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Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
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MESH Headings
- Humans
- Liver Cirrhosis/genetics
- Liver Cirrhosis/pathology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/virology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Epigenesis, Genetic
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/pathology
- Hepatitis B virus/genetics
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- Animals
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
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Wysoczańska B, Dratwa M, Nieszporek A, Niepiekło-Miniewska W, Kamińska D, Ramuś T, Rasała J, Krajewska M, Bogunia-Kubik K. Analysis of IL-17A, IL-17F, and miR-146a-5p Prior to Transplantation and Their Role in Kidney Transplant Recipients. J Clin Med 2024; 13:2920. [PMID: 38792460 PMCID: PMC11122464 DOI: 10.3390/jcm13102920] [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: 04/04/2024] [Revised: 04/29/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Background/Objectives: The balance between regulatory and Th17 cells plays an important role in maintaining the immune tolerance after kidney transplantation (KTx) which is essential for transplantation success, defined as a long graft survival and an absence of organ rejection. The present study aimed to assess whether the pretransplant characteristics of IL-17A and IL-17F, their receptors, as well as miR-146a-5p, an miRNA associated with IL-17A/F regulation, can predict KTx outcomes. Methods: A group of 108 pre-KTx dialysis patients and 125 healthy controls were investigated for single nucleotide substitutions within genes coding for IL-17A, IL-17F, their IL-17RA/RC receptors, and miR-146a-5p. Genotyping was performed using LightSNiP assays. In addition, IL17-A/F serum concentrations were determined using ELISA while miR-146a-5p expression was analyzed by RT-PCR. Results: The IL-17F (rs763780) G allele prevailed in KTx recipients as compared to healthy individuals (OR = 23.59, p < 0.0001) and was associated with a higher IL-17F serum level (p = 0.0381) prior to transplantation. Higher miR-146a-5p expression before KTx was more frequently detected in recipients with an increased IL-17A serum concentration (p = 0.0177). Moreover, IL-17A (rs2275913) GG homozygosity was found to be associated with an increased incidence of deaths before KTx (OR = 4.17, p = 0.0307). T-cell or acute rejection episodes were more frequently observed among patients with the C allele of miR-146a-5p (rs2910164) (OR = 5.38, p = 0.0531). IL17-RA/-RC genetic variants (p < 0.05) seem to be associated with eGFR values. Conclusions: These results imply that IL-17F (rs763780) polymorphism is associated with the serum level of this cytokine and may be related to the risk of renal disease and transplant rejection together with miR-146a-5p (rs2910164), while the IL-17A (rs2275913) genotype may affect patients' survival before KTx.
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Affiliation(s)
- Barbara Wysoczańska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
| | - Marta Dratwa
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
| | - Artur Nieszporek
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
- Biobank Research Group, Lukasiewicz Research Network—PORT Polish Center for Technology Development, 54-066 Wroclaw, Poland
| | - Wanda Niepiekło-Miniewska
- Laboratory of Tissue Immunology, Medical Center, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
| | - Dorota Kamińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (D.K.); (M.K.)
| | - Tomasz Ramuś
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | | | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (D.K.); (M.K.)
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
- Laboratory of Tissue Immunology, Medical Center, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
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Zhang Y, Zuo C, Li Y, Liu L, Yang B, Xia J, Cui J, Xu K, Wu X, Gong W, Liu Y. Single-cell characterization of infiltrating T cells identifies novel targets for gallbladder cancer immunotherapy. Cancer Lett 2024; 586:216675. [PMID: 38280478 DOI: 10.1016/j.canlet.2024.216675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024]
Abstract
Gallbladder cancer (GBC) is among the most common malignancies of biliary tract system due to its limited treatments. The immunotherapeutic targets for T cells are appealing, however, heterogeneity of T cells hinds its further development. We systematically construct T cell atlas by single-cell RNA sequencing; and utilized the identified gene signatures of high_CNV_T cells to predict molecular subtyping towards personalized therapeutic treatments for GBC. We identified 12 T cell subtypes, where exhausted CD8+ T cells, activated/exhausted CD8+ T cells, and regulatory T cells were predominant in tumors. There appeared to be an inverse relationship between Th17 and Treg populations with Th17 levels significantly reduced, whereas Tregs were concomitantly increased. Furthermore, we first established subtyping criterion to identify three subtypes of GBC based on their pro-tumorigenic microenvironments, e.g., the type 1 group shows more M2 macrophages infiltration, while the type 2 group is infiltrated by highly exhausted CD8+ T cells, B cells and Tregs with suppressive activities. Our study provides valuable insights into T cell heterogeneity and suggests that molecular subtyping based on T cells might provide a potential immunotherapeutic strategy to improve GBC treatment.
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Affiliation(s)
- Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Chunman Zuo
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China; Key Laboratory of Symbolic Computation and knowledge Engineering of Ministry of Education, Jilin University, Changchun, 130022, China.
| | - Yang Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Liguo Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Bo Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China
| | - Junjie Xia
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China
| | - Jiangnan Cui
- Institute of Artificial Intelligence, Donghua University, Shanghai, 201620, China
| | - Keren Xu
- CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xiangsong Wu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai, 200127, China; Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China.
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Gupta S, Parveen S. Potential role of microRNAs in personalized medicine against hepatitis: a futuristic approach. Arch Virol 2024; 169:33. [PMID: 38245876 DOI: 10.1007/s00705-023-05955-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/21/2023] [Indexed: 01/23/2024]
Abstract
MicroRNAs (miRNAs) have been the subject of extensive research for many years, primarily in the context of diseases such as cancer. However, our appreciation of their significance in viral infections, particularly in hepatitis, has increased due to the discovery of their association with both the host and the virus. Hepatitis is a major global health concern and can be caused by various viruses, including hepatitis A to E. This review highlights the key factors associated with miRNAs and their involvement in infections with various viruses that cause hepatitis. The review not only emphasizes the expression profiles of miRNAs in hepatitis but also puts a spotlight on their potential for diagnostics and therapeutic interventions. Ongoing extensive studies are propelling the therapeutic application of miRNAs, addressing both current limitations and potential strategies for the future of miRNAs in personalized medicine. Here, we discuss the potential of miRNAs to influence future medical research and an attempt to provide a thorough understanding of their diverse roles in hepatitis and beyond.
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Affiliation(s)
- Sonam Gupta
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Shama Parveen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
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Kim KU, Han K, Kim J, Kwon DH, Ji YW, Yi DY, Min H. The Protective Role of Exosome-Derived MicroRNAs and Proteins from Human Breast Milk against Infectious Agents. Metabolites 2023; 13:metabo13050635. [PMID: 37233676 DOI: 10.3390/metabo13050635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023] Open
Abstract
Human breast milk (HBM)-derived exosomes contain various biological and immunological components. However, comprehensive immune-related and antimicrobial factor analysis requires transcriptomic, proteomic, and multiple databases for functional analyses, and has yet to be conducted. Therefore, we isolated and confirmed HBM-derived exosomes by detecting specific markers and examining their morphology using western blot and transmission electron microscopy. Moreover, we implemented small RNA sequencing and liquid chromatography-mass spectrometry to investigate substances within the HBM-derived exosomes and their roles in combating pathogenic effects, identifying 208 miRNAs and 377 proteins associated with immunological pathways and diseases. Integrated omics analyses identified a connection between the exosomal substances and microbial infections. In addition, gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses demonstrated that HBM-derived exosomal miRNA and proteins influence immune-related functions and pathogenic infections. Finally, protein-protein interaction analysis identified three primary proteins (ICAM1, TLR2, and FN1) associated with microbial infections mediating pro-inflammation, controlling infection, and facilitating microbial elimination. Our findings determine that HBM-derived exosomes modulate the immune system and could offer therapeutic strategies for regulating pathogenic microbial infection.
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Affiliation(s)
- Ki-Uk Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Kyusun Han
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jisu Kim
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Da Hyeon Kwon
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yong Woo Ji
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Department of Ophthalmology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin 16995, Republic of Korea
| | - Dae Yong Yi
- Department of Pediatrics, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea
| | - Hyeyoung Min
- College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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Reddy-Vari H, Kim Y, Rajput C, Sajjan US. Increased expression of miR146a dysregulates TLR2-induced HBD2 in airway epithelial cells from patients with COPD. ERJ Open Res 2023; 9:00694-2022. [PMID: 37228294 PMCID: PMC10204848 DOI: 10.1183/23120541.00694-2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/23/2023] [Indexed: 05/27/2023] Open
Abstract
Background Airway epithelial cells from patients with COPD show suboptimal innate immune responses to nontypeable Haemophilus influenzae (NTHi) and Toll-like receptor (TLR)2 ligands despite expressing TLR2 similar to normal airway epithelial cells, but the underlying mechanisms are poorly understood. Methods Normal or COPD mucociliary-differentiated airway epithelial cells were treated with TLR2 agonists or infected with NTHi and expression of β-defensin (HBD)2 was examined. Interleukin-1 receptor-associated kinase (IRAK)-1 and microRNA (miR)146a were genetically inhibited in normal and COPD airway epithelial cell cultures, respectively, and HBD2 responses to TLR2 ligands were determined. IRAK-1 expression in lung sections was determined by immunofluorescence microscopy. Results Compared to normal, COPD airway epithelial cell cultures showed impaired expression of HBD2 in response to TLR2 agonists or NTHi infection. Apical secretions from TLR2 agonist-treated normal, but not COPD, airway epithelial cells efficiently killed NTHi. Knockdown of HBD2 significantly reduced NTHi killing by apical secretions of normal airway epithelial cells. Compared to normal, COPD cells showed significantly reduced expression of IRAK-1 and this was associated with increased expression of miR146a. Inhibition of miR146a increased the expression of IRAK-1, improved the expression of HBD2 in response to TLR2 agonists in COPD cells and enhanced the killing of bacteria by apical secretions obtained from TLR2 agonist-treated COPD cells. Bronchial epithelium of COPD patients showed reduced expression of IRAK-1. Conclusions These results suggest that reduced levels of IRAK-1 due to increased expression of miR146a may contribute to impaired expression of TLR2-induced HBD2 in COPD airway epithelial cells.
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Affiliation(s)
- Hymavathi Reddy-Vari
- Department of Microbiology Immunology and Inflammation, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
| | - Yerin Kim
- Department of Microbiology Immunology and Inflammation, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
| | - Charu Rajput
- Department of Microbiology Immunology and Inflammation, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
| | - Umadevi S. Sajjan
- Department of Microbiology Immunology and Inflammation, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
- Department of Thoracic Surgery and Medicine, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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Novel roles of LSECtin in gastric cancer cell adhesion, migration, invasion, and lymphatic metastasis. Cell Death Dis 2022; 13:593. [PMID: 35821222 PMCID: PMC9276708 DOI: 10.1038/s41419-022-05026-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/01/2022] [Accepted: 06/15/2022] [Indexed: 01/21/2023]
Abstract
Liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin) plays an important regulatory role in a variety of diseases, including tumors. However, the underlying mechanism of LSECtin in gastric cancer (GC) remains largely unknown. In our research, LSECtin promoted the adhesion and invasion of GC cells, and was involved in lymphatic metastasis of GC cells. Mechanistically, LSECtin promoted the adhesion, proliferation and migration of GC cells by downregulating STAT1 expression. The circular RNA circFBXL4, which is regulated by LSECtin, sponges the microRNA miR-146a-5p to regulate STAT1 expression. The promotion of GC cell proliferation, migration and invasion mediated by LSECtin was largely inhibited by circFBXL4 overexpression or miR-146a-5p silencing. Moreover, in its role as a transcription factor, STAT1 modulated the expression of FN1 and CHD4. In conclusion, LSECtin might be involved in the lymphatic metastasis of GC by upregulating the expression of FN1 and CHD4 via the circFBXL4/miR-146a-5p/STAT1 axis, possibly indicating a newly discovered pathogenic mechanism.
