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Culina S, Commère PH, Turc E, Jouy A, Pellegrini S, Roux T, Hasan M, Monot M, Michel F. MicroRNA signatures of CD4 + T cell subsets in healthy and multiple sclerosis subjects determined by small RNA-sequencing. J Neuroimmunol 2025; 401:578531. [PMID: 40010156 DOI: 10.1016/j.jneuroim.2025.578531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 01/13/2025] [Accepted: 01/19/2025] [Indexed: 02/28/2025]
Abstract
Diverse CD4+ T cell subsets with specialized functions operate at different phases of the immune response. Among these are phenotypically and functionally characterized naïve, central memory (CM), effector memory (EM), and regulatory (Treg) cells. Using small RNA-sequencing, we have profiled miRNAs in these cell subsets from healthy subjects and untreated patients with relapsing-remitting multiple sclerosis (RRMS). MiRNA genomic clustering and abundance were also investigated. From the 60 most differentially expressed miRNAs, broad and highly selective core signatures were determined for naïve and memory cells at homeostasis, while miR-146a-5p was strongly upregulated in Treg cells. In line with other studies, a 5-miRNA core was identified for naïve cells (miR-125b-5p, miR-99a-5p, miR-365a-3p, miR-365b-3p, miR-193b-3p). In memory cells, a number of identical miRNAs were more expressed in EM than CM cells, supporting the progressive T cell differentiation model. This was particularly the case for an 8-miRNA core (members from miR-23a∼27a∼24-2, miR-23b∼27b∼24-1, miR-221∼222 clusters, miR-22-3p, miR-181c-5p) and for the large ChrXq27.3 miR-506∼514 cluster. Interestingly, most of these miRNAs were reported to negatively regulate cell proliferation and survival. Finally, we found that the miRNA core signatures of naïve and memory CD4+ T cells were conserved in RRMS patients. Only few miRNAs were quantitatively modified and, among these, miR-1248 was validated to be downregulated in EM cells. Overall, this study expands and provides novel insights into miRNA profiling of CD4+ T cell subsets that may be useful for further investigations.
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Affiliation(s)
- Slobodan Culina
- Single Cell Biomarkers UTechS, Paris Cité University, Institut Pasteur, Paris, France
| | | | - Elodie Turc
- Biomics Technological Platform, Paris Cité University, Institut Pasteur, Paris, France
| | - Axel Jouy
- Paris Saclay University, Saclay, France; T cell activation and function DIO3 team, Department of Immunology, Paris Cité University, Institut Pasteur, Paris, France
| | - Sandra Pellegrini
- Unit of Cytokine Signaling, Inserm U1224, Paris Cité University, Institut Pasteur, Paris, France
| | - Thomas Roux
- CRC-SEP, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France
| | - Milena Hasan
- Single Cell Biomarkers UTechS, Paris Cité University, Institut Pasteur, Paris, France
| | - Marc Monot
- Biomics Technological Platform, Paris Cité University, Institut Pasteur, Paris, France
| | - Frédérique Michel
- Unit of Cytokine Signaling, Inserm U1224, Paris Cité University, Institut Pasteur, Paris, France; T cell activation and function DIO3 team, Department of Immunology, Paris Cité University, Institut Pasteur, Paris, France.
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Choi M, Choi S, Cho M, Kim C. Metabolic Signaling as a Driver of T Cell Aging. Immune Netw 2025; 25:e14. [PMID: 40078788 PMCID: PMC11896665 DOI: 10.4110/in.2025.25.e14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Aging significantly diminishes T cell immunity, increasing susceptibility to infections and reducing vaccine efficacy in older individuals. Metabolism plays a key role in T cell function, shaping their energy requirements, activation, and differentiation. Recent studies highlight altered metabolic signaling as a pivotal factor in T cell aging, influencing the ability of T cells to maintain quiescence, respond to activation, and differentiate into functional subsets. Aberrant metabolic pathways disrupt the quiescence of aged T cells and skew their differentiation toward short-lived, pro-inflammatory effector T cells while hindering the generation of long-lived memory and T follicular helper cells. These changes contribute to a hyper-inflammatory state, exacerbate chronic low-grade inflammation, and compromise immune homeostasis. In this review, we explore how metabolic signaling is altered during T cell aging and the resulting functional impacts. We also discuss therapeutic approaches aimed at restoring proper T cell differentiation, improving vaccine responses, and rejuvenating immune function in older populations.
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Affiliation(s)
- Minju Choi
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Korea
- Vaccine Innovation Center, Korea University College of Medicine, Seoul 02708, Korea
| | - Sujin Choi
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Korea
- Vaccine Innovation Center, Korea University College of Medicine, Seoul 02708, Korea
| | - Minkyeong Cho
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Korea
- Vaccine Innovation Center, Korea University College of Medicine, Seoul 02708, Korea
| | - Chulwoo Kim
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Korea
- Vaccine Innovation Center, Korea University College of Medicine, Seoul 02708, Korea
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Mishra S, Puzhankara L. Periodontal Tissue Homoeostasis, Immunity, the Red Complex Pathogens, and Dysbiosis: Unraveling the microRNA Effect. Microrna 2025; 14:9-18. [PMID: 39069708 DOI: 10.2174/0122115366305491240708060422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 07/30/2024]
Abstract
microRNAs are a family of small, non-coding RNA molecules that can regulate the translation of messenger RNAs (mRNAs). Numerous miRNAs have been proposed as potential indicators for periodontal disease, and their regulation might serve as a potent means of restricting the disease process. MiRNAs act as important immune system regulators that promote the production of many cytokines, including interferon (IFN), tumour necrosis factor (TNF), and IL-1as well as RANK. Investigations pertaining to the use of specific miRNAs as therapeutic agents are underway. They can influence a variety of regulatory organs and target several genes. Additionally, distinct components of the same expression pathway can be controlled by combining miRNAs and their antagonists. In recent years, many miRNA delivery methods have been created for therapeutic applications. Studies pertaining to the role of miRNAs in periodontal disease pathogenesis may pave the way for the use of miRNAs as biomarkers of periodontal disease. A complete understanding of the role of miRNA in periodontal disease and its mechanism of action can pave the way towards therapeutic strategies that can reduce or even prevent the progression of periodontal diseases.
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Affiliation(s)
- Swastik Mishra
- Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher education, Manipal, Karnataka, 576104, India
| | - Lakshmi Puzhankara
- Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher education, Manipal, Karnataka, 576104, India
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Harshithkumar R, Kaul M, Chandane-Tak M, Siddiqi NJ, Malik A, Khan AA, Mukherjee A. Harnessing miRNA dynamics in HIV-1-infected macrophages: Unveiling new targeted therapeutics using systems biology. Comput Struct Biotechnol J 2025; 27:1754-1771. [DOI: 10.1016/j.csbj.2025.04.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
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5
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Padzińska-Pruszyńska IB, Taciak B, Kiraga Ł, Smolarska A, Górczak M, Kucharzewska P, Kubiak M, Szeliga J, Matejuk A, Król M. Targeting Cancer: Microenvironment and Immunotherapy Innovations. Int J Mol Sci 2024; 25:13569. [PMID: 39769334 PMCID: PMC11679359 DOI: 10.3390/ijms252413569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
In 2024, the United States was projected to experience 2 million new cancer diagnoses and approximately 611,720 cancer-related deaths, reflecting a broader global trend in which cancer cases are anticipated to exceed 35 million by 2050. This increasing burden highlights ongoing challenges in cancer treatment despite significant advances that have reduced cancer mortality by 31% since 1991. Key obstacles include the disease's inherent heterogeneity and complexity, such as treatment resistance, cancer stem cells, and the multifaceted tumor microenvironment (TME). The TME-comprising various tumor and immune cells, blood vessels, and biochemical factors-plays a crucial role in tumor growth and resistance to therapies. Recent innovations in cancer treatment, particularly in the field of immuno-oncology, have leveraged insights into TME interactions. An emerging example is the FDA-approved therapy using tumor-infiltrating lymphocytes (TILs), demonstrating the potential of cell-based approaches in solid tumors. However, TIL therapy is just one of many strategies being explored. This review provides a comprehensive overview of the emerging field of immuno-oncology, focusing on how novel therapies targeting or harnessing components of the TME could enhance treatment efficacy and address persistent challenges in cancer care.
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Affiliation(s)
- Irena Barbara Padzińska-Pruszyńska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Bartłomiej Taciak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Łukasz Kiraga
- Division of Pharmacology and Toxicology, Department of Preclinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | - Anna Smolarska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Małgorzata Górczak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Paulina Kucharzewska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Małgorzata Kubiak
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Jacek Szeliga
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
| | - Agata Matejuk
- Department of Immunology, Collegium Medicum, University of Zielona Góra, 65-046 Zielona Góra, Poland;
| | - Magdalena Król
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, 02-787 Warsaw, Poland; (I.B.P.-P.); (B.T.); (A.S.); (M.G.); (P.K.); (M.K.); (J.S.)
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Iijima N, Yamaguchi M, Hayashi T, Rui Y, Ohira Y, Miyamoto Y, Niino M, Okuno T, Suzuki O, Oka M, Ishii KJ. miR-147-3p in pathogenic CD4 T cells controls chemokine receptor expression for the development of experimental autoimmune diseases. J Autoimmun 2024; 149:103319. [PMID: 39395343 DOI: 10.1016/j.jaut.2024.103319] [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: 09/03/2024] [Accepted: 09/16/2024] [Indexed: 10/14/2024]
Abstract
Incomplete Freund's adjuvant (IFA) has long been used to trigger autoimmune diseases in animal models, such as experimental autoimmune encephalitis and collagen-induced arthritis. However, the molecular mechanisms that control CD4 T cell effector functions and lead to the development of autoimmune diseases are not well understood. A self-antigen and heat-killed Mycobacterium tuberculosis emulsified in IFA augmented the activation of CD4 T cells, leading to the differentiation of pathogenic CD4 T cells in the draining lymph nodes. In contrast, IFA emulsification did not elicit Foxp3+ regulatory T cell expansion. We found that pathogenic Th1 cells expressed miR-147-3p, which targets multiple genes to affect T cell function. Finally, miR-147-3p expressed in CXCR6+SLAMF6- Th1 cells was required for the onset of neurological symptoms through the control of CXCR3 expression. Our findings demonstrate that miR-147-3p expressed in pathogenic CD4 T cells regulates the migratory potential in peripheral tissues and impacts the development of autoimmune diseases.
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MESH Headings
- Animals
- MicroRNAs/genetics
- Mice
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Disease Models, Animal
- Gene Expression Regulation
- Autoimmune Diseases/immunology
- Autoimmune Diseases/genetics
- Receptors, Chemokine/metabolism
- Receptors, Chemokine/genetics
- Th1 Cells/immunology
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Mice, Inbred C57BL
- Lymphocyte Activation/immunology
- Lymphocyte Activation/genetics
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Affiliation(s)
- Norifumi Iijima
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan.
| | - Masaya Yamaguchi
- Bioinformatics Research Unit, Osaka University Graduate School of Dentistry, Suita Osaka, Japan; Bioinformatics Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Department of Microbiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan; Center for Infectious Diseases Education and Research, Osaka University, Suita, Osaka, Japan
| | - Tomoya Hayashi
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Yuxiang Rui
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Yuta Ohira
- Central Research Laboratories, Zeria Pharmaceutical Co, Ltd, Kumagaya-shi, Saitama, Japan
| | - Yoichi Miyamoto
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Masaaki Niino
- Department of Clinical Research, National Hospital Organization Hokkaido Medical Center, Sapporo, Hokkaido, Japan
| | - Tatsusada Okuno
- Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Osamu Suzuki
- Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Asagi Saito, Ibaraki, Osaka, Japan
| | - Masahiro Oka
- Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan
| | - Ken J Ishii
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Saito Asagi, Ibaraki, Osaka, Japan; Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; WPI Immunology Frontier Research Center (IFReC), Osaka Univerisity, Suita, Osaka, Japan.
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Israni DK, Patel ML, Dodiya RK. Exploring the versatility of miRNA-128: a comprehensive review on its role as a biomarker and therapeutic target in clinical pathways. Mol Biol Rep 2024; 51:860. [PMID: 39068606 DOI: 10.1007/s11033-024-09822-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
MicroRNAs (miRNAs/ miRs) are short, noncoding RNAs, usually consisting of 18 to 24 nucleotides, that control gene expression after the process of transcription and have crucial roles in several clinical processes. This article seeks to provide an in-depth review and evaluation of the many activities of miR-128, accentuating its potential as a versatile biomarker and target for therapy; The circulating miR-128 has garnered interest because of its substantial influence on gene regulation and its simplicity in extraction. Several miRNAs, such as miR-128, have been extracted from circulating blood cells, cerebrospinal fluid, and plasma/serum. The miR-128 molecule can specifically target a diverse range of genes, enabling it to have intricate physiological impacts by concurrently regulating many interrelated pathways. It has a vital function in several biological processes, such as modulating the immune system, regulating brain plasticity, organizing the cytoskeleton, and inducing neuronal death. In addition, miR-128 modulates genes associated with cell proliferation, the cell cycle, apoptosis, plasma LDL levels, and gene expression regulation in cardiac development. The dysregulation of miR-128 expression and activity is associated with the development of immunological responses, changes in neural plasticity, programmed cell death, cholesterol metabolism, and heightened vulnerability to autoimmune illnesses, neuroimmune disorders, cancer, and cardiac problems; The paper highlights the importance of studying the consequences of miR-128 dysregulation in these specific locations. By examining the implications of miRNA-128 dysregulation in these areas, the article underscores its significance in diagnosis and treatment, providing a foundation for research and clinical applications.
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Affiliation(s)
- Dipa K Israni
- Department of Pharmacology, L.J. Institute of Pharmacy, LJ University, SG Highway, Sanand Cross-Road, Ahmedabad, Gujarat, 382210, India.
| | - Manish L Patel
- LJ Institute of Pharmacy, LJ University, Ahmedabad, Gujarat, India
| | - Rohinee K Dodiya
- Department of Pharmacology, L.J. Institute of Pharmacy, LJ University, SG Highway, Sanand Cross-Road, Ahmedabad, Gujarat, 382210, India
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Qassim HA, Mohammed ST, Muhamed HJ. The impact of miRNA-155 in acute and chronic toxoplasmosis in Iraqi women. Acta Trop 2024; 255:107211. [PMID: 38678844 DOI: 10.1016/j.actatropica.2024.107211] [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: 12/20/2023] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 05/01/2024]
Abstract
Toxoplasmosis is a prevalent parasitic infection caused by Toxoplasma gondii known to induce complex immune responses, to control the infection. MicroRNAs (miRNAs) are a cluster of small noncoding RNAs that are reported to have regulatory functions in the immune response. The objective of this study is to assess the expression of miR-155 and its targets, Src homology-2 domain-containing inositol 5- phosphatase 1 (SHIP-1) and suppressor of cytokine signaling-1 (SOCS1), in non-pregnant Iraqi women seropositive for toxoplasmosis. The study included 55 non-pregnant women positive for toxoplasmosis (20 in the acute phase and 35 in the chronic phase) and 35 non-pregnant women negative for toxoplasmosis (control group). Serum samples were collected from all participants to investigate the expression of miR-155 by RT‒PCR, in addition to the levels of SOCS1 and SHIP-1 measured by ELISA. The results showed a significant increase in the expression of miR-155 in both groups of acute and chronic toxoplasmosis compared to the control group. Lower levels of SOCS1 and SHIP-1 were found in acutely infected women compared to those with chronic infection and non-infected women. These findings showed the possible critical impact of miR-155 on host immune response during T.gondii infection, proposing that miR-155 can be explored as a prospective target to support host immune response against infectious diseases, with special help in early detection and management of toxoplasmosis in high-risk immunocompromised patients. Further studies are needed to evaluate the molecular pathways by which miRNAs improve immunity against toxoplasmosis.
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Affiliation(s)
- Hiba A Qassim
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq.
| | - Sabaa T Mohammed
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq
| | - Haider J Muhamed
- Department of Biology, College of Science, Al-Mustansiriyah University, Baghdad, Iraq
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Wen Y, Wang H, Tian D, Wang G. TH17 cell: a double-edged sword in the development of inflammatory bowel disease. Therap Adv Gastroenterol 2024; 17:17562848241230896. [PMID: 38390028 PMCID: PMC10883129 DOI: 10.1177/17562848241230896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.
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Affiliation(s)
- Yue Wen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ge Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
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Chatterjee B, Sarkar M, Bose S, Alam MT, Chaudhary AA, Dixit AK, Tripathi PP, Srivastava AK. MicroRNAs: Key modulators of inflammation-associated diseases. Semin Cell Dev Biol 2024; 154:364-373. [PMID: 36670037 DOI: 10.1016/j.semcdb.2023.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 12/06/2022] [Accepted: 01/11/2023] [Indexed: 01/20/2023]
Abstract
Inflammation is a multifaceted biological and pathophysiological response to injuries, infections, toxins, and inflammatory mechanisms that plays a central role in the progression of various diseases. MicroRNAs (miRNAs) are tiny, 19-25 nucleotides long, non-coding RNAs that regulate gene expression via post-transcriptional repression. In this review, we highlight the recent findings related to the significant roles of miRNAs in regulating various inflammatory cascades and immunological processes in the context of many lifestyle-related diseases such as diabetes, cardiovascular diseases, cancer, etc. We also converse on how miRNAs can have a dual impact on inflammatory responses, suggesting that regulation of their functions for therapeutic purposes may be disease-specific.
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Affiliation(s)
- Bilash Chatterjee
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mrinmoy Sarkar
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India
| | - Subhankar Bose
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Md Tanjim Alam
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSUI), Riyadh, Saudi Arabia
| | | | - Prem Prakash Tripathi
- Cell Biology & Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amit Kumar Srivastava
- Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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11
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Li D, Yao Y, Cheng W, Hou Z, Wang Z, Xiang Y. Self-Priming Cyclic Amplification Accelerating CRISPR Sensor for Sensitive and Specific MicroRNA Analysis with No Background. Anal Chem 2024; 96:1717-1724. [PMID: 38217876 DOI: 10.1021/acs.analchem.3c04866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2024]
Abstract
In this work, we demonstrate for the first time the application of the phosphorothioated-terminal hairpin formation and self-priming extension (PS-THSP) reaction for miRNA assays. A self-priming amplification accelerating CRISPR sensor was well-established for sensitive and specific miRNA detection by integrating the PS-THSP reaction and CRISPR/Cas12a system. The sensor consists of three steps: (1) the formation of a complete PS-THSP template in the presence of target miRNA and ligase; (2) the exponential isothermal amplification of the PS-THSP reaction under the action of DNA polymerase; (3) the activation of the CRISPR/Cas12a fluorescence system to generate signals. We used miR-21 as a model target. The sensor can achieve sensitive detection of miR-21 without the involvement of any primers, and the special design of the CRISPR proto-spacer neighbor motif (PAM) sequence effectively avoids the interference of the background signal. In addition, the sensor can not only identify single-base mutant homologous sequences but also show stable performance in complex biological matrices. We have successfully used this sensor to accurately analyze miR-21 in different cell lines and real clinical samples, demonstrating its great potential in clinical diagnosis.
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Affiliation(s)
- Dayong Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Yanheng Yao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Wenting Cheng
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Zhiqiang Hou
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Zhongyun Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P. R. China
| | - Yang Xiang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. China
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12
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Xu SJ, Chen JH, Chang S, Li HL. The role of miRNAs in T helper cell development, activation, fate decisions and tumor immunity. Front Immunol 2024; 14:1320305. [PMID: 38264670 PMCID: PMC10803515 DOI: 10.3389/fimmu.2023.1320305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/20/2023] [Indexed: 01/25/2024] Open
Abstract
T helper (Th) cells are central members of adaptive immunity and comprise the last line of defense against pathogen infection and malignant cell invasion by secreting specific cytokines. These cytokines then attract or induce the activation and differentiation of other immune cells, including antibody-producing B cells and cytotoxic CD8+ T cells. Therefore, the bidirectional communication between Th cells and tumor cells and their positioning within the tumor microenvironment (TME), especially the tumor immune microenvironment (TIME), sculpt the tumor immune landscape, which affects disease initiation and progression. The type, number, and condition of Th cells in the TME and TIME strongly affect tumor immunity, which is precisely regulated by key effectors, such as granzymes, perforins, cytokines, and chemokines. Moreover, microRNAs (miRNAs) have emerged as important regulators of Th cells. In this review, we discuss the role of miRNAs in regulating Th cell mediated adaptive immunity, focusing on the development, activation, fate decisions, and tumor immunity.
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Affiliation(s)
- Shi-Jun Xu
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
- Henan Medical Device Engineering Research Center of Interventional Therapy for Non-vascular Tumors, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Jin-Hua Chen
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Suhwan Chang
- Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Hai-Liang Li
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
- Henan Medical Device Engineering Research Center of Interventional Therapy for Non-vascular Tumors, Henan Cancer Hospital, Zhengzhou, Henan, China
- Department of Radiology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
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13
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Santana-da-Silva MN, Sena-dos-Santos C, Cáceres-Durán MÁ, de Souza FG, Gobbo AR, Pinto P, Salgado CG, dos Santos SEB. ncRNAs: an unexplored cellular defense mechanism in leprosy. Front Genet 2023; 14:1295586. [PMID: 38116294 PMCID: PMC10729009 DOI: 10.3389/fgene.2023.1295586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/24/2023] [Indexed: 12/21/2023] Open
Abstract
Leprosy is an infectious disease primarily caused by the obligate intracellular parasite Mycobacterium leprae. Although it has been considered eradicated in many countries, leprosy continues to be a health issue in developing nations. Besides the social stigma associated with it, individuals affected by leprosy may experience nerve damage leading to physical disabilities if the disease is not properly treated or early diagnosed. Leprosy is recognized as a complex disease wherein socioenvironmental factors, immune response, and host genetics interact to contribute to its development. Recently, a new field of study called epigenetics has emerged, revealing that the immune response and other mechanisms related to infectious diseases can be influenced by noncoding RNAs. This review aims to summarize the significant advancements concerning non-coding RNAs in leprosy, discussing the key perspectives on this novel approach to comprehending the pathophysiology of the disease and identifying molecular markers. In our view, investigations on non-coding RNAs in leprosy hold promise and warrant increased attention from researches in this field.
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Affiliation(s)
- Mayara Natália Santana-da-Silva
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
- Laboratório de Imunologia, Seção de Virologia (SAVIR), Instituto Evandro Chagas, Ananindeua, Brazil
| | - Camille Sena-dos-Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Miguel Ángel Cáceres-Durán
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Felipe Gouvea de Souza
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Angelica Rita Gobbo
- Laboratório de Dermato-Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Pablo Pinto
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
- Laboratório de Dermato-Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Claudio Guedes Salgado
- Laboratório de Dermato-Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
| | - Sidney Emanuel Batista dos Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
- Laboratório de Dermato-Imunologia, Instituto de Ciências Biológicas (ICB), Universidade Federal do Pará (UFPA), Belém, Brazil
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14
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Yang LR, Li L, Meng MY, Li TT, Zhao YY, Yang SL, Gao H, Tang WW, Yang Y, Yang LL, Wang WJ, Liao LW, Hou ZL. IL-7 promotes CD19-directed CAR-T cells proliferation through miRNA-98-5p by targeting CDKN1A. Int Immunopharmacol 2023; 124:110974. [PMID: 37757633 DOI: 10.1016/j.intimp.2023.110974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Abstract
CAR-T targeting CD19 have achieved significant effects in the treatment of B-line leukemia and lymphoma. However, the treated patients frequently relapsed and could not achieve complete remission. Therefore, improving the proliferation and cytotoxicity of CAR-T cells, reducing exhaustion and enhancing infiltration capacity are still issues to be solved. The IL-7 has been shown to enhance the memory characteristics of CAR-T cells, but the specific mechanism has yet to be elaborated. miRNAs play an important role in T cell activity. However, whether miRNA is involved in the activation of CAR-T cells by IL-7 has not yet been reported. Our previous study had established the 3rd generation CAR-T cells. The present study further found that IL-7 significantly increased the proliferation of anti-CD19 CAR-T cells, the ratio of CD4 + CAR + cells and the S phase of cell cycle. In vivo study NAMALWA xenograft model showed that IL-7-stimulated CAR-T cells possessed stronger tumoricidal efficiency. Further we validated that IL-7 induced CAR-T cells had low expression of CDKN1A and high expression of miRNA-98-5p. Additionally, CDKN1A was associated with miRNA-98-5p. Our results, for the first time, suggested IL-7 could conspicuously enhance the proliferation of CAR-T cells through miRNA-98-5p targeting CDKN1A expression, which should be applied to CAR-T production.
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Affiliation(s)
- Li-Rong Yang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Department of Oncology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Lin Li
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Ming-Yao Meng
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Tian-Tian Li
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Kunming Medical University, Kunming, Yunnan Province, China
| | - Yi-Yi Zhao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Song-Lin Yang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Kunming Medical University, Kunming, Yunnan Province, China
| | - Hui Gao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Wei-Wei Tang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Yang Yang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Kunming Medical University, Kunming, Yunnan Province, China
| | - Li-Li Yang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Kunming Medical University, Kunming, Yunnan Province, China
| | - Wen-Ju Wang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China
| | - Li-Wei Liao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China.
| | - Zong-Liu Hou
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, China; Key Laboratory of Tumor Immunological Prevention and Treatment, Yunnan Province, China; Yunnan Cell Biology and Clinical Translation Research Center, China.
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15
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Zhu WS, Wheeler BD, Ansel KM. RNA circuits and RNA-binding proteins in T cells. Trends Immunol 2023; 44:792-806. [PMID: 37599172 PMCID: PMC10890840 DOI: 10.1016/j.it.2023.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023]
Abstract
RNA is integral to the regulatory circuits that control cell identity and behavior. Cis-regulatory elements in mRNAs interact with RNA-binding proteins (RBPs) that can alter RNA sequence, stability, and translation into protein. Similarly, long noncoding RNAs (lncRNAs) scaffold ribonucleoprotein complexes that mediate transcriptional and post-transcriptional regulation of gene expression. Indeed, cell programming is fundamental to multicellular life and, in this era of cellular therapies, it is of particular interest in T cells. Here, we review key concepts and recent advances in our understanding of the RNA circuits and RBPs that govern mammalian T cell differentiation and immune function.
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Affiliation(s)
- Wandi S Zhu
- Department of Microbiology & Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Benjamin D Wheeler
- Department of Microbiology & Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - K Mark Ansel
- Department of Microbiology & Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
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16
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Hasiuk M, Dölz M, Marone R, Jeker LT. Leveraging microRNAs for cellular therapy. Immunol Lett 2023; 262:27-35. [PMID: 37660892 DOI: 10.1016/j.imlet.2023.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/16/2023] [Accepted: 08/30/2023] [Indexed: 09/05/2023]
Abstract
Owing to Karl Landsteiner's discovery of blood groups, blood transfusions became safe cellular therapies in the early 1900s. Since then, cellular therapy made great advances from transfusions with unmodified cells to today's commercially available chimeric antigen receptor (CAR) T cells requiring complex manufacturing. Modern cellular therapy products can be improved using basic knowledge of cell biology and molecular genetics. Emerging genome engineering tools are becoming ever more versatile and precise and thus catalyze rapid progress towards programmable therapeutic cells that compute input and respond with defined output. Despite a large body of literature describing important functions of non-coding RNAs including microRNAs (miRNAs), the vast majority of cell engineering efforts focuses on proteins. However, miRNAs form an important layer of posttranscriptional regulation of gene expression. Here, we highlight examples of how miRNAs can successfully be incorporated into engineered cellular therapies.
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Affiliation(s)
- Marko Hasiuk
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Marianne Dölz
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Romina Marone
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Lukas T Jeker
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland; Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
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17
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Mohammadi-Kordkhayli M, Sahraian MA, Ghorbani S, Mansouri F, Talebi F, Noorbakhsh F, Saboor-Yaraghi AA. Vitamins A and D Enhance the Expression of Ror-γ-Targeting miRNAs in a Mouse Model of Multiple Sclerosis. Mol Neurobiol 2023; 60:5853-5865. [PMID: 37353624 DOI: 10.1007/s12035-023-03427-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/05/2023] [Indexed: 06/25/2023]
Abstract
Autoreactive T cells, particularly those characterized by a Th17 phenotype, exert significant influence on the pathogenesis of multiple sclerosis (MS). The present study aimed to elucidate the impact of individual and combined administration of vitamin A and D on neuroinflammation, and microRNAs (miRNAs) involved in T helper (Th)17 development, utilizing a murine model of experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice, and 3 days prior to immunization, intraperitoneal injections of vitamins A and D or their combination were administered. Th17 cell percentages were determined in splenocytes utilizing intracellular staining and flow cytometry. Furthermore, the expression of Ror γ-t, miR-98-5p and Let-7a-5p, was measured in both splenocytes and spinal cord tissues using RT-PCR. Treatment with vitamin A and D resulted in a reduction in both disease severity in EAE mice. Treated mice showed a decreased frequency of Th17 cells and lower expression levels of IL17 and Ror γ-t in splenocytes and spinal cord. The spinal cord tissues and splenocytes of mice treated with vitamins A, D, and combined A+D showed a significant upregulation of miR-98-5p and Let-7a-5p compared to the EAE group. Statistical analysis indicated a strong negative correlation between miR-98-5p and Let-7a-5p levels in splenocytes and Ror-t expression. Our findings indicate that the administration of vitamins A and D exerts a suppressive effect on neuroinflammation in EAE that is associated with a reduction in the differentiation of T cells into the Th17 phenotype and is mediated by the upregulation of miR-98-5p and Let-7a-5p, which target the Ror γ-t.
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Affiliation(s)
- Marziyeh Mohammadi-Kordkhayli
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Alberta, Canada
| | - Mohammad Ali Sahraian
- Sina MS Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Ghorbani
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Alberta, Canada
| | - Fatemeh Mansouri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Talebi
- Immunoregulation Research Center, Shahed University, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ali Akbar Saboor-Yaraghi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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18
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Mohammadinasr M, Montazersaheb S, Molavi O, Kahroba H, Talebi M, Ayromlou H, Hejazi MS. Multiplex Analysis of Cerebrospinal Fluid and Serum Exosomes MicroRNAs of Untreated Relapsing Remitting Multiple Sclerosis (RRMS) and Proposing Noninvasive Diagnostic Biomarkers. Neuromolecular Med 2023; 25:402-414. [PMID: 37020076 DOI: 10.1007/s12017-023-08744-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 03/19/2023] [Indexed: 04/07/2023]
Abstract
Exosomal microRNAs (miRNAs) are emerging diagnostic biomarkers for neurodegenerative diseases. In this study, we aimed to detect relapsing-remitting multiple sclerosis (RRMS)-specific miRNAs in cerebrospinal fluid (CSF) and serum exosomes with diagnostic potential. One ml of CSF and serum sample were collected from each of the 30 untreated RRMS patients and healthy controls (HCs). A panel of 18 miRNAs affecting inflammatory responses was applied, and qRT-PCR was conducted to detect differentially expressed exosomal miRNAs in CSF and serum of RRMS patients. We identified that 17 out of 18 miRNAs displayed different patterns in RRMS patients compared to HCs. Let-7 g-5p, miR-18a-5p, miR-145-5p, and miR-374a-5p with dual pro-inflammatory and anti-inflammatory actions and miR-150-5p and miR-342-3p with anti-inflammatory action were significantly upregulated in both CSF and serum-derived exosomes of RRMS patients compared to corresponding HCs. Additionally, anti-inflammatory miR-132-5p and pro-inflammatory miR-320a-5p were significantly downregulated in both CSF and serum-derived exosomes of RRMS patients compared to HCs. Ten of 18 miRNAs were differentially expressed in CSF and serum exosomes of the patients. Furthermore, miR-15a-5p, miR-19b-3p, and miR-432-5p were upregulated, and miR-17-5p was downregulated only in CSF exosomes. Interestingly, U6 housekeeping gene was differentially expressed in CSF and serum exosomes, in both RRMS and HCs. As the first report describing CSF exosomal miRNAs expression profile compared to that of serum exosomes in untreated RRMS patients, we showed that CSF and serum exosomes are not identical in terms of biological compounds and display different patterns in miRNAs and U6 expression.
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Affiliation(s)
- Mina Mohammadinasr
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ommoleila Molavi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School of Oncology and Development Biology, Maastricht University, Maastricht, The Netherlands
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Mahnaz Talebi
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hormoz Ayromlou
- Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Hejazi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Madaan P, Sharma U, Tyagi N, Brar BK, Bansal S, Kushwaha HR, Kapoor HS, Jain A, Jain M. A panel of blood-based circulatory miRNAs with diagnostic potential in patients with psoriasis. Front Med (Lausanne) 2023; 10:1207993. [PMID: 37700769 PMCID: PMC10493330 DOI: 10.3389/fmed.2023.1207993] [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: 04/18/2023] [Accepted: 07/28/2023] [Indexed: 09/14/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin disease with keratinocyte hyperproliferation and T cells as key mediators of lesional and systemic inflammatory changes. To date, no suitable differential biomarkers are available for the disease diagnosis. More recently, microRNAs have been identified as critical regulators of lesional and systemic immune changes in psoriasis with diagnostic potential. We have performed expression profiling of T cell-specific miRNAs in 38 plasma samples from psoriasis vulgaris patients and an equal number of age- and gender-matched healthy subjects. Our findings have identified a panel of five blood-based circulatory miRNAs with a significant change in their expression levels, comprising miR-215, miR-148a, miR-125b-5p, miR-223, and miR-142-3p, which can differentiate psoriasis vulgaris patients from healthy individuals. The receiver operating characteristic (ROC) curves for all five miRNAs individually and in combination exhibited a significant disease discriminatory area under the curve with an AUC of 0.762 and a p < 0.0001 for all the miRNAs together. Statistically, all five miRNAs in combination depicted the best-fit model in relation to disease severity (PASI) compared with individual miRNAs, with the highest R2 value of 0.94 and the lowest AIC score of 131.8. Each of the miRNAs also exhibited a significant association with at least one of the other miRNAs in the panel. Importantly, the five miRNAs in the panel regulate one or more immune-inflammation pathways based on target prediction, pathway network analysis, and validated roles in the literature. The miRNA panel provides a rationalized combination of biomarkers that can be tested further on an expanded cohort of patients for their diagnostic value.
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Affiliation(s)
- Priyanka Madaan
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Nipanshi Tyagi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Balvinder Kaur Brar
- Department of Skin and VD, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - Shivani Bansal
- Department of Dermatology, All India Institute of Medical Sciences, Bathinda, Punjab, India
| | | | | | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, India
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20
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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21
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Margiana R, Kzar HH, Hussam F, Hameed NM, Al-Qaim ZH, Al-Gazally ME, Kandee M, Saleh MM, Toshbekov BBU, Tursunbaev F, Karampoor S, Mirzaei R. Exploring the impact of miR-128 in inflammatory diseases: A comprehensive study on autoimmune diseases. Pathol Res Pract 2023; 248:154705. [PMID: 37499519 DOI: 10.1016/j.prp.2023.154705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/19/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023]
Abstract
microRNAs (miRNAs) play a crucial role in various biological processes, including immune system regulation, such as cell proliferation, tolerance (central and peripheral), and T helper cell development. Dysregulation of miRNA expression and activity can disrupt immune responses and increase susceptibility to neuroimmune disorders. Conversely, miRNAs have been shown to have a protective role in modulating immune responses and preventing autoimmunity. Specifically, reducing the expression of miRNA-128 (miR-128) in an Alzheimer's disease (AD) mouse model has been found to improve cognitive deficits and reduce neuropathology. This comprehensive review focuses on the significance of miR-128 in the pathogenesis of neuroautoimmune disorders, including multiple sclerosis (MS), AD, Parkinson's disease (PD), Huntington's disease (HD), epilepsy, as well as other immune-mediated diseases such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Additionally, we present compelling evidence supporting the potential use of miR-128 as a diagnostic or therapeutic biomarker for neuroimmune disorders. Collectively, the available literature suggests that targeting miR-128 could be a promising strategy to alleviate the behavioral symptoms associated with neuroimmune diseases. Furthermore, further research in this area may uncover new insights into the molecular mechanisms underlying these disorders and potentially lead to the development of novel therapeutic approaches.
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Affiliation(s)
- Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Hamzah H Kzar
- Veterinary Medicine College, Al-Qasim Green University, Al-Qasim, Iraq
| | - Fadhil Hussam
- College of Medical Technology, Medical Lab Techniques, Al-farahidi University, Iraq
| | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Iraq
| | | | | | - Mahmoud Kandee
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Hofuf 31982, Al-Ahsa, Saudi Arabia; Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh 33516, Egypt
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University Of Anbar, Anbar, Iraq
| | | | - Farkhod Tursunbaev
- MD, Independent Researcher, "Medcloud" educational centre, Tashkent, Uzbekistan
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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22
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Galbiati V, Lefevre MA, Maddalon A, Vocanson M, Iulini M, Marinovich M, Corsini E. Role of miR-24-3p and miR-146a-5p in dendritic cells' maturation process induced by contact sensitizers. Arch Toxicol 2023; 97:2183-2191. [PMID: 37326882 PMCID: PMC10322961 DOI: 10.1007/s00204-023-03542-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/06/2023] [Indexed: 06/17/2023]
Abstract
MiRNAs are non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Although allergic contact dermatitis has been studied extensively, few studies addressed miRNA expression and their role in dendritic cell activation. The main aim of this work was to investigate the role of miRNAs in the underlying mechanism of dendritic cell maturation induced by contact sensitizers of different potency. Experiments were conducted using THP-1-derived immature DCs (iDCs). Contact allergens of different potency were used: p-benzoquinone, Bandrowski's base, and 2,4-dinitrochlorobenzene as extreme; nickel sulfate hexahydrate, diethyl maleate and 2-mercaptobenzothiazole as moderate; and α-hexyl cinnamaldehyde, eugenol, and imidazolidinyl urea as weak. Selective inhibitor and mimic miRNAs were then used and several cell surface markers was evaluated as targets. Also, patients patch tested with nickel were analyzed to determine miRNAs expression. Results indicate an important role of miR-24-3p and miR-146a-5p in DCs activation. miR-24-3p was up-regulated by extreme and weak contact allergens, while miR-146a-5p was up-regulated by weak and moderate contact allergens and down-regulated only by the extreme ones. Also, the involvement of PKCβ in contact allergen-induced miR-24-3p and miR-146a-5p expression was demonstrated. Furthermore, the expression of the two miRNAs maintains the same trend of expression in both in vitro and in human conditions after nickel exposure. Results obtained suggest the involvement of miR-24 and miR-146a in DCs maturation process in the proposed in vitro model, supported also by human evidences.
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Affiliation(s)
- Valentina Galbiati
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy.
| | - Marine-Alexia Lefevre
- CIRI, Centre International de Recherche en Infectiologie, (Team Epidermal Immunity and Allergy), Univ Lyon; Inserm, U1111, Université Claude Bernard Lyon 1; CNRS, UMR5308; ENS de Lyon, Lyon, France
| | - Ambra Maddalon
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
| | - Marc Vocanson
- CIRI, Centre International de Recherche en Infectiologie, (Team Epidermal Immunity and Allergy), Univ Lyon; Inserm, U1111, Université Claude Bernard Lyon 1; CNRS, UMR5308; ENS de Lyon, Lyon, France
| | - Martina Iulini
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
| | - Marina Marinovich
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
| | - Emanuela Corsini
- Laboratory of Toxicology, DiSFeB, Università degli Studi di Milano, Milan, Italy
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23
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Jiang Q, Wang Q, Tan S, Cai J, Ye X, Su G, Yang P. Effects of Plasma-Derived Exosomal miRNA-19b-3p on Treg/T Helper 17 Cell Imbalance in Behçet's Uveitis. Invest Ophthalmol Vis Sci 2023; 64:28. [PMID: 37093132 PMCID: PMC10148662 DOI: 10.1167/iovs.64.4.28] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
Purpose To explore the potential role of plasma-derived exosomal microRNAs (miRNAs) in the development of regulatory T cell (Treg)/T helper 17 (Th17) cell imbalances in Behçet's uveitis (BU). Methods The exosome treatment was conducted to evaluate the effects of plasma exosomes from patients with active BU and healthy controls on the Treg/Th17 cell balance. miRNA sequencing analysis of plasma exosomes was conducted to identify differentially expressed miRNAs between patients with active BU and healthy controls. miRTarBase analysis and dual-luciferase reporter assays were conducted to identify the target genes of miR-19b-3p. CD4+T cells were transfected with miR-19b-3p mimic or inhibitor to evaluate its regulation of the Treg/Th17 cell balance. The Treg/Th17 cell balance in CD4+T cells was evaluated by flow cytometry and enzyme-linked immunosorbent assay. Results Exosomes from patients with active BU promoted Th17 cell differentiation and inhibited Treg cell differentiation. MiRNA sequencing analysis revealed 177 upregulated and 274 downregulated miRNAs in plasma exosomes of patients with active BU. Among them, miR-19b-3p was significantly elevated, and its target genes were identified as being involved in T-cell differentiation. miR-19b-3p overexpression downregulated CD46 expression and the Treg/Th17 cell ratio in CD4+T cells from healthy controls, whereas miR-19b-3p inhibition reversed these regulatory effects and restored the Treg/Th17 cell balance of CD4+T cells from patients with active BU. Conclusions Plasma-derived exosomes from patients with active BU showed a markedly differential miRNA expression in comparison to healthy controls. Highly expressed miRNA-19b-3p could induce a Treg/Th17 cell imbalance, probably by downregulating CD46 expression.
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Affiliation(s)
- Qingyan Jiang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Qingfeng Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Shiyao Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Jinyu Cai
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Xingsheng Ye
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China
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24
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Crosstalk of Transcriptional Regulators of Adaptive Immune System and microRNAs: An Insight into Differentiation and Development. Cells 2023; 12:cells12040635. [PMID: 36831302 PMCID: PMC9953855 DOI: 10.3390/cells12040635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/27/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
MicroRNAs (miRNAs), as small regulatory RNA molecules, are involved in gene expression at the post-transcriptional level. Hence, miRNAs contribute to gene regulation of various steps of different cell subsets' differentiation, maturation, and activation. The adaptive immune system arm, which exhibits the most specific immune responses, is also modulated by miRNAs. The generation and maturation of various T-cell subsets concomitant with B-cells is under precise regulation of miRNAs which function directly on the hallmark genes of each cell subset or indirectly through regulation of signaling pathway mediators and/or transcription factors involved in this maturation journey. In this review, we first discussed the origination process of common lymphocyte progenitors from hematopoietic stem cells, which further differentiate into various T-cell subsets under strict regulation of miRNAs and transcription factors. Subsequently, the differentiation of B-cells from common lymphocyte progenitors in bone marrow and periphery were discussed in association with a network of miRNAs and transcription factors.
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25
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Assadiasl S, Rajabinejad M, Soleimanifar N, Makiyan F, Azizi E, Rezaiemanesh A, Nicknam MH. MicroRNAs-mediated regulation pathways in rheumatic diseases. Inflammopharmacology 2023; 31:129-144. [PMID: 36469219 DOI: 10.1007/s10787-022-01097-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 10/29/2022] [Indexed: 12/09/2022]
Abstract
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are two common rheumatic disorders marked by persistent inflammatory joint disease. Patients with RA have osteodestructive symptoms, but those with AS have osteoproliferative manifestations. Ligaments, joints, tendons, bones, and muscles are all affected by rheumatic disorders. In recent years, many epigenetic factors contributing to the pathogenesis of rheumatoid disorders have been studied. MicroRNAs (miRNAs) are small, non-coding RNA molecules implicated as potential therapeutic targets or biomarkers in rheumatic diseases. MiRNAs play a critical role in the modulation of bone homeostasis and joint remodeling by controlling fibroblast-like synoviocytes (FLSs), chondrocytes, and osteocytes. Several miRNAs have been shown to be dysregulated in rheumatic diseases, including miR-10a, 16, 17, 18a, 19, 20a, 21, 27a, 29a, 34a, 103a, 125b, 132, 137, 143, 145, 146a, 155, 192, 203, 221, 222, 301a, 346, and 548a.The major molecular pathways governed by miRNAs in these cells are Wnt, bone-morphogenic protein (BMP), nuclear factor (NF)-κB, receptor activator of NF-κB (RANK)-RANK ligand (RANKL), and macrophage colony-stimulating factor (M-CSF) receptor pathway. This review aimed to provide an overview of the most important signaling pathways controlled by miRNAs in rheumatic diseases.
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Affiliation(s)
- Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Misagh Rajabinejad
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Narjes Soleimanifar
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Makiyan
- Division of Nanobiotechnology, Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Esfandiar Azizi
- Department of Immunology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, PO-Box: 6714869914, Bākhtarān, Iran.
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26
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Qin X, Wang X, Xu K, Zhang Y, Tian H, Li Y, Qi B, Yang X. Quantitative analysis of miRNAs using SplintR ligase-mediated ligation of complementary-pairing probes enhanced by RNase H (SPLICER)-qPCR. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 31:241-255. [PMID: 36700047 PMCID: PMC9842969 DOI: 10.1016/j.omtn.2022.12.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Here, a method using SplintR ligase-mediated ligation of complementary-pairing probes enhanced by RNase H (SPLICER) for miRNAs quantification was established. The strategy has two steps: (1) ligation of two DNA probes specifically hybridize to target miRNA and (2) qPCR amplifying the ligated probe. The miRNA-binding regions of the probes are stem-looped, a motif significantly reduces nonspecific ligation at high ligation temperature (65°C). The ends of the probes are designed complementary to form a paired probe, facilitating the recognition of target miRNAs with low concentrations. RNase H proved to be able to stabilize the heteroduplex formed by the probe and target miRNA, contributing to enhanced sensitivity (limit of detection = 60 copies). High specificity (discriminating homology miRNAs differing only one nucleotide), wide dynamic range (seven orders of magnitude) and ability to accurately detect plant miRNAs (immune to hindrance of 2'-O-methyl moiety) enable SPLICER comparable with the commercially available TaqMan and miRCURY assays. SYBR green I, rather than expensive hydrolysis or locked nucleic acid probes indispensable to TaqMan and miRCURY assays, is adequate for SPLICER. The method was efficient (<1 h), economical ($7 per sample), and robust (able to detect xeno-miRNAs in mammalian bodies), making it a powerful tool for molecular diagnosis and corresponding therapy.
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Affiliation(s)
- Xinshu Qin
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China
| | - Xingyu Wang
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China,Corresponding author: Xingyu Wang, College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710054, Shaanxi, China.
| | - Ke Xu
- Department of Joint Surgery, Hong Hui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi, China
| | - Yi Zhang
- Department of Food Science, The Pennsylvania State University, University Park, PA 16802, USA
| | - Hongye Tian
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China
| | - Yinglei Li
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China
| | - Bangran Qi
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China
| | - Xingbin Yang
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710062, Shaanxi, China,Corresponding author: Xingbin Yang, College of Food Engineering and Nutritional Science, Shaanxi Normal University, No. 620 West Chang’an Avenue, Xi’an 710054, Shaanxi, China.
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27
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MicroRNAs in T Cell-Immunotherapy. Int J Mol Sci 2022; 24:ijms24010250. [PMID: 36613706 PMCID: PMC9820302 DOI: 10.3390/ijms24010250] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/06/2022] [Accepted: 12/15/2022] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.
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28
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Dölz M, Hasiuk M, Gagnon JD, Kornete M, Marone R, Bantug G, Kageyama R, Hess C, Ansel KM, Seyres D, Roux J, Jeker LT. Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4 + T cells. iScience 2022; 25:105372. [PMID: 36388982 PMCID: PMC9646923 DOI: 10.1016/j.isci.2022.105372] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 08/12/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
CD28 provides the prototypical costimulatory signal required for productive T-cell activation. Known molecular consequences of CD28 costimulation are mostly based on studies of protein signaling molecules. The microRNA cluster miR-17∼92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17∼92 cell-intrinsically largely overcomes defects caused by CD28 deficiency. Combining genetics, transcriptomics, bioinformatics, and biochemical miRNA:mRNA interaction maps we empirically validate miR-17∼92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17∼92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17∼92 targets Pten and Nrbp1 in naive CD28-/- CD4+ T cells differentially increases proliferation and expression of the activation markers CD25 and CD44, respectively. Thus, we propose that miR-17∼92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation by dampening multiple brakes that prevent T cell activation.
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Affiliation(s)
- Marianne Dölz
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Marko Hasiuk
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - John D. Gagnon
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Mara Kornete
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
| | - Romina Marone
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Glenn Bantug
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
| | - Robin Kageyama
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Christoph Hess
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Department of Medicine – CITIID, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK
| | - K. Mark Ansel
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Denis Seyres
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
| | - Julien Roux
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Lukas T. Jeker
- Department of Biomedicine, Basel University Hospital and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland
- Transplantation Immunology & Nephrology, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
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29
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Choi JO, Ham JH, Hwang SS. RNA Metabolism in T Lymphocytes. Immune Netw 2022; 22:e39. [PMID: 36381959 PMCID: PMC9634142 DOI: 10.4110/in.2022.22.e39] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 01/25/2023] Open
Abstract
RNA metabolism plays a central role in regulating of T cell-mediated immunity. RNA processing, modifications, and regulations of RNA decay influence the tight and rapid regulation of gene expression during T cell phase transition. Thymic selection, quiescence maintenance, activation, differentiation, and effector functions of T cells are dependent on selective RNA modulations. Recent technical improvements have unveiled the complex crosstalk between RNAs and T cells. Moreover, resting T cells contain large amounts of untranslated mRNAs, implying that the regulation of RNA metabolism might be a key step in controlling gene expression. Considering the immunological significance of T cells for disease treatment, an understanding of RNA metabolism in T cells could provide new directions in harnessing T cells for therapeutic implications.
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Affiliation(s)
- Jin Ouk Choi
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jeong Hyeon Ham
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Soo Seok Hwang
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Severance Biomedical Science Institute and Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea.,Chronic Intractable Disease Systems Medicine Research Center, Institute of Genetic Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea
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30
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He L, Liu J, Wang X, Wang Y, Zhu J, Kang X. Identifying a novel serum microRNA biomarker panel for the diagnosis of childhood asthma. Exp Biol Med (Maywood) 2022; 247:1732-1740. [PMID: 36000159 PMCID: PMC9638957 DOI: 10.1177/15353702221114870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The pathological mechanism of childhood asthma is complex, and timely diagnosis is the key to effective prevention and control of childhood asthma. We collected 170 serum samples from 95 children with asthma and 75 healthy children. Serum miRNA biomarkers were analyzed by Illumina sequencing for childhood asthma. Differentially serum miRNAs were confirmed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. The Illumina sequencing data showed the differential expression of 111 serum miRNAs among asthmatic and healthy children. After confirmation of miRNAs expression through qRT-PCR, four of them (namely hsa-miR-106a-5p, hsa-miR-18a-5p, hsa-miR-144-3p, and hsa-miR-375) manifested significant differential expression between asthmatic children and healthy controls. The biomarkers classification tree model created with these four miRNAs using the Biomarker Patterns Software could effectively separate childhood asthma and healthy children, with a specificity of 88.3%, a sensitivity of 95.0%, and an area under the curve (AUC) value of 0.942. The regulatory networks containing miRNAs and their gene targets suggested that the four miRNAs might have gene targets implicated in inflammation, immunity, and transcriptional efficiency. Taken together, this four-serum-miRNA panel is a promising biomarker to diagnose childhood asthma noninvasively.
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Affiliation(s)
- Linjuan He
- College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 311121, China
| | - Jiyan Liu
- College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 311121, China,Department of Academic Journals, Hangzhou Normal University, Hangzhou 311121, China,Jiyan Liu.
| | - Xiaoyue Wang
- Department of Academic Journals, Hangzhou Normal University, Hangzhou 311121, China
| | - Yuanzhao Wang
- Department of Pediatrics, Zhejiang Hospital of Traditional Chinese Medicine, Hangzhou 310006, China
| | - Jiawen Zhu
- Department of Pediatrics, Zhejiang Hospital of Traditional Chinese Medicine, Hangzhou 310006, China
| | - Xuexue Kang
- College of Life and Environmental Science, Hangzhou Normal University, Hangzhou 311121, China
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31
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Lee MF, Voon GZ, Lim HX, Chua ML, Poh CL. Innate and adaptive immune evasion by dengue virus. Front Cell Infect Microbiol 2022; 12:1004608. [PMID: 36189361 PMCID: PMC9523788 DOI: 10.3389/fcimb.2022.1004608] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/26/2022] [Indexed: 11/26/2022] Open
Abstract
Dengue is a mosquito-borne disease which causes significant public health concerns in tropical and subtropical countries. Dengue virus (DENV) has evolved various strategies to manipulate the innate immune responses of the host such as ‘hiding’ in the ultrastructure of the host, interfering with the signaling pathway through RNA modifications, inhibiting type 1 IFN production, as well as inhibiting STAT1 phosphorylation. DENV is also able to evade the adaptive immune responses of the host through antigenic variation, antigen-dependent enhancement (ADE), partial maturation of prM proteins, and inhibition of antigen presentation. miRNAs are important regulators of both innate and adaptive immunity and they have been shown to play important roles in DENV replication and pathogenesis. This makes them suitable candidates for the development of anti-dengue therapeutics. This review discusses the various strategies employed by DENV to evade innate and adaptive immunity. The role of miRNAs and DENV non-structural proteins (NS) are promising targets for the development of anti-dengue therapeutics.
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Vajari MK, Moradinasab S, Yousefi AM, Bashash D. Noncoding RNAs in diagnosis and prognosis of graft-versus-host disease (GVHD). J Cell Physiol 2022; 237:3480-3495. [PMID: 35842836 DOI: 10.1002/jcp.30830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/22/2022] [Accepted: 06/30/2022] [Indexed: 11/11/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a functional therapy for a plethora of hematologic malignancies and immune disorders. Graft-versus-host disease (GVHD), on the other hand, is one of the major complications ahead of a successful HSCT, contributing to transplant-associated morbidity and mortality. Notably, little is known about the underlying mechanism of this event; therefore, exploring precise biomarkers and uncovering the molecular pathogenesis of GVHD is valuable for early diagnosis and treatment optimization. Thanks to the advances in sequencing techniques, the noncoding sequences of the human genome-formerly considered "junk"-are now identified as functional molecules. Noncoding RNAs (ncRNA) control cellular responses by regulating gene expression, and previous studies have shown that these tiny molecules, especially microRNAs (miRNAs), can affