmune diseases will help to clarify the pathogenesis of these diseases and explore new diagnostic markers and therapeutic targets.
Collapse
|
|
29
|
Lo Gullo A, Mandraffino G, Rodríguez-Carrio J, Scuruchi M, Sinicropi D, Postorino M, Morace C, Giuffrida C, Sciortino D, Gallizzi R, Loddo S, Zito C, Squadrito G. Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension. Biomedicines 2021; 9:533. [PMID: 34064667 PMCID: PMC8150353 DOI: 10.3390/biomedicines9050533] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud's phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: -0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: -0.311, p < 0.01), and E/A ratio (r: -0.487, p < 0.001), but not with ejection fraction (r: -0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: -0.619, p < 0.001), sPAP (r: -0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.
Collapse
Affiliation(s)
- Alberto Lo Gullo
- Medicine and Urgency Unit, Piemonte Hospital, IRCCS Neurolesi Bonino Pulejo, 98121 Messina, Italy;
| | - Giuseppe Mandraffino
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (D.S.); (M.P.); (C.M.); (G.S.)
| | - Javier Rodríguez-Carrio
- Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain;
- Instituto de Investigación Sanitaria Del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Bone and Mineral Research Unit, Instituto Reina Sofía de Investigación Nefrológica, REDinREN Del ISCIII, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Michele Scuruchi
- Molecular Biology Lab, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Davide Sinicropi
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (D.S.); (M.P.); (C.M.); (G.S.)
| | - Maria Postorino
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (D.S.); (M.P.); (C.M.); (G.S.)
| | - Carmela Morace
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (D.S.); (M.P.); (C.M.); (G.S.)
| | - Clemente Giuffrida
- Medicine and Urgency Unit, Piemonte Hospital, IRCCS Neurolesi Bonino Pulejo, 98121 Messina, Italy;
| | - Davide Sciortino
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Romina Gallizzi
- Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy;
- Pediatric Unit, Department of Medical of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Saverio Loddo
- Laboratory Medicine, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Concetta Zito
- Cardiology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Giovanni Squadrito
- Internal Medicine Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (D.S.); (M.P.); (C.M.); (G.S.)
| |
Collapse
|
|
30
|
Condorelli AG, El Hachem M, Zambruno G, Nystrom A, Candi E, Castiglia D. Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway. J Biomed Sci 2021; 28:36. [PMID: 33966637 PMCID: PMC8106838 DOI: 10.1186/s12929-021-00732-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under development.
Collapse
Affiliation(s)
- Angelo Giuseppe Condorelli
- Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy.
| | - May El Hachem
- Dermatology Unit and Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy
| | - Giovanna Zambruno
- Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy
| | - Alexander Nystrom
- Department of Dermatology, Medical Faculty, Medical Center, University of Freiburg, Freiburg, Germany
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome "Tor Vergata", via Montpellier, 1, 00133, Rome, Italy.,IDI-IRCCS, via Monti di Creta 104, 00167, Rome, Italy
| | - Daniele Castiglia
- Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167, Rome, Italy
| |
Collapse
|
|
31
|
The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol 2020; 411:115384. [PMID: 33359661 DOI: 10.1016/j.taap.2020.115384] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 12/21/2020] [Indexed: 12/17/2022]
Abstract
Benign prostatic hyperplasia (BPH) is an age-related disease in men. Mesenchymal /stromal and epithelial cells interactions are essential to prostate functions. In this study, human nonmalignant prostate epithelial RWPE-1 cells were cocultured with testosterone (TE) -exposed prostate stromal fibroblasts WPMY-1 cells (TE-WPMY-1). The survival rate, epithelial-mesenchymal transition (EMT) and collagen deposition of RWPE-1 were observed. The expression profiles of circRNAs, lncRNAs and mRNAs in WPMY-1-derived exosome-like vesicles (WPMY-1-exo) were explored by high-throughput RNA sequencing. Firstly, both TE-WPMY-1 and TE-WPMY-1-exo significantly promoted RWPE-1 cells proliferation. Secondly, 41 circRNAs, 132 lncRNAs and 1057 mRNAs were differentially expressed (DE) between TE-WPMY-1-exo and the control. Functional enrichment analyses, co-expression analyses and quantitative real-time PCR verification showed that the DE RNAs played important roles in cell proliferation, structure, phenotype and fibrosis. Lastly, blocking WPMY-1-exo biogenesis/release by GW4869 can attenuate TE-WPMY-1-stimulated RWPE-1 cells EMT and collagen deposition. Taken together, our results indicated that WPMY-1-exo modulated the phenotypes changes and collagen deposition of prostate epithelial cells. It provided a novel basis for understanding the underlying mechanisms of RWPE-1 cells EMT and fibrosis induced by WPMY-1 in BPH.