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Liu Y, Qin L, Wang J, Xie X, Zhang Y, Li C, Guan Z, Qian L, Chen L, Hu J, Meng S. miR-146a Maintains Immune Tolerance of Kupffer Cells and Facilitates Hepatitis B Virus Persistence in Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2558-2572. [PMID: 35562117 DOI: 10.4049/jimmunol.2100618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 03/23/2022] [Indexed: 06/15/2023]
Abstract
Kupffer cells (KCs), the largest tissue-resident macrophage population in the body, play a central role in maintaining a delicate balance between immune tolerance and immunity in the liver. However, the underlying molecular mechanism remains elusive. In this study, we show that KCs express high levels of miR-146a, which is under control of the PU.1 transcription factor. miR-146a deficiency promoted KCs differentiation toward a proinflammatory phenotype; conversely, miR-146a overexpression suppressed this phenotypic differentiation. We found that hepatitis B virus (HBV) persistence or HBV surface Ag treatment significantly upregulated miR-146a expression and thereby impaired polarization of KCs toward a proinflammatory phenotype. Furthermore, in an HBV carrier mouse model, KCs depletion by clodronate liposomes dramatically promoted HBV clearance and enhanced an HBV-specific hepatic CD8+ T cell and CD4+ T cell response. Consistent with this finding, miR-146a knockout mice cleared HBV faster and elicited a stronger adaptive antiviral immunity than wild-type mice. In vivo IL-12 blockade promoted HBV persistence and tempered the HBV-specific CTL response in the liver of miR-146a knockout mice. Taken together, our results identified miR-146a as a critical intrinsic regulator of an immunosuppressive phenotype in KCs under inflammatory stimuli, which may be beneficial in maintenance of liver homeostasis under physiological condition. Meanwhile, during HBV infection, miR-146a contributed to viral persistence by inhibiting KCs proinflammatory polarization, highlighting its potential as a therapeutic target in HBV infection.
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Affiliation(s)
- Yongai Liu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Lijuan Qin
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jiuru Wang
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xialin Xie
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu Zhang
- Department of Pathology and Hepatology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China; and
| | - Changfei Li
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zeliang Guan
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liyuan Qian
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China
| | - Lizhao Chen
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jun Hu
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;
| | - Songdong Meng
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;
- University of Chinese Academy of Sciences, Beijing, China
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Carvalho-Silva AC, Da Silva Junior AR, Rigaud VOC, Martins WK, Coelho V, Pfrimer IAH, Kalil J, Fonseca SG, Cunha-Neto E, Ferreira LRP. A Major Downregulation of Circulating microRNAs in Zika Acutely Infected Patients: Potential Implications in Innate and Adaptive Immune Response Signaling Pathways. Front Genet 2022; 13:857728. [PMID: 35719399 PMCID: PMC9199004 DOI: 10.3389/fgene.2022.857728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/18/2022] [Indexed: 11/29/2022] Open
Abstract
Zika virus (ZIKV) is an arbovirus mainly transmitted by mosquitos of the genus Aedes. The first cases of ZIKV infection in South America occurred in Brazil in 2015. The infection in humans causes diverse symptoms from asymptomatic to a syndrome-like dengue infection with fever, arthralgia, and myalgia. Furthermore, ZIKV infection during pregnancy is associated with fetal microcephaly and neurological disorders. The identification of host molecular mechanisms responsible for the modulation of different signaling pathways in response to ZIKV is the first step to finding potential biomarkers and therapeutic targets and understanding disease outcomes. In the last decade, it has been shown that microRNAs (miRNAs) are important post-transcriptional regulators involved in virtually all cellular processes. miRNAs present in body fluids can not only serve as key biomarkers for diagnostics and prognosis of human disorders but also contribute to cellular signaling offering new insights into pathological mechanisms. Here, we describe for the first time ZIKV-induced changes in miRNA plasma levels in patients during the acute and recovery phases of infection. We observed that during ZIKV acute infection, among the dysregulated miRNAs (DMs), the majority is with decreased levels when compared to convalescent and control patients. We used systems biology tools to build and highlight biological interactions between miRNAs and their multiple direct and indirect target molecules. Among the 24 DMs identified in ZIKV + patients, miR-146, miR-125a-5p, miR-30-5p, and miR-142-3p were related to signaling pathways modulated during infection and immune response. The results presented here are an effort to open new vistas for the key roles of miRNAs during ZIKV infection.
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Affiliation(s)
- Ana Carolina Carvalho-Silva
- RNA Systems Biology Laboratory (RSBL), Departmento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Programa de Pós-Graduação em Biologia Celular, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Almir Ribeiro Da Silva Junior
- Laboratory of Immunology, Heart Institute (InCor) School of Medicine, University of São Paulo, São Paulo, Brazil
- Institute for Investigation in Immunology, iii-INCT (National Institute of Science and Technology), São Paulo, Brazil
- Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Waleska Kerllen Martins
- Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
- Universidade Anhanguera, São Paulo, Brazil
| | - Verônica Coelho
- Laboratory of Immunology, Heart Institute (InCor) School of Medicine, University of São Paulo, São Paulo, Brazil
- Institute for Investigation in Immunology, iii-INCT (National Institute of Science and Technology), São Paulo, Brazil
- Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Jorge Kalil
- Laboratory of Immunology, Heart Institute (InCor) School of Medicine, University of São Paulo, São Paulo, Brazil
- Institute for Investigation in Immunology, iii-INCT (National Institute of Science and Technology), São Paulo, Brazil
- Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Simone Gonçalves Fonseca
- Institute for Investigation in Immunology, iii-INCT (National Institute of Science and Technology), São Paulo, Brazil
| | - Edecio Cunha-Neto
- Laboratory of Immunology, Heart Institute (InCor) School of Medicine, University of São Paulo, São Paulo, Brazil
- Institute for Investigation in Immunology, iii-INCT (National Institute of Science and Technology), São Paulo, Brazil
- Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Ludmila Rodrigues Pinto Ferreira
- National Institute of Science and Technology for Vaccines (INCTV), Belo Horizonte, Brazil
- Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Ludmila Rodrigues Pinto Ferreira,
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11
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Kim SJ, Russell AE, Wang W, Gemoets DE, Sarkar SN, Simpkins JW, Brown CM. miR-146a Dysregulates Energy Metabolism During Neuroinflammation. J Neuroimmune Pharmacol 2022; 17:228-241. [PMID: 34028667 PMCID: PMC8611101 DOI: 10.1007/s11481-021-09999-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/13/2021] [Indexed: 12/29/2022]
Abstract
Alzheimer's disease (AD) and other neurodegenerative diseases are characterized by chronic neuroinflammation and a reduction in brain energy metabolism. An important role has emerged for small, non-coding RNA molecules known as microRNAs (miRNAs) in the pathophysiology of many neurodegenerative disorders. As epigenetic regulators, miRNAs possess the capacity to regulate and fine tune protein production by inhibiting translation. Several miRNAs, which include miR-146a, are elevated in the brain, CSF, and plasma of AD patients. miR-146a participates in pathways that regulate immune activation and has several mRNA targets which encode for proteins involved in cellular energy metabolism. An additional role for extracellular vesicles (EVs) has also emerged in the progression AD, as EVs can transfer functionally active proteins and RNAs from diseased to healthy cells. In the current study, we exposed various cell types present within the CNS to immunomodulatory molecules and observed significant upregulation of miR-146a expression, both within cells and within their secreted EVs. Further, we assessed the effects of miR-146a overexpression on bioenergetic function in primary rat glial cells and found significant reductions in oxidative phosphorylation and glycolysis. Lastly, we correlated miR-146a expression levels within various regions of the AD brain to disease staging and found significant, positive correlations. These novel results demonstrate that the modulation of miR-146a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function in cells, thereby contributing to the progression of beta-amyloid and tau pathology in the AD brain. Multiple inflammatory stimuli can upregulate miRNA-146a expression within neurons, mixed glial cells, and brain endothelial cells, which is either retained within these cells or released from them as extracellular vesicle cargo. The upregulation of miR-146a disrupts cellular bioenergetics in mixed glial cells. This mechanism may play a critical role in the neuroinflammatory response observed during Alzheimer's disease.
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Affiliation(s)
- Sujung Jun Kim
- Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506
| | - Ashley E. Russell
- Department of Neuroscience and Center for Basic and Translational Stroke Research, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506,Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States, 26506
| | - Wei Wang
- Department of Neuroscience and Center for Basic and Translational Stroke Research, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506
| | - Darren E. Gemoets
- Department of Biostatistics, School of Public Health, West Virginia University, Morgantown, WV United States 26506
| | - Saumyendra N. Sarkar
- Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506
| | - James W. Simpkins
- Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506,Department of Neuroscience and Center for Basic and Translational Stroke Research, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506,Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States, 26506
| | - Candice M. Brown
- Department of Neuroscience and Center for Basic and Translational Stroke Research, School of Medicine, West Virginia University, Morgantown, WV, United States, 26506,Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States, 26506
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12
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Stelekati E, Cai Z, Manne S, Chen Z, Beltra JC, Buchness LA, Leng X, Ristin S, Nzingha K, Ekshyyan V, Niavi C, Abdel-Hakeem MS, Ali MA, Drury S, Lau CW, Gao Z, Ban Y, Zhou SK, Ansel KM, Kurachi M, Jordan MS, Villarino AV, Ngiow SF, Wherry EJ. MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection. Proc Natl Acad Sci U S A 2022; 119:e2106083119. [PMID: 35446623 PMCID: PMC9169946 DOI: 10.1073/pnas.2106083119] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 02/02/2022] [Indexed: 11/18/2022] Open
Abstract
CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.
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Affiliation(s)
- Erietta Stelekati
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Zhangying Cai
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Sasikanth Manne
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Zeyu Chen
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Jean-Christophe Beltra
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Lance Alec Buchness
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Xuebing Leng
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Svetlana Ristin
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Kito Nzingha
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Viktoriya Ekshyyan
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Christina Niavi
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Mohamed S. Abdel-Hakeem
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Mohammed-Alkhatim Ali
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Sydney Drury
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Chi Wai Lau
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Zhen Gao
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
- Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Yuguang Ban
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Simon K. Zhou
- Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143
- Department of Microbiology & Immunology, University of California, San Francisco, CA 94143
| | - K. Mark Ansel
- Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143
- Department of Microbiology & Immunology, University of California, San Francisco, CA 94143
| | - Makoto Kurachi
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Martha S. Jordan
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Alejandro V. Villarino
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - Shin Foong Ngiow
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - E. John Wherry
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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13
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Wang J, Du L, Tang H. Suppression of Interferon-α Treatment Response by Host Negative Factors in Hepatitis B Virus Infection. Front Med (Lausanne) 2021; 8:784172. [PMID: 34901094 PMCID: PMC8651562 DOI: 10.3389/fmed.2021.784172] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/03/2021] [Indexed: 02/05/2023] Open
Abstract
Chronic hepatitis B virus (CHB) infection remains a major global public health issue for which there is still lacking effective curative treatment. Interferon-α (IFN-α) and its pegylated form have been approved as an anti-HBV drug with the advantage of antiviral activity and host immunity against HBV infection enhancement, however, IFN-α treatment failure in CHB patients is a challenging obstacle with 70% of CHB patients respond poorly to exogenous IFN-α treatment. The IFN-α treatment response is negatively regulated by both viral and host factors, and the role of viral factors has been extensively illustrated, while much less attention has been paid to host negative factors. Here, we summarized evidence of host negative regulators and parameters involved in IFN-α therapy failure, review the mechanisms responsible for these effects, and discuss the possible improvement of IFN-based therapy and the rationale of combining the inhibitors of negative regulators in achieving an HBV cure.
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Affiliation(s)
- Jiayi Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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14
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Hefzy EM, Hassuna NA, Shaker OG, Masoud M, Abelhameed TA, Ahmed TI, Hemeda NF, Abdelhakeem MA, Mahmoud RH. miR-155 T/A (rs767649) and miR-146a A/G (rs57095329) single nucleotide polymorphisms as risk factors for chronic hepatitis B virus infection among Egyptian patients. PLoS One 2021; 16:e0256724. [PMID: 34437653 PMCID: PMC8389509 DOI: 10.1371/journal.pone.0256724] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Genetic variants in microRNAs (miRNAs) can alter the miRNAs expression and/or function, accordingly, affecting the related biological pathways and disease risk. Dysregulation of miR-155 and miR-146a expression levels has been well-described in viral hepatitis B (HBV). In the current study, we aimed to assess rs767649 T/A and rs57095329 A/G polymorphisms in miR-155, and miR-146a genes, respectively, as risk factors for Chronic HBV (CHBV) in the Egyptian population. Also, we aimed to do in silico analysis to investigate the molecules that primarily target these miRNAs. One hundred patients diagnosed as CHBV and one hundred age and sex-matched controls with evidence of past HBV infection were genotyped for miR-155 (rs767649) and miR-146a (rs57095329) using real-time polymerase chain reaction. The rs767649 AT and AA genotypes in CHBV patients confer four folds and ten folds risk respectively, as compared to control subjects [(AOR = 4.245 (95%CI 2.009–8.970), p<0.0001) and AOR = 10.583 (95%CI 4.012–27.919), p<0.0001, respectively)]. The rs767649 A allele was associated with an increased risk of developing CHBV (AOR = 2.777 (95%CI 1.847–4.175), p<0.0001). There was a significant difference in the frequency of rs57095329 AG and GG genotypes in CHBV patients compared to controls. AG and GG genotypes showed an increase in the risk of developing CHBV by about three and six folds respectively [AOR = 2.610 (95%CI 1.362–5.000), p = 0.004] and [AOR = 5.604 (95%CI 2.157–14.563), p<0.0001].We concluded that rs57095329 and rs767649 SNPs can act as potential risk factors for the development of CHBV in the Egyptian population.
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Affiliation(s)
- Enas M. Hefzy
- Faculty of Medicine, Department of Medical Microbiology and Immunology, Fayoum University, Fayoum, Egypt
- * E-mail:
| | - Noha A. Hassuna
- Faculty of Medicine, Department of Medical Microbiology and Immunology, Minia University, Minia, Egypt
| | - Olfat G. Shaker
- Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology, Cairo University, Cairo, Egypt
| | - Mohamed Masoud
- Faculty of Medicine, Department of Public Health, Fayoum University, Fayoum, Egypt
| | | | - Tarek I. Ahmed
- Faculty of Medicine, Department of Internal Medicine, Fayoum University, Fayoum, Egypt
| | - Nada F. Hemeda
- Faculty of Agriculture, Department of Genetics, Fayoum University, Fayoum, Egypt
| | | | - Rania H. Mahmoud
- Department of Medical Biochemistry and Molecular Biology, Fayoum University, Fayoum, Egypt
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15
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Pogue AI, Lukiw WJ. microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD). Int J Mol Sci 2021; 22:ijms22179198. [PMID: 34502105 PMCID: PMC8431499 DOI: 10.3390/ijms22179198] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer’s disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.
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Affiliation(s)
| | - Walter J. Lukiw
- LSU Neuroscience Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
- Department of Ophthalmology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
- Department of Neurology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
- Correspondence:
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16
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Zhu X, Guo Q, Zou J, Wang B, Zhang Z, Wei R, Zhao L, Zhang Y, Chu C, Fu X, Li X. MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway. Front Pharmacol 2021; 12:614044. [PMID: 34017248 PMCID: PMC8129022 DOI: 10.3389/fphar.2021.614044] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/22/2021] [Indexed: 12/24/2022] Open
Abstract
Macrophages, an important type of immune cells, are generally polarized to classically activated macrophage (M1) or alternatively activated macrophage (M2) to respond to environmental stimuli. Signal transducer and activator of transcription 1 (STAT1), a very important transcription factor, can promote M1 macrophage polarization. However, the mechanisms of regulating STAT1 in macrophage polarization remain unclear. In the present study, STAT1 was markedly elevated, however, miR-19a-3p was down-regulated in interferon (IFN)-γ and lipopolysaccharide (LPS) treated RAW264.7 cells, and dual-luciferase reporter assay identified that miR-19a-3p directly targeted STAT1 by binding to its 3′UTR. Up-regulated miR-19a-3p inhibited M1 polarization by targeting STAT1/interferon regulatory factor 1 (IRF1) and vice versa in vitro. Consistently, overexpression of miR-19a-3p in LPS treated mice by systemically administering agomiR-19a-3p effectively reduced the inflammation in mouse lung tissues, and inhibited M1 macrophage polarization via suppressing STAT1/IRF1 pathway. In summary, our study confirmed that miR-19a-3p, as a direct regulator of STAT1, inhibited M1 macrophages polarization. The miR-19a-3p/STAT1/IRF1 pathway can potentially be used to design novel immunotherapy for modulating macrophage polarization.
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Affiliation(s)
- Xiaoxiao Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Qiang Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jing Zou
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bin Wang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Ran Wei
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Lin Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Yunhong Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chu Chu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Xiaoxiao Fu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Xia Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Key Laboratory of Laparoscopic Technology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
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17
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van Nguyen D, Chu HC, Vidal C, Anderson J, Nguyen NN, Quynh Do NT, Tran TL, Nguyen TN, Thu Nguyen HT, Fulton RB, van Nunen S, Fernando S. Gene expression profiling in allopurinol-induced severe cutaneous adverse reactions in Vietnamese. Pharmacogenomics 2020; 21:985-994. [PMID: 32896208 DOI: 10.2217/pgs-2020-0014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To examine gene expression in different clinical phenotypes of allopurinol-induced severe cutaneous adverse reactions (SCARs). Materials & methods: Gene expression profiling was performed using microarray on 11 RNA samples (four controls, three hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms, four Stevens-Johnson syndrome/toxic epidermal necrolysis) followed by quantitative real-time PCR in a total of 11 SCARs patients and 11 controls. Results: The biological pathways which were significantly enriched in differentially expressed genes in Stevens-Johnson syndrome/toxic epidermal necrolysis compared with hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms patients included; cell surface interactions at the vascular wall, immunoregulatory interactions at the immunological synapse and MyD88 signaling pathways. Overexpression of miR146a occurred in allopurinol-tolerant HLA-B*58:01 carriers. Conclusion: Biological pathways are identified which appear to be implicated in determining clinical phenotypes in allopurinol-induced SCARs. Overexpression of miR146a is potentially important for allopurinol tolerance in HLA-B*58:01 carriers.
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Affiliation(s)
- Dinh van Nguyen
- Vinmec Healthcare System, Hanoi, 10000, Vietnam.,College of Health Science, VinUniversity, Hanoi, 10000, Vietnam.,Sydney Medical School-Northern, The University of Sydney, Sydney, 2006, Australia.,ImmunoRheumatology Laboratory, NSW Health Pathology-North, Royal North Shore Hospital, St Leonards, 2065, Australia
| | - Hieu Chi Chu
- Center of Allergology & Clinical Immunology, Bach Mai Hospital, Hanoi, 10000, Vietnam
| | - Christopher Vidal
- Sydney Medical School-Northern, The University of Sydney, Sydney, 2006, Australia
| | - Janet Anderson
- ImmunoRheumatology Laboratory, NSW Health Pathology-North, Royal North Shore Hospital, St Leonards, 2065, Australia
| | - Nguyet Nhu Nguyen
- Center of Allergology & Clinical Immunology, Bach Mai Hospital, Hanoi, 10000, Vietnam
| | - Nga Thi Quynh Do
- Department of Immunology & Molecular Biology, National Institute of Hygiene & Epidemiology, Hanoi, 100000, Vietnam
| | | | | | - Ha Thi Thu Nguyen
- Department of Allergy & Clinical Immunology, Hanoi Medical University, Hanoi, 116001, Vietnam
| | - Richard B Fulton
- ImmunoRheumatology Laboratory, NSW Health Pathology-North, Royal North Shore Hospital, St Leonards, 2065, Australia
| | - Sheryl van Nunen
- Sydney Medical School-Northern, The University of Sydney, Sydney, 2006, Australia.,Department of Clinical Immunology & Allergy, Royal North Shore Hospital, Sydney, 2065, Australia
| | - Suran Fernando
- Sydney Medical School-Northern, The University of Sydney, Sydney, 2006, Australia.,ImmunoRheumatology Laboratory, NSW Health Pathology-North, Royal North Shore Hospital, St Leonards, 2065, Australia.,Department of Clinical Immunology & Allergy, Royal North Shore Hospital, Sydney, 2065, Australia
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18
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Mortazavi-Jahromi SS, Aslani M, Mirshafiey A. A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases. Immunol Lett 2020; 227:8-27. [PMID: 32810557 DOI: 10.1016/j.imlet.2020.07.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/10/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases. Its deregulated expression pattern and inefficient function have been reported in a wide spectrum of these illnesses. Based on the existing evidence, this miRNA qualifies as an ideal biomarker for diagnosis, prognosis, and activity evaluation of immune and non-immune inflammatory disorders. Moreover, much attention has recently been paid to therapeutic potential of miR-146a and several researchers have assessed the effects of different drugs on expression and function of this miRNA at diverse experimental, animal, besides human levels, reporting motivating results in the treatment of the diseases. Here, in this comprehensive review, we provide an overview of miR-146a role in the pathogenesis and progression of several immune and non-immune inflammatory diseases such as Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Multiple sclerosis, Psoriasis, Graves' disease, Atherosclerosis, Hepatitis, Chronic obstructive pulmonary disease, etc., discuss about its eligibility for being a desirable biomarker for these disorders, and also highlight its therapeutic potential. Understanding these mechanisms underlies the selecting and designing the proper therapeutic targets and medications, which eventually facilitate the treatment process.
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Affiliation(s)
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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19
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Ji M, Mei X, Jing X, Xu X, Chen X, Pan W. The cooperative complex of Argonaute-2 and microRNA-146a regulates hepatitis B virus replication through flap endonuclease 1. Life Sci 2020; 257:118089. [PMID: 32659369 DOI: 10.1016/j.lfs.2020.118089] [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: 03/19/2020] [Revised: 06/18/2020] [Accepted: 07/08/2020] [Indexed: 02/08/2023]
Abstract
AIM Hepatitis B virus (HBV) is a major cause of a variety of liver diseases. Existing antiviral drugs cannot eradicate HBV from our body, and the main reason is unclear on the molecular mechanism of HBV replication. Flap endonuclease 1 (FEN1) can repair relaxed circular DNA (HBV rcDNA) to covalently closed circular DNA (HBV cccDNA) that promotes HBV DNA replication, while its specific regulatory detail remains unclear. In addition, miR-146a is close related to regulation in HBV replication. This study aims to explore whether miR-146a regulates HBV cccDNA formation through FEN1. MAIN METHODS We investigated the expression of miR-146a, FEN1 and HBV copies in HBV stable replication cell line HepG2.2.15 and its parent cell line HepG2 transfected miR-146a and FEN1 plasmid by qRT-PCR and western blot, to identify the cooperation of Argonaute-2 (Ago2) and miR-146a by Ago2 siRNA and Ago2 RNA Binding Protein Immunoprecipitation (RIP). KEY FINDINGS Compared with the control group, we found that the expression of miR-146a was significantly up-regulated in HepG2.2.15, and the expression of FEN1 and HBV copies were also significantly up-regulated. On contrary, the expression of target gene of miR-146a, interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor-6 (TRAF6), was significantly decreased in HepG2.2.15. With the use of Ago2 siRNA and then Ago2 RIP, we found that Ago2 performed as a carrier for miR-146a to promote HBV replication. SIGNIFICANCE The results suggest a novel miR-146a → FEN1 → HBV DNA regulatory axis in HBV replication life. Ago2 cooperates with miR-146a to regulate the transcription and expression level of FEN1 protein through the downstream target gene IRAK1/TRAF6, and to promote HBV replication.
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Affiliation(s)
- Min Ji
- Experimental Teaching Center for Pathogen Biology and Immunology & Department of Microbiology and Immunology, North Sichuan Medical College, Nanchong 637000, China; Department of Infectious Diseases, Affiliated Hospital of North Sichuan Medical College, Nanchong 637100, China; People's Hospital of Jianyang, Chengdu, Sichuan 641400, China
| | - Xiaoping Mei
- Department of Infectious Diseases, Affiliated Hospital of North Sichuan Medical College, Nanchong 637100, China
| | - Xueming Jing
- Department of Infectious Diseases, Affiliated Hospital of North Sichuan Medical College, Nanchong 637100, China
| | - Xu Xu
- Experimental Teaching Center for Pathogen Biology and Immunology & Department of Microbiology and Immunology, North Sichuan Medical College, Nanchong 637000, China
| | - Xing Chen
- Department of Infectious Diseases, Affiliated Hospital of North Sichuan Medical College, Nanchong 637100, China
| | - Wanlong Pan
- Experimental Teaching Center for Pathogen Biology and Immunology & Department of Microbiology and Immunology, North Sichuan Medical College, Nanchong 637000, China.
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20
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Yuan C, Wang D, Zhang N, Wang Z, Yang F, He J, Sun R, Yang X, Hu J, Wu M. DNA damage/cGAS-triggered up-regulation of MALAT1 promotes undesirable inflammatory responses in radiotherapy of cancer. Biochem Biophys Res Commun 2020; 528:746-752. [PMID: 32532422 DOI: 10.1016/j.bbrc.2020.05.064] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 05/10/2020] [Indexed: 01/27/2023]
Abstract
Radiotherapy is the most common strategy for treating cancer. However, the radiation-induced inflammatory responses, acute or chronic, in the normal tissues of the irradiated region may result in undesirable side effects, such as lung injury and atherosclerosis. MALAT1 is believed to function in the onset, development, progression and metastasis of various cancers. Silencing MALAT1 may be a promising treatment for rescuing cancer. Nevertheless, whether MALAT1 promotes the radiation-induced undesirable inflammatory response is still uncovered. The present study reveals that radiation-induced DNA damage triggers cGAS signaling and subsequently increases the expression of MALAT1. Overexpression of MALAT1 inhibits the function of miR146a in the suppression of STAT1, which results in the boost of adhesion molecules and eventually induces acute lung injury and atherosclerosis. Thus, silencing MALAT1 may facilitate the reduction of radiation-induced acute and chronic complications in the radiotherapy of cancer.
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Affiliation(s)
- Chuang Yuan
- Postdoctoral Research Station of Clinical Medicine & Department of Hematology, the 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China; Department of Critical Care Medicine & Infection Prevention and Control, The Second People's Hospital of Shenzhen & First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, 518035, PR China; Medical Research Center, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Di Wang
- Departments of Oncology and Radiotherapy, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Na Zhang
- Department of Pathology, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Zhigan Wang
- Department of Pathology, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Fanfan Yang
- Departments of Oncology and Radiotherapy, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Jun He
- Departments of Oncology and Radiotherapy, Changsha Central Hospital, Changsha, Hunan, 410004, PR China
| | - Ruili Sun
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, PR China
| | - Xinyu Yang
- Postdoctoral Research Station of Clinical Medicine & Department of Hematology, the 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital, Changsha, Hunan, 410004, PR China.
| | - Ming Wu
- Department of Critical Care Medicine & Infection Prevention and Control, The Second People's Hospital of Shenzhen & First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, 518035, PR China.
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21
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Wong RR, Abd-Aziz N, Affendi S, Poh CL. Role of microRNAs in antiviral responses to dengue infection. J Biomed Sci 2020; 27:4. [PMID: 31898495 PMCID: PMC6941309 DOI: 10.1186/s12929-019-0614-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 12/29/2019] [Indexed: 12/13/2022] Open
Abstract
Dengue virus (DENV) is the etiological agent of dengue fever. Severe dengue could be fatal and there is currently no effective antiviral agent or vaccine. The only licensed vaccine, Dengvaxia, has low efficacy against serotypes 1 and 2. Cellular miRNAs are post-transcriptional regulators that could play a role in direct regulation of viral genes. Host miRNA expressions could either promote or repress viral replications. Induction of some cellular miRNAs could help the virus to evade the host immune response by suppressing the IFN-α/β signaling pathway while others could upregulate IFN-α/β production and inhibit the viral infection. Understanding miRNA expressions and functions during dengue infections would provide insights into the development of miRNA-based therapeutics which could be strategized to act either as miRNA antagonists or miRNA mimics. The known mechanisms of how miRNAs impact DENV replication are diverse. They could suppress DENV multiplication by directly binding to the viral genome, resulting in translational repression. Other miRNA actions include modulation of host factors. In addition, miRNAs that could modulate immunopathogenesis are discussed. Major hurdles lie in the development of chemical modifications and delivery systems for in vivo delivery. Nevertheless, advancement in miRNA formulations and delivery systems hold great promise for the therapeutic potential of miRNA-based therapy, as supported by Miravirsen for treatment of Hepatitis C infection which has successfully completed phase II clinical trial.
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Affiliation(s)
- Rui Rui Wong
- Centre for Virus and Vaccine Research (CVVR), Sunway University, 47500, Subang Jaya, Selangor, Malaysia
| | - Noraini Abd-Aziz
- Centre for Virus and Vaccine Research (CVVR), Sunway University, 47500, Subang Jaya, Selangor, Malaysia
| | - Sarah Affendi
- Centre for Virus and Vaccine Research (CVVR), Sunway University, 47500, Subang Jaya, Selangor, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research (CVVR), Sunway University, 47500, Subang Jaya, Selangor, Malaysia.
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22
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Rapani A, Nikiforaki D, Karagkouni D, Sfakianoudis K, Tsioulou P, Grigoriadis S, Maziotis E, Pantou A, Voutsina A, Pantou A, Koutsilieris M, Hatzigeorgiou A, Pantos K, Simopoulou M. Reporting on the Role of miRNAs and Affected Pathways on the Molecular Backbone of Ovarian Insufficiency: A Systematic Review and Critical Analysis Mapping of Future Research. Front Cell Dev Biol 2020; 8:590106. [PMID: 33511114 PMCID: PMC7835544 DOI: 10.3389/fcell.2020.590106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 11/30/2020] [Indexed: 12/19/2022] Open
Abstract
Ovarian insufficiency is identified as a perplexing entity in the long list of pathologies impairing fertility dynamics. The three distinct classifications of ovarian insufficiency are poor ovarian response, premature ovarian insufficiency/failure, and advanced maternal age, sharing the common denominator of deteriorated ovarian reserve. Despite efforts to define clear lines among the three, the vast heterogeneity and overlap of clinical characteristics renders their diagnosis and management challenging. Lack of a consensus has prompted an empirically based management coupled by uncertainty from the clinicians' perspective. Profiling of patients in the era of precision medicine seems to be the way forward, while the necessity for a novel approach is underlined. Implicating miRNAs in the quest for patient profiling is promising in light of their fundamental role in cellular and gene expression regulation. To this end, the current study sets out to explore and compare the three pathophysiologies-from a molecular point of view-in order to enable profiling of patients in the context of in vitro fertilization treatment and enrich the data required to practice individualized medicine. Following a systematic investigation of literature, data referring to miRNAs were collected for each patient category based on five included studies. miRNA-target pairs were retrieved from the DIANA-TarBase repository and microT-CDS. Gene and miRNA annotations were derived from Ensembl and miRbase. A subsequent gene-set enrichment analysis of miRNA targets was performed for each category separately. A literature review on the most crucial of the detected pathways was performed to reveal their relevance to fertility deterioration. Results supported that all three pathophysiologies share a common ground regarding the affected pathways, naturally attributed to the common denominator of ovarian insufficiency. As evidenced, miRNAs could be employed to explore the fine lines and diverse nature of pathophysiology since they constitute invaluable biomarkers. Interestingly, it is the differentiation through miRNAs and not through the molecular affected pathways that corresponds to the three distinctive categories. Alarming discrepancies among publications were revealed, pertaining to employment of empirical and arbitrary criteria in categorizing the patients. Following bioinformatic analysis, the final step of the current study consisted of a critical analysis of the molecular data sourced, providing a clear and unique insight into the physiological mechanisms involved. It is our intention to contribute to mapping future research dedicated to ovarian insufficiency and to help researchers navigate the overwhelming information published in molecular studies.
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Affiliation(s)
- Anna Rapani
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Nikiforaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Karagkouni
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | | | - Petroula Tsioulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Sokratis Grigoriadis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Maziotis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Amelia Pantou
- Centre for Human Reproduction, Genesis Athens Clinic, Athens, Greece
| | | | - Agni Pantou
- Centre for Human Reproduction, Genesis Athens Clinic, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Artemis Hatzigeorgiou
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia, Greece
- Hellenic Pasteur Institute, Athens, Greece
| | | | - Mara Simopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- *Correspondence: Mara Simopoulou,
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23
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Nahand JS, Karimzadeh MR, Nezamnia M, Fatemipour M, Khatami A, Jamshidi S, Moghoofei M, Taghizadieh M, Hajighadimi S, Shafiee A, Sadeghian M, Bokharaei-Salim F, Mirzaei H. The role of miR-146a in viral infection. IUBMB Life 2019; 72:343-360. [PMID: 31889417 DOI: 10.1002/iub.2222] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 12/16/2019] [Indexed: 12/12/2022]
Abstract
Cellular microRNAs (miRNAs) were identified as a key player in the posttranscriptional regulation of cellular-genes regulatory pathways. They also emerged as a significant regulator of the immune response. In particular, miR-146a acts as an importance modulator of function and differentiation cells of the innate and adaptive immunity. It has been associated with disorder including cancer and viral infections. Given its significance in the regulation of key cellular processes, it is not surprising which virus infection have found ways to dysregulation of miRNAs. miR-146a has been identified in exosomes (exosomal miR-146a). After the exosomes release from donor cells, they are taken up by the recipient cell and probably the exosomal miR-146a is able to modulate the antiviral response in the recipient cell and result in making them more susceptible to virus infection. In this review, we discuss recent reports regarding miR-146a expression levels, target genes, function, and contributing role in the pathogenesis of the viral infection and provide a clue to develop the new therapeutic and preventive strategies for viral disease in the future.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Karimzadeh
- Department of Medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Maria Nezamnia
- Department of Obstetrics and Gynecology, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Maryam Fatemipour
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Khatami
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sogol Jamshidi
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarah Hajighadimi
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Alimohammad Shafiee
- Division of General Internal Medicine, Toronto General Hospital, Toronto, Canada
| | - Mohammad Sadeghian
- Orthopedic Surgeon Fellowship of Spine Surgery, Sasan General Hospital, Tehran, Iran
| | - Farah Bokharaei-Salim
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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24
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Yu T, Ju Z, Luo M, Hu R, Teng Y, Xie L, Zhong C, Chen L, Hou W, Xiong Y, Feng Y. Elevated expression of miR-146a correlates with high levels of immune cell exhaustion markers and suppresses cellular immune function in chronic HIV-1-infected patients. Sci Rep 2019; 9:18829. [PMID: 31827152 PMCID: PMC6906421 DOI: 10.1038/s41598-019-55100-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/22/2019] [Indexed: 12/16/2022] Open
Abstract
Functional exhaustion of immune cells is a defining characteristic of HIV-1 chronic infections, exhibiting dysregulation of cellular immune responses and expression of co-inhibitory receptors. Although the molecular mechanisms controlling immune-cell exhaustion retains largely unknown, immune checkpoint blockade strategy has shown inspiring potential to reinvigorate T cell functions in chronic infections. In this study, we investigated peripheral blood mononuclear cells (PBMCs) exhaustion markers from 109 chronic HIV-1-infected patients and found they correlated positively with microRNA-146a, which was inversely correlated with CD4+ T cell count. Intriguingly, ex vivo neutralization of miR-146a in PBMCs from chronic HIV-1 infection exhibited an elevated antiviral cytokines production as well as the expression of GZMB and perforin, while simultaneously, decreased the inhibitory receptors expression such as PD-1, CTLA-4, TIM-3 and LAG-3. These results highlight the importance of miR-146a to HIV-1 induced immune cell exhaustion, and uncover a novel layer of HIV/AIDS pathogenesis and provide potential targets for improved immune intervention.
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Affiliation(s)
- Ting Yu
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.,Precision Medicine Laboratory, Wuhan Children's Hospital, Wuhan, 430015, Hubei, People's Republic of China
| | - Zhao Ju
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Mingqi Luo
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Ronghua Hu
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Yan Teng
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Linlin Xie
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Chaojie Zhong
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Lang Chen
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China
| | - Wei Hou
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
| | - Yong Feng
- State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy & Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
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25
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Luly FR, Lévêque M, Licursi V, Cimino G, Martin-Chouly C, Théret N, Negri R, Cavinato L, Ascenzioni F, Del Porto P. MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages. Sci Rep 2019; 9:16259. [PMID: 31700158 PMCID: PMC6838115 DOI: 10.1038/s41598-019-52770-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
Abstract
Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.
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Affiliation(s)
- Francesco R Luly
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy
| | - Manuella Lévêque
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy.,Service de Dermatologie CHU de Poitiers, University of Poitiers, Poitiers, France
| | - Valerio Licursi
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy
| | | | - Corinne Martin-Chouly
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR S 1085, F-35000 University of Rennes, Rennes, France
| | - Nathalie Théret
- Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR S 1085, F-35000 University of Rennes, Rennes, France
| | - Rodolfo Negri
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy.,Institute of Molecular Biology and Pathology, Italian National Research Council, Rome, Italy
| | - Luca Cavinato
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy
| | - Fiorentina Ascenzioni
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy
| | - Paola Del Porto
- Department of Biology and Biotechnology, "C. Darwin" Sapienza University, Rome, Italy.
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Yan F, Meng W, Ye S, Zhang X, Mo X, Liu J, Chen D, Lin Y. MicroRNA‑146a as a potential regulator involved in the pathogenesis of atopic dermatitis. Mol Med Rep 2019; 20:4645-4653. [PMID: 31545496 PMCID: PMC6797935 DOI: 10.3892/mmr.2019.10695] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 08/23/2019] [Indexed: 01/27/2023] Open
Abstract
Previous studies have demonstrated that microRNA (miR)‑146a is involved in the inflammatory response of atopic dermatitis (AD). The aim of the present study was to investigate the expression of miR‑146a in the serum of patients with AD and in skin lesions of AD animal models. In addition, we aimed to predict and verify the target genes of miR‑146a. miR‑146a expression was measured in AD patient serum via reverse transcription‑quantitative PCR. T‑helper (Th)1 [CD4+; interferon (IFN)‑γ+] and Th2 [CD4+; interleukin (IL)‑4+] expression in peripheral blood mononuclear cells was evaluated using flow cytometry. Following the establishment of a 2,4‑dinitrofluorobenzene‑induced C57BL/6 mouse AD model, Th1 (CD4+IFN‑γ+) and Th2 (CD4+IL‑4+) expression was analyzed in murine spleen cells via flow cytometry. Plasmids were transfected into 293T cells and at 48 h post‑transfection, cells were analyzed using a luciferase assay system. The results revealed that the AD group had a significantly lower Th1/Th2 ratio and a significantly higher miR‑146a expression compared with the control group (P<0.05). Furthermore, a decreased Th1/Th2 ratio and a significantly increased miR‑146a expression were observed in the model group compared with the control group (P<0.01). We also conducted a dual‑luciferase assay to determine whether small ubiquitin‑related modifier 1 (SUMO1) if the target gene of miR‑146a. We observed a ~30% decrease in the relative luciferase activity in cells containing the 3'‑untranslated region of SUMO1 + miR‑146a). The results of the luciferase assay indicated that may be a direct mRNA target of miR‑146a; however, the quantification of band density of SUMO1 expression following western blotting did not significantly differ. The development of animal models in AD research is of vital importance. The results revealed that miR‑146a may be a potential regulator involved in the pathogenesis of AD. Furthermore, the current study determined that miR‑146a could be a valuable marker of AD and thus, may be applied in the development of therapeutic strategies for treating AD.
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Affiliation(s)
- Fenggen Yan
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Weiwei Meng
- Department of Dermatology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Provincial Hospital of Chinese Medicine, Henan, Zhengzhou 450000, P.R. China
| | - Siqi Ye
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Xian Zhang
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Xiumei Mo
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Junfeng Liu
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Dacan Chen
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
| | - Ying Lin
- Department of Dermatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China
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Wang H, Li X, Li T, Wang L, Wu X, Liu J, Xu Y, Wei W. Multiple roles of microRNA-146a in immune responses and hepatocellular carcinoma. Oncol Lett 2019; 18:5033-5042. [PMID: 31612014 PMCID: PMC6781720 DOI: 10.3892/ol.2019.10862] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 08/06/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs/miRs), consisting of ~22 nucleotides of single-stranded RNA, participate in post-transcriptional gene regulation by binding to the 3′-untranslated region (UTR) of mRNAs, repressing their translation and promoting their degradation. Studies have shown that certain miRNAs play a key role in the control of various cellular activities, such as inhibiting inflammation, modulating cell differentiation and suppressing cancer growth. The role of miR-146a in the immune response and in the pathogenesis of hepatocellular carcinoma (HCC) has also been investigated. Although some studies have shown that increased miR-146a levels are associated with HCC, others have revealed that miR-146a suppresses cancer cell proliferation, invasion and metastasis. Toll-like receptor 4 (TLR4) signaling has an important role in regulating innate and adaptive immune responses. In addition, TLR4 is functionally expressed in HCC cells and promotes HCC cell proliferation, which can be regulated by miR-146a. The present review focuses on the recent progress in analyzing the multiple roles of miR-146a in mediating the TLR4 pathway and adaptive immune response. Finally, the function of miR-146a in the pathogenesis of HCC is also discussed.
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Affiliation(s)
- Huihui Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xuemei Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Tao Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Lianzi Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xian Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Jiaqing Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yuanhong Xu
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Abstract
The aim of this study was to investigate the alterations of urinary microRNA (miRNA) expression and explore its clinical significance in patients with chronic hepatitis B (CHB).The expression levels of urinary miRNA were detected by miRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 106 CHB and 40 healthy controls (Ctrl) subjects. The correlation between the levels of miRNA expression and clinical characteristics were analyzed. Receiver-operator characteristic (ROC) curves were generated to determine the specificity and sensitivity of each individual miRNA. MiRNAs expression were further measured by PCR from exosomes, which were isolated from urine samples. LX2 cells were transfected with miRNA inhibitor and accumulation of cytoplasmic lipid droplets was analyzed by Oil Red O staining.miRNA expression profile analysis showed that 22 miRNAs were upregulated and 55 miRNAs were downregulated in CHB patients compared with Ctrl subjects (fold-change>1.5 and P < .05). miR-92b-3p, miR-770-5p, miR-5196-5p, and miR-7855-5p were significantly higher (P < .0001) in CHB subjects than in Ctrl subjects. ROC curve analysis showed that these four miRNAs were sensitive and specific enough to distinguish CHB and Ctrl subjects. The levels of miR-92b-3p expression were negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and APOA-1. Moreover, in vitro experiments indicated that inhibition of miR-92b-3p increased lipid droplet formation in LX2 cells.Aberrant expression of miRNAs has been observed in urine of CHB patients. Our findings may provide novel insights into the pathogenesis of CHB and may assist in the diagnosis of patients with CHB.
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Affiliation(s)
- Jia-Wei Shang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Xiu-Li Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
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Ouyang Y, Fu X, Peng S, Tan D, Fu L. Plasma miR-146a predicts serological conversion of hepatitis B e-antigen (HBeAg) in chronic hepatitis B patients treated with nucleotide analogs. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:449. [PMID: 31700885 DOI: 10.21037/atm.2019.08.72] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background To investigate the association of plasma miR-146a with serological conversion of hepatitis B e-antigen (HBeAg) in patients with chronic hepatitis B (CHB) treated with nucleotide analogs (NAs). Methods This was a retrospective study of 115 HBeAg-positive patients with CHB treated at Xiangya Hospital, Central South University, Changsha, China, between September 2009 and March 2014. Patients were grouped according to whether they had achieved seroconversion of HBeAg by 104 weeks of NAs treatment. We assessed plasma miR-146a using miScript polymerase chain reaction (PCR). Serum alanine transaminase (ALT), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load, hepatitis B surface antigen (HBsAg) titer, HBeAg titer, and plasma miR-146a were measured at 0, 24, 48, and 104 weeks of treatment. Finally, we also determined ΔmiR-146a24w and ΔmiR-146a48w. Results ΔmiR-146a48w was independently associated with seroconversion of HBeAg at 104 weeks [odds ratio (OR) =1.302; 95% confidence interval (CI), 1.159-1.962; P=0.029]. We obtained an area under the receiver operating characteristic (ROC) curve (AUC) of ΔmiR-14648w of 0.757 for seroconversion of HBeAg (P=0.013). At the optimal cutoff value equivalent to a Youden index of 67.9%, the specificity and sensitivity of ΔmiR-14648w were 63.7% and 88.3%, respectively. Positive (PPV) and negative (NPV) predictive values were 70.87% and 84.48%, respectively. Conclusions ΔmiR-146a48w was independently associated with seroconversion of HBeAg in CHB patients treated with NAs.
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Affiliation(s)
- Yi Ouyang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Viral Hepatitis, Changsha 410008, China
| | - Xiaoyu Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Viral Hepatitis, Changsha 410008, China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Viral Hepatitis, Changsha 410008, China
| | - Deming Tan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Viral Hepatitis, Changsha 410008, China
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.,Hunan Key Laboratory of Viral Hepatitis, Changsha 410008, China
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30
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Bronisz-Budzyńska I, Chwalenia K, Mucha O, Podkalicka P, Karolina-Bukowska-Strakova, Józkowicz A, Łoboda A, Kozakowska M, Dulak J. miR-146a deficiency does not aggravate muscular dystrophy in mdx mice. Skelet Muscle 2019; 9:22. [PMID: 31412923 PMCID: PMC6693262 DOI: 10.1186/s13395-019-0207-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/31/2019] [Indexed: 01/02/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease evoked by a mutation in the dystrophin gene. It is associated with progressive muscle degeneration and increased inflammation. Up to this date, mainly anti-inflammatory treatment is available for patients suffering from DMD. miR-146a is known to diminish inflammation and fibrosis in different tissues by downregulating the expression of proinflammatory cytokines. However, its role in DMD has not been studied so far. In our work, we have generated mice globally lacking both dystrophin and miR-146a (miR-146a−/−mdx) and examined them together with wild-type, single miR-146a knockout and dystrophic (mdx—lacking dystrophin) mice in a variety of aspects associated with DMD pathophysiology (muscle degeneration, inflammatory reaction, muscle satellite cells, muscle regeneration, and fibrosis). We have shown that miR-146a level is increased in dystrophic muscles in comparison to wild-type mice. Its deficiency augments the expression of proinflammatory cytokines (IL-1β, CCL2, TNFα). However, muscle degeneration was not significantly worsened in mdx mice lacking miR-146a up to 24 weeks of age, although some aggravation of muscle damage and inflammation was evident in 12-week-old animals, though no effect of miR-146a deficiency was visible on quantity, proliferation, and in vitro differentiation of muscle satellite cells isolated from miR-146a−/−mdx mice vs. mdx. Similarly, muscle regeneration and collagen deposition were not changed by miR-146a deficiency. Nevertheless, the lack of miR-146a is associated with decreased Vegfa and increased Tgfb1. Overall, the lack of miR-146a did not aggravate significantly the dystrophic conditions in mdx mice, but its effect on DMD in more severe conditions warrants further investigation.
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Affiliation(s)
- Iwona Bronisz-Budzyńska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Katarzyna Chwalenia
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Karolina-Bukowska-Strakova
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.,Department of Clinical Immunology and Transplantology, Institute of Paediatrics, Medical College, Jagiellonian University, Wielicka 265, 30-663, Krakow, Poland
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Magdalena Kozakowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
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31
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Qian L, Fan H, Ju Y, Chen L, Li X, Ye X, Luo Y, Li C, Meng S. A peptide-based inhibitor of gp96 suppresses HBsAg expression and HBV replication by upregulation of p53. J Gen Virol 2019; 100:1241-1252. [PMID: 31204972 DOI: 10.1099/jgv.0.001289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In hepatitis B virus (HBV) infection, the virus produces redundant hepatitis B surface antigen (HBsAg) that plays a key role in driving T-cell tolerance and viral persistence. However, currently available anti-HBV agents have no direct effect on HBsAg transcription and protein expression. In this study, we designed a heat shock protein gp96 inhibitor p37 with the cell penetrating peptide PTD (protein transduction domain of trans-activator of transcription), which mediated p37 internalization into hepatocytes. PTD-p37 effectively suppressed HBsAg expression and viral replication both in vitro and in vivo. We further provide evidence that PTD-p37 suppressed HBV enhancer/promoter activity via p53 upregulation. Moreover, PTD-p37 had antiviral activity against a lamivudine-resistant HBV strain. Considering that suppression of HBsAg expression is a major goal for treatment of HBV infection, our results provide a basis for developing a new therapeutic approaches targeting host factors against viral expression.
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Affiliation(s)
- Liyuan Qian
- Beijing Key Laboratory of Environmental and Viral Oncology, College of life Science and Bio-Engineering, Beijing University of Technology, Beijing, PR China.,CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Hongxia Fan
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Ying Ju
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Lizhao Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Xin Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Xin Ye
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Yunjing Luo
- Beijing Key Laboratory of Environmental and Viral Oncology, College of life Science and Bio-Engineering, Beijing University of Technology, Beijing, PR China
| | - Changfei Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
| | - Songdong Meng
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, PR China.,CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China
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32
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Zhao Y, Yu Y, Ye L. MiR-3613-3p impairs IFN-induced immune response by targeting CMPK1 in chronic hepatitis B. INFECTION GENETICS AND EVOLUTION 2019; 74:103919. [PMID: 31201869 DOI: 10.1016/j.meegid.2019.103919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/02/2019] [Accepted: 06/11/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND This study aims to investigate the effects of miR-3613-3p and its underlying mechanisms on chronic hepatitis B. METHODS Expressions of miR-3613-3p were determined in clinical samples from chronic hepatitis B patients and healthy volunteers. HBV-transfected hepatoma cell lines were constructed for in vitro study. HBV-infected animal model was established in vivo study. Quantitative real-time reverse transcription PCR (qRT-PCR) was used to determine mRNA expressions. Western blotting and ELISA were used to determine protein expressions. Luciferase reporter and biotin pull-down assays were used to analyze RNA-RNA interactions. siRNA silencing was used to knockdown miR-3613-3p and CMPK1. RESULTS MiR-3613-3p was upregulated in the chronic hepatitis B patients, as compared with healthy volunteers. Inhibition of miR-3613-3p decreased relative expressions of IFN-α and IFN-β, HBV DNA copies, and increased the hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels, whereas miR-3613-3p overexpression reversed these changes in vitro and in vivo. MiR-3613-3p directly targeted CMPK1 and interactions between CMPK1 and miR-3613-3p regulated the anti-HBV efficiency of IFN. CONCLUSION MiR-3613-3p impaired IFN-induced immune response by targeting CMPK1 in chronic hepatitis B.
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Affiliation(s)
- Yanping Zhao
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang, China
| | - Yaping Yu
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang, China
| | - Lei Ye
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang, China.
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Gustafson CE, Cavanagh MM, Jin J, Weyand CM, Goronzy JJ. Functional pathways regulated by microRNA networks in CD8 T-cell aging. Aging Cell 2019; 18:e12879. [PMID: 30488559 PMCID: PMC6351841 DOI: 10.1111/acel.12879] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/26/2018] [Accepted: 10/21/2018] [Indexed: 12/13/2022] Open
Abstract
One of the most prominent immunological changes during human aging is the alteration in CD8 T-cell subset distribution, predominated by a loss of naïve CD8 T cells. The molecular mechanisms that contribute to the loss of naïve CD8 T-cells during aging remain unclear. Considering that many CD8 T-cell functions are influenced by microRNAs (miRNAs), we explored miRNA expression profiling to identify novel dysfunctions that contribute to naïve CD8 T-cell loss during aging. Here, we describe age-dependent miRNA expression changes in naïve, central memory, and effector memory CD8 T-cell subsets. Changes in old naïve CD8 T-cells partially resembled those driven by an underlying shift in cellular differentiation toward a young central memory phenotype. Pathways enriched for targets of age-dependent miRNAs included FOXO1, NF-κB, and PI3K-AKT signaling. Transcriptome analysis of old naïve CD8 T-cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF-κB activities. Of particular interest, IL-7R expression, controlled by FOXO1 signaling, declines on naïve CD8 T cells with age and directly correlates with the frequencies of naïve CD8 T cells. Thus, age-associated changes in miRNA networks may ultimately contribute to the failure in CD8 T-cell homeostasis exemplified by the loss in naïve cells.
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Affiliation(s)
- Claire E Gustafson
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Mary M Cavanagh
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Jun Jin
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
- Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, California
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Khanizadeh S, Hasanvand B, Nikoo HR, Anbari K, Adhikary H, Shirkhani S, Lashgarian HE. Association between miRNA-146a rs2910164 (G/C) polymorphism with the susceptibility to chronic HBV infection and spontaneous viral clearance in an Iranian population. J Med Virol 2019; 91:1063-1068. [PMID: 30624803 DOI: 10.1002/jmv.25394] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/08/2018] [Accepted: 12/14/2018] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV) infection is one of the clinical dilemmas in chronic liver diseases. MicroRNAs (miRNAs) are small noncoding RNA molecules that play an important role in the pathogenesis of liver diseases and single nucleotide polymorphisms (SNPs) in miRNA genes affect the clinical course of HBV infection. Previous studies have shown that miRNA-146a rs2910164 polymorphism can be associated with the pathogenesis of liver diseases such as hepatocellular carcinoma. The present study investigated the association between miRNA-146a rs2910164 polymorphism and susceptibility to HBV infection in an Iranian population. The study comprised 266 patients with chronic HBV infection, 172 patients with spontaneous viral clearance (SVC) after acute HBV infection, and 266 healthy control adjusted for sex and age. The genotyping of the miRNA-146a rs2910164 polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our data revealed that GG genotype and G allele of miRNA-146a rs2910164 SNP is dominated (P < 0.001) in patients with chronic HBV infection (Odds ratio [OR] = 3.92; 95% confidence interval [CI] = 2.1-7.32). miRNA-146a rs2910164 polymorphism showed a statistically significant association (P < 0.001) between CC genotype and allele C with SVC (OR = 2.92; 95% CI = 1.56-546). Our findings suggest miRNA-146a SNP (C/G) in our population may be associated with the susceptibility to HBV infection and CC genotype is associated with SVC. Also, the GG genotype and G allele at miRNA-146a rs2910164 is associated with chronic HBV infection in our population.
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Affiliation(s)
- Sayyad Khanizadeh
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Virology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Banafsheh Hasanvand
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hadi Razavi Nikoo
- Infectious Disease Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Khatereh Anbari
- School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hemanta Adhikary
- Laboratory Dr Kyle K Biggar, Nesbitt Biology Building, Carleton University, Ottawa, Ontario, Canada
| | - Somayeh Shirkhani
- Department of Virology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Hamed Esmaeili Lashgarian
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.,Department of Biotechnology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
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35
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Pesce S, Squillario M, Greppi M, Loiacono F, Moretta L, Moretta A, Sivori S, Castagnola P, Barla A, Candiani S, Marcenaro E. New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression. Front Immunol 2018; 9:2360. [PMID: 30374356 PMCID: PMC6196268 DOI: 10.3389/fimmu.2018.02360] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/24/2018] [Indexed: 12/21/2022] Open
Abstract
Natural killer cells are cytotoxic innate lymphoid cells that play an important role for early host defenses against infectious pathogens and surveillance against tumor. In humans, NK cells may be divided in various subsets on the basis of the relative CD56 expression and of the low-affinity FcγRIIIA CD16. In particular, the two main NK cell subsets are represented by the CD56bright/CD16−/dim and the CD56dim/CD16bright NK cells. Experimental evidences indicate that CD56bright and CD56dim NK cells represent different maturative stages of the NK cell developmental pathway. We identified multiple miRNAs differentially expressed in CD56bright/CD16− and CD56dim/CD16bright NK cells using both univariate and multivariate analyses. Among these, we found a few miRNAs with a consistent differential expression in the two NK cell subsets, and with an intermediate expression in the CD56bright/CD16dim NK cell subset, representing a transitional step of maturation of NK cells. These analyses allowed us to establish the existence of a miRNA signature able to efficiently discriminate the two main NK cell subsets regardless of their surface phenotype. In addition, by analyzing the putative targets of representative miRNAs we show that hsa-miR-146a-5p, may be involved in the regulation of killer Ig-like receptor (KIR) expression. These results contribute to a better understanding of the physiologic significance of miRNAs in the regulation of the development/function of human NK cells. Moreover, our results suggest that hsa-miR-146a-5p targeting, resulting in KIR down-regulation, may be exploited to generate/increment the effect of NK KIR-mismatching against HLA-class I+ tumor cells and thus improve the NK-mediated anti-tumor activity.
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Affiliation(s)
- Silvia Pesce
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Margherita Squillario
- Department of Informatic Bioengeneering, Robotic and System Engeneering, University of Genoa, Genoa, Italy
| | - Marco Greppi
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.,Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Fabrizio Loiacono
- Immunology Operative Unit, IRCCS San Martino Polyclinical Hospital, Genoa, Italy
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Alessandro Moretta
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.,Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Simona Sivori
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.,Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Patrizio Castagnola
- Department of Integrated Oncological Therapies, IRCCS San Martino Polyclinical Hospital, Genoa, Italy
| | - Annalisa Barla
- Department of Informatic Bioengeneering, Robotic and System Engeneering, University of Genoa, Genoa, Italy
| | - Simona Candiani
- Department of Earth Science, Environment and Life (DISTAV), University of Genoa, Genoa, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.,Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
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MicroRNA-146a is induced by inflammatory stimuli in airway epithelial cells and augments the anti-inflammatory effects of glucocorticoids. PLoS One 2018; 13:e0205434. [PMID: 30300399 PMCID: PMC6177187 DOI: 10.1371/journal.pone.0205434] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/25/2018] [Indexed: 01/13/2023] Open
Abstract
Background MicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects. Objective We aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids. Methods and results MicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids. Conclusions We propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.
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Sagnelli E, Potenza N, Onorato L, Sagnelli C, Coppola N, Russo A. Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. World J Hepatol 2018; 10:558-570. [PMID: 30310534 PMCID: PMC6177563 DOI: 10.4254/wjh.v10.i9.558] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/24/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicoletta Potenza
- DISTABIF, University of Campania “Luigi Vanvitelli”, Naples 80100, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Aniello Russo
- DISTABIF, University of Campania “Luigi Vanvitelli”, Naples 80100, Italy
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Giri BR, Mahato RI, Cheng G. Roles of microRNAs in T cell immunity: Implications for strategy development against infectious diseases. Med Res Rev 2018; 39:706-732. [PMID: 30272819 DOI: 10.1002/med.21539] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/19/2022]
Abstract
T cell immunity plays a vital role in pathogen infections. MicroRNA (miRNAs) are small, single-stranded noncoding RNAs that regulate T cell immunity by targeting key transcriptional factors, signaling proteins, and cytokines associated with T cell activation, differentiation, and function. The dysregulation of miRNA expression in T cells may lead to specific immune responses and can provide new therapeutic opportunities against various infectious diseases. Here, we summarize recent studies that focus on the roles of miRNAs in T cell immunity and highlight miRNA functions in prevalent infectious diseases. Additionally, we also provide insights into the functions of extracellular vesicle miRNAs and attempt to delineate the mechanism of miRNA sorting into extracellular vesicles and their immunomodulatory functions. Moreover, methodologies and strategies for miRNA delivery against infectious diseases are summarized. Finally, potential strategies for miRNA-based therapies are proposed.
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Affiliation(s)
- Bikash R Giri
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Guofeng Cheng
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
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CRISPR/Cas9-mediated deletion of miR-146a enhances antiviral response in HIV-1 infected cells. Genes Immun 2018; 20:327-337. [PMID: 29961753 DOI: 10.1038/s41435-018-0036-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 02/07/2023]
Abstract
The human immunodeficiency virus type 1 (HIV-1) causes persistent infection in human and induces miR-146a expression in infected cells. miR-146a represses the innate immune response by inhibiting the expression of TRAF6 and IRAK1 genes, thus negatively controls the NF-κB-related cytokines and interferon stimulated genes. Here we reported that lentiviral CRISPR/Cas9 system was highly efficient in introducing mutations in the precursor miR-146a genomic sequences, resulting in a loss of miR-146a expression and function. miR-146a ablation led to increasing cytokines production in LPS-stimulated A549 cells. Moreover, miR-146a knockout in HIV-1 infected MT2 cells markedly increased the expression of cytokines and HIV-1 restriction factors and reversed T cell exhaustion markers expression, thus influencing HIV-1 replication. Our study indicates that lentiviral CRISPR/Cas9-mediated gene editing is an effective approach to abrogate miR-146a expression, which consequently inhibits HIV-1 replication as well as proviral reactivation by enhancing the expression of cytokines and HIV-1 restriction factors.
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Xu WX, Zhang Q, Zhu X, Lin CS, Chen YM, Deng H, Mei YY, Zhao ZX, Xie DY, Gao ZL, Xie C, Peng L. 48-Week Outcome after Cessation of Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Patient and the Associated Factors with Relapse. Can J Gastroenterol Hepatol 2018; 2018:1817680. [PMID: 29862225 PMCID: PMC5971349 DOI: 10.1155/2018/1817680] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 02/26/2018] [Accepted: 03/19/2018] [Indexed: 12/19/2022] Open
Abstract
Background and Aims We aimed to ascertain the feasibility and safety of NA cessation, the status of patients after cessation, and the predictive factors for relapse and subsequent retreatment. Methods A total of 92 patients were enrolled in this prospective study. Patients were monitored every month for the first 3 months after cessation and every 3 months thereafter. Results Sixty-two patients finished 48 weeks of follow-up. None died or developed liver failure, cirrhosis, or HCC. The 62 patients could be divided into 4 categories according to the 48-week clinical development of relapse. Virologic relapses occurred in 39 (62.9%) patients, with 72.7% occurring in the first 24 weeks in origin HBeAg positive patients and 82.4% in the first 12 weeks in origin HBeAg negative patients. Age (OR = 1.06, 95% CI = 1.02-1.10; p = 0.003), the HBsAg level (OR = 2.21, 95% CI = 1.47-3.32; p < 0.001), and positive origin HBeAg status (OR = 0.32, 95% CI = 0.14-0.74; p = 0.008) were predictive factors to virologic relapse. HBV DNA level (OR = 1.34, 95% CI = 1.13-1.58; p < 0.001) was predictive factor to retreatment. Conclusions NA cessation is safe under supervision. Age, HBsAg level, and origin HBeAg status can be predictive factors for virologic relapse. The study was submitted to ClinicalTrials.gov Protocol Registration and Results System with the assigned NCT ID NCT02883647.
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Affiliation(s)
- Wen-xiong Xu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Qian Zhang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Xiang Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Chao-shuang Lin
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - You-ming Chen
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Hong Deng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Yong-yu Mei
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Zhi-xin Zhao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Dong-ying Xie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Zhi-liang Gao
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Chan Xie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
- Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China
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Gazdic M, Markovic BS, Arsenijevic A, Jovicic N, Acovic A, Harrell CR, Fellabaum C, Djonov V, Arsenijevic N, Lukic ML, Volarevic V. Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury. Liver Transpl 2018; 24:687-702. [PMID: 29500914 DOI: 10.1002/lt.25049] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 02/08/2018] [Accepted: 02/12/2018] [Indexed: 12/15/2022]
Abstract
One of the therapeutic options for the treatment of fulminant hepatitis is repopulation of intrahepatic regulatory cells because their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of regulatory T cells (Tregs) and regulatory B cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of interleukin (IL) 10-producing CD4+ CD25+ forkhead box P3+ Tregs and IL10- and transforming growth factor β-producing marginal zone-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, whereas depletion of Tregs completely abrogated hepatoprotective effects of MSCs and inhibited their capacity to attenuate hepatotoxicity of liver natural killer T cells (NKTs), indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in a paracrine, indoleamine 2,3-dioxygenase-dependent manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and to suppress hepatotoxicity of liver NKTs. Accordingly, adoptive transfer of MSC-primed Tregs resulted in the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicated the significance of MSC-mediated priming of Tregs as a new therapeutic approach in Treg-based therapy of acute liver injury. Liver Transplantation 24 687-702 2018 AASLD.
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Affiliation(s)
- Marina Gazdic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojana Simovic Markovic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Arsenijevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Nemanja Jovicic
- Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Acovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | | | | | | | - Nebojsa Arsenijevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Miodrag L Lukic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Vladislav Volarevic
- Department of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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Inácio DP, Amado T, Silva-Santos B, Gomes AQ. Control of T cell effector functions by miRNAs. Cancer Lett 2018; 427:63-73. [PMID: 29679611 DOI: 10.1016/j.canlet.2018.04.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/23/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
The differentiation of effector T cells is a tightly regulated process that relies on the selective expression of lineage-defining master regulators that orchestrate unique transcriptional programs, including the production of distinct sets of effector cytokines. miRNAs are post-transcriptional regulators that are now viewed as critical players in these gene expression networks and help defining cell identity and function. This review summarises the role of individual miRNAs in the regulation of the differentiation of effector T cell subsets, including CD4+ T helper cells, cytotoxic CD8+ T cells and innate-like NKT cells. Moreover, we refer to miRNAs that have been identified to affect simultaneously two or more effector T cell populations, impacting on the balance between effector T cells in vivo, thus constituting potential biomarkers or targets for therapies aiming at boosting immunity or controlling autoimmunity.
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Affiliation(s)
- Daniel P Inácio
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Tiago Amado
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Bruno Silva-Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal
| | - Anita Q Gomes
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal; Escola Superior de Tecnologia da Saúde de Lisboa, 1990-096, Lisboa, Portugal.
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Serum levels of miRNA in patients with hepatitis B virus-associated acute-on-chronic liver failure. Hepatobiliary Pancreat Dis Int 2018; 17:126-132. [PMID: 29602672 DOI: 10.1016/j.hbpd.2018.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 01/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum miRNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF. METHODS Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to 30 chronic asymptomatic HBV carriers as controls. The miRNAs expressions were measured by real-time quantitative PCR (q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed miRNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model. RESULTS Real-time q-PCR indicated that serum miR-146a-5p, miR-122-3p and miR-328-3p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and miR-122-3p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+ - 1.72 × INR - 4.963 × gastrointestinal bleeding (Yes = 0; No = 1)-0.278 × (miR-122-3p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve (AUROC) was 0.847. CONCLUSIONS Expression levels of these miRNAs (miR-146a-5p, miR-122-3p and miR-328-3p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.
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Li Z, Zhang S, Wan Y, Cai M, Wang W, Zhu Y, Li Z, Hu Y, Wang H, Chen H, Cui L, Zhang X, Zhang J, He W. MicroRNA-146a Overexpression Impairs the Positive Selection during T Cell Development. Front Immunol 2018; 8:2006. [PMID: 29410664 PMCID: PMC5787067 DOI: 10.3389/fimmu.2017.02006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 12/26/2017] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs play crucial roles in modulating immune system. miR-146a, a potent feedback suppressor of NF-κB signaling, was shown to limit the innate immune response and myelopoiesis in a knockout mouse model. Here, we observed high lymphopoiesis demonstrated as mild splenomegaly and severe lymphadenopathy in a miR-146a transgenic mouse model. Overexpression of miR-146a resulted in enhanced proliferation and reduced apoptosis of T cells. More activated CD4+ T cells or effector memory T cells were observed in transgenic mice even under physiological conditions. Importantly, as one of the key steps to generate central tolerance, the positive selection of thymocytes is impaired in transgenic mice, resulting in more CD4+CD8+ double-positive thymocytes but fewer CD4+CD8− and CD4−CD8+ single-positive thymocytes. The maturation of selected CD4−CD8+ thymocytes was also impaired, leading to more severe loss of CD4−CD8+ than CD4+CD8− thymocytes in thymus of transgenic mice. Gene expression profiling analysis identified nine positive selection-associated genes, which were downregulated in transgenic mice, including genes encoding major histocompatibility complex class I/II molecules, IL-7 receptor α chain, and Gimap4, whose downregulation may contribute to the impairment of positive selection. Gimap4 was verified as a novel target of miR-146a. These findings further extend our understanding of the function of miR-146a in T cell biology and identify a novel regulatory mechanism underlying the positive selection during T cell development.
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Affiliation(s)
- Zinan Li
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Siya Zhang
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Ying Wan
- Biomedical Analysis Center, Third Military Medical University, Chongqing, China
| | - Menghua Cai
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Weiqing Wang
- Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union College, Beijing, China
| | - Yuli Zhu
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Zhen Li
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Yu Hu
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Huaishan Wang
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Hui Chen
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Lianxian Cui
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianmin Zhang
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
| | - Wei He
- Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, China
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MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats. Mediators Inflamm 2017; 2017:9601349. [PMID: 29434444 PMCID: PMC5757132 DOI: 10.1155/2017/9601349] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 11/12/2017] [Indexed: 01/10/2023] Open
Abstract
Purpose This study aimed to determine the effect and roles of microRNA (miRNA, miR) treatment in experimental autoimmune anterior uveitis (EAAU). Materials and Methods Uveitis was induced in Lewis rats by simultaneous injections of bovine melanin-associated antigen into the hind footpad and the intraperitoneal cavity. The animals were injected intravitreally with low-dose (0.5 μg) or high-dose (1.5 μg) miR-146a. The clinical scores, leukocyte count in the aqueous humor, and histology were assessed. Cytokine changes were evaluated by relative mRNA expression and enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) was assessed by immunofluorescence and Western blotting. Evaluation of the DNA-binding activity of NF-κB was performed by electrophoretic mobility shift assay (EMSA). Results Treatment with miR-146a significantly attenuated clinical scores and leukocyte infiltration in a dose-dependent manner, a result that was compatible with histological findings. Following miR-146a injections, downregulation of interleukin- (IL-) 1β, IL-6, and IL-12 and interferon- (IFN-) γ and upregulation of IL-10 and IL-17 were noted. The decreased NF-κB expression on immunofluorescence and Western blotting and reduced DNA-binding activity on EMSA were demonstrated following miR-146a treatment. Conclusions miR-146a effectively reduced intraocular inflammation in EAAU through the inhibition of NF-κB. miR-146a might be a new treatment choice for uveitis.
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Nan Y, Wu C, Zhang YJ. Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism. Front Immunol 2017; 8:1758. [PMID: 29312301 PMCID: PMC5732261 DOI: 10.3389/fimmu.2017.01758] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/27/2017] [Indexed: 12/13/2022] Open
Abstract
Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism.
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Affiliation(s)
- Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.,Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, MD, United States
| | - Chunyan Wu
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yan-Jin Zhang
- Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, MD, United States
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Ge J, Huang Z, Liu H, Chen J, Xie Z, Chen Z, Peng J, Sun J, Hou J, Zhang X. Lower Expression of MicroRNA-155 Contributes to Dysfunction of Natural Killer Cells in Patients with Chronic Hepatitis B. Front Immunol 2017; 8:1173. [PMID: 29018442 PMCID: PMC5614978 DOI: 10.3389/fimmu.2017.01173] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 09/05/2017] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs have been reported to be regulated in different ways in a variety of liver diseases. As a key modulator of cellular function in both innate and adaptive immunity, the role of miR-155 in chronic hepatitis B virus infection remains largely unknown. Here, we investigated the expression and function of miR-155 in chronic hepatitis B (CHB) patients. It was found that miR-155 expression in peripheral blood mononuclear cells (PBMCs) was lower in CHB patients than healthy controls (HC). Among CHB infection, immune-active (IA) patients with abnormal alanine aminotransferase (ALT) levels had relatively higher miR-155 expression in PBMCs and serum than immune-tolerant carriers, but were comparable to inactive carriers. Moreover, there was a positive correlation between miR-155 expression and ALT levels in CHB patients. Particularly, miR-155 expression in natural killer (NK) cells was significantly downregulated in IA patients compared with HC. Inversely, suppressor of cytokine signaling 1 (SOCS1), a target of miR-155, was upregulated in NK cells of IA patients. Overexpression of miR-155 in NK cells from IA patients led to a decrease in SOCS1 expression and an increase of IFN-γ production. Finally, accompanied by the normalization of ALT, miR-155 expression in PBMCs gradually decreased during telbivudine or peg-IFN-α-2a therapy. Interestingly, higher miR-155 expression at baseline was associated with better response to telbivudine therapy, but not peg-IFN-α-2a. In conclusion, our data suggested that miR-155 downregulation in NK cells of IA patients impaired IFN-γ production by targeting SOCS1, which may contribute to immune dysfunction during CHB infection. Additionally, baseline miR-155 expression could predict the treatment response to telbivudine therapy.
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Affiliation(s)
- Jun Ge
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Haptobiliary Hospital of Fujian Medical University, Fuzhou, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, China
| | - Hongyan Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiehua Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanglian Xie
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zide Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Gazdic M, Simovic Markovic B, Vucicevic L, Nikolic T, Djonov V, Arsenijevic N, Trajkovic V, Lukic ML, Volarevic V. Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependent manner. J Tissue Eng Regen Med 2017; 12:e1173-e1185. [PMID: 28488390 DOI: 10.1002/term.2452] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 02/03/2017] [Accepted: 05/04/2017] [Indexed: 12/25/2022]
Abstract
The effects of mesenchymal stem cells (MSCs) on the phenotype and function of natural killer T (NKT) cells is not understood. We used concanavalin A (Con A) and α-galactosylceramide (α-GalCer)-induced liver injury to evaluate the effects of MSCs on NKT-dependent hepatotoxicity. Mouse MSCs (mMSCs) significantly reduced Con A- and α-GalCer-mediated hepatitis in C57Bl/6 mice, as demonstrated by histopathological and biochemical analysis, attenuated the influx of inflammatory [T-bet+ , tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ)-producing and GATA3+ , interleukin-4 (IL-4)-producing] liver NKT cells and downregulated TNF-α, IFN-γ and IL-4 levels in the sera. The liver NKT cells cultured in vitro with mMSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. mMSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells and suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. mMSCs reduced the cytotoxicity of liver NKT cells against hepatocytes in vitro. The presence of 1-methyl-dl-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), or l-NG -monomethyl arginine citrate, a specific inhibitor of inducible nitric oxide synthase (iNOS), in mMSC-conditioned medium injected into α-GalCer-treated mice, counteracted the hepatoprotective effect of mMSCs in vivo and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. Human MSCs attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells in an iNOS- and IDO-dependent manner and reduced their cytotoxicity against HepG2 cells. In conclusion, MSCs protect from acute liver injury by attenuating the cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in an iNOS- and IDO-dependent manner.
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Affiliation(s)
- Marina Gazdic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojana Simovic Markovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ljubica Vucicevic
- Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Tamara Nikolic
- Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | | | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Vladimir Trajkovic
- Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Miodrag L Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Vladislav Volarevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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Milosavljevic N, Gazdic M, Simovic Markovic B, Arsenijevic A, Nurkovic J, Dolicanin Z, Djonov V, Lukic ML, Volarevic V. Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl 2017; 23:1040-1050. [PMID: 28481005 DOI: 10.1002/lt.24784] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 03/28/2017] [Accepted: 04/27/2017] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune-mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17-producing cells in acute liver injury, is still unknown. By using 2 well-established murine models of neutrophil and NKT cell-mediated acute liver failure (induced by carbon tetrachloride and α-galactoceramide), we investigated molecular and cellular mechanisms involved in MSC-mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17-producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10-producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC-treated mice. MSCs did not significantly alter the total number of IL17-producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell-conditioned medium (MSC-CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1-methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO-dependent manner may be used as a new therapeutic approach in IL17-driven liver inflammation. Liver Transplantation 23 1040-1050 2017 AASLD.
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Affiliation(s)
- Neda Milosavljevic
- Departments of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Marina Gazdic
- Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojana Simovic Markovic
- Departments of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Aleksandar Arsenijevic
- Departments of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Jasmin Nurkovic
- Department of Biomedical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
| | - Zana Dolicanin
- Department of Biomedical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
| | | | - Miodrag L Lukic
- Departments of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
| | - Vladislav Volarevic
- Departments of Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research
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50
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Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response. Stem Cells Int 2017; 2017:6294717. [PMID: 28798777 PMCID: PMC5534320 DOI: 10.1155/2017/6294717] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 06/04/2017] [Accepted: 06/05/2017] [Indexed: 01/08/2023] Open
Abstract
Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.
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