Collapse
|
|
32
|
Khan AQ, Akhtar S, Prabhu KS, Zarif L, Khan R, Alam M, Buddenkotte J, Ahmad A, Steinhoff M, Uddin S. Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases. Int J Mol Sci 2020; 21:9264. [PMID: 33291683 PMCID: PMC7730213 DOI: 10.3390/ijms21239264] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.
Collapse
Affiliation(s)
- Abdul Q. Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
| | - Sabah Akhtar
- Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar; (S.A.); (L.Z.)
| | - Kirti S. Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
| | - Lubna Zarif
- Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar; (S.A.); (L.Z.)
| | - Rehan Khan
- Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Phase 10, Sector 64, Mohali, Punjab 160062, India;
| | - Majid Alam
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Joerg Buddenkotte
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| | - Aamir Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar
- Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
- College of Medicine, Qatar University, Doha 2713, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (A.Q.K.); (K.S.P.); (M.A.); (J.B.)
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
| |
Collapse
|
|
33
|
Wong PM, Yang L, Yang L, Wu H, Li W, Ma X, Katayama I, Zhang H. New insight into the role of exosomes in vitiligo. Autoimmun Rev 2020; 19:102664. [DOI: 10.1016/j.autrev.2020.102664] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023]
|
|
34
|
The Phosphodiesterase Type 5 Inhibitor Sildenafil Improves DNA Stability and Redox Homeostasis in Systemic Sclerosis Fibroblasts Exposed to Reactive Oxygen Species. Antioxidants (Basel) 2020; 9:antiox9090786. [PMID: 32854347 PMCID: PMC7555932 DOI: 10.3390/antiox9090786] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Systemic sclerosis (SSc) is a multi-system connective tissue disease characterized by the increased deposition of extracellular matrix proteins such as collagen and fibronectin. Although the pathogenesis is not completely understood, a number of studies suggest that free radicals could be the major contributors to the disease. Indeed, different studies demonstrated how oxidative stress could contribute to the fibrotic process activation at the level of the skin and visceral organs. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), which protects different cell lines from the cell damage induced by reactive oxygen species (ROS). These data make sildenafil a good candidate for therapeutic treatment aimed to protect biological macromolecules against oxidative damage, thus preserving cell viability. The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to prevent/reduce the DNA damage due to ROS action. Additionally, we evaluated the capacity for sildenafil to influence redox homeostasis and cytotoxicity, as well as cell proliferation and cell cycle progression. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment reduced ROS-induced DNA damage, counteracted the negative effects of ROS on cell viability and proliferation, and promoted the activity of specific enzymes involved in redox homeostasis maintenance. To our knowledge, in this report, we demonstrate, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results expand the use of PDE5i as therapeutic agents in SSc by indicating a protective role in tissue damage induced by oxidative insult.
Collapse
|
|
35
|
Wermuth PJ, Jimenez SA. Molecular characteristics and functional differences of anti-PM/Scl autoantibodies and two other distinct and unique supramolecular structures known as "EXOSOMES". Autoimmun Rev 2020; 19:102644. [PMID: 32801042 DOI: 10.1016/j.autrev.2020.102644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
The term "exosome" has been applied to three distinct supramolecular entities, namely the PM/Scl autoantibodies or "RNA exosomes", transforming DNA fragments termed "DNA exosomes", and small size extracellular vesicles knows as "exosomes". Some of the molecular components of the "PM/Scl exosome complex" or "RNA exosome" are recognized by specific autoantibodies present in the serum from some Systemic Sclerosis (SSc), polymyositis (PM) and polymyositis SSc (PM/Scl) overlap syndrome patients. On the other hand, one of the most active focuses of laboratory investigation in the last decade has been the biogenesis and role of extracellular vesicles known as "exosomes". The remarkable ability of these "exosome" vesicles to alter the cellular phenotype following fusion with target cells and the release of their macromolecular cargo has revealed a possible role in the pathogenesis of numerous diseases, including malignant, inflammatory, and autoimmune disorders and may allow them to serve as theranostic agents for personalized and precision medicine. The indiscriminate use of the term "exosome" to refer to these three distinct molecular entities has engendered great confusion in the scientific literature. Here, we review the molecular characteristics and functional differences between the three molecular structures identified as "exosomes". Given the rapidly growing scientific interest in extravesicular exosomes, unless a solution is found the confusion in the literature resulting from the use of the term "exosomes" will markedly increase.
Collapse
Affiliation(s)
- Peter J Wermuth
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Sergio A Jimenez
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| |
Collapse
|
|
36
|
Jiang M, Fang H, Dang E, Zhang J, Qiao P, Yu C, Yang A, Wang G. Small Extracellular Vesicles Containing miR-381-3p from Keratinocytes Promote T Helper Type 1 and T Helper Type 17 Polarization in Psoriasis. J Invest Dermatol 2020; 141:563-574. [PMID: 32712160 DOI: 10.1016/j.jid.2020.07.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/01/2020] [Accepted: 07/05/2020] [Indexed: 02/08/2023]
Abstract
T helper cells are crucial for psoriasis pathogenesis. Communication between T cells and psoriatic keratinocytes (KCs) helps drive the Th1 and Th17 response, but the underlying mechanism is not well-understood. Small extracellular vesicles (sEVs) are emerging mediators of intercellular communication. Here, we investigated the role of KC-derived sEVs in the Th1 and Th17 response in psoriasis. We isolated and characterized sEVs from KCs under normal (untreated) and psoriatic (cytokine-treated) conditions. sEVs under both conditions exhibited a cup-shaped morphology and expressed markers CD63 and CD81. sEVs from cytokine-treated KCs can be taken up by CD4+T cells, leading to the induction of Th1 and Th17 polarization. Small RNA sequencing revealed that miR-381-3p was significantly increased in sEVs from cytokine-treated KCs and in CD4+T cells from patients with psoriasis. Moreover, sEVs-containing miR-381-3p was responsible for sEVs-induced Th1 and Th17 polarization. We further found that the miR-381-3p targeted to the 3' untranslated region of E3 ubiquitin-ligase UBR5 and stabilized RORγt protein expression. It also targeted to the 3' untranslated region of FOXO1, associated with activated T-bet and RORγt transcription. Taken together, we propose that psoriatic KCs transfer miR-381-3p to CD4+T cells through sEVs, inducing Th1 and Th17 polarization and promoting psoriasis development. Our findings motivate future studies of KC-derived sEVs or their specific cargoes as therapeutic candidates for psoriasis.
Collapse
Affiliation(s)
- Man Jiang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Hui Fang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Erle Dang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jieyu Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Pei Qiao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chen Yu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Angang Yang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China; The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| |
Collapse
|
|
37
|
Feng D, Gerarduzzi C. Emerging Roles of Matricellular Proteins in Systemic Sclerosis. Int J Mol Sci 2020; 21:E4776. [PMID: 32640520 PMCID: PMC7369781 DOI: 10.3390/ijms21134776] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors. Accordingly, MCPs have been described in the context of fibrosis in sclerosis (SSc) as predictive disease biomarkers and regulators of ECM synthesis, with promising therapeutic potential. In this present review, an informative summary of major MCPs is presented highlighting their clear correlations to SSc- fibrosis.
Collapse
Affiliation(s)
- Daniel Feng
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
- Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l’Université de Montréal, Montréal, QC H1T 2M4, Canada
| | - Casimiro Gerarduzzi
- Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
- Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Faculté de Médecine, Centre affilié à l’Université de Montréal, Montréal, QC H1T 2M4, Canada
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada
| |
Collapse
|
|
38
|
Liu CS, Schmezer P, Popanda O. Diacylglycerol Kinase Alpha in Radiation-Induced Fibrosis: Potential as a Predictive Marker or Therapeutic Target. Front Oncol 2020; 10:737. [PMID: 32477950 PMCID: PMC7235333 DOI: 10.3389/fonc.2020.00737] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022] Open
Abstract
Radiotherapy is an efficient tool in cancer treatment, but it brings along the risk of side effects such as fibrosis in the irradiated healthy tissue thus limiting tumor control and impairing quality of life of cancer survivors. Knowledge on radiation-related fibrosis risk and therapeutic options is still limited and requires further research. Recent studies demonstrated that epigenetic regulation of diacylglycerol kinase alpha (DGKA) is associated with radiation-induced fibrosis. However, the specific mechanisms are still unknown. In this review, we scrutinized the role of DGKA in the radiation response and in further cellular functions to show the potential of DGKA as a predictive marker or a novel target in fibrosis treatment. DGKA was reported to participate in immune response, lipid signaling, exosome production, and migration as well as cell proliferation, all processes which are suggested to be critical steps in fibrogenesis. Most of these functions are based on the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) at plasma membranes, but DGKA might have also other, yet not well-known functions in the nucleus. Current evidence summarized here underlines that DGKA activation may play a central role in fibrosis formation post-irradiation and shows a potential of direct DGKA inhibitors or epigenetic modulators to attenuate pro-fibrotic reactions, thus providing novel therapeutic choices.
Collapse
Affiliation(s)
- Chun-Shan Liu
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schmezer
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Odilia Popanda
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
39
|
Tsai CY, Hsieh SC, Wu TH, Li KJ, Shen CY, Liao HT, Wu CH, Kuo YM, Lu CS, Yu CL. Pathogenic Roles of Autoantibodies and Aberrant Epigenetic Regulation of Immune and Connective Tissue Cells in the Tissue Fibrosis of Patients with Systemic Sclerosis. Int J Mol Sci 2020; 21:ijms21093069. [PMID: 32349208 PMCID: PMC7246753 DOI: 10.3390/ijms21093069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/19/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022] Open
Abstract
Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-β, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-β receptors on MFB, the downstream Wnt/β-catenin triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested.
Collapse
Affiliation(s)
- Chang-Youh Tsai
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan;
- Correspondence: (C.-Y.T.); (C.-L.Y.); Fax: +886-2-28717483 (C.-Y.T.); +886-2-23957801 (C.-L.Y.)
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
| | - Tsai-Hung Wu
- Division of Nephrology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan;
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
| | - Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Hsien-Tzung Liao
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan;
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Cheng-Shiun Lu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan; (S.-C.H.); (K.-J.L.); (C.-Y.S.); (C.-H.W.); (Y.-M.K.); (C.-S.L.)
- Correspondence: (C.-Y.T.); (C.-L.Y.); Fax: +886-2-28717483 (C.-Y.T.); +886-2-23957801 (C.-L.Y.)
| |
Collapse
|
|
40
|
Inducible Polarized Secretion of Exosomes in T and B Lymphocytes. Int J Mol Sci 2020; 21:ijms21072631. [PMID: 32290050 PMCID: PMC7177964 DOI: 10.3390/ijms21072631] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/19/2022] Open
Abstract
Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and a limited number of cell surface receptors. Among these, exosome secretion is induced in T lymphocytes and B lymphocytes when stimulated at the immune synapse (IS) via T-cell receptors (TCR) and B-cell receptors (BCR), respectively. IS formation by T and B lymphocytes constitutes a crucial event involved in antigen-specific, cellular, and humoral immune responses. Upon IS formation by T and B lymphocytes with antigen-presenting cells (APC), the convergence of MVB towards the microtubule organization center (MTOC), and MTOC polarization to the IS, are involved in polarized exosome secretion at the synaptic cleft. This specialized mechanism provides the immune system with a finely-tuned strategy to increase the specificity and efficiency of crucial secretory effector functions of B and T lymphocytes. As inducible exosome secretion by antigen-receptors is a critical and unique feature of the immune system this review considers the study of the traffic events leading to polarized exosome secretion at the IS and some of their biological consequences.
Collapse
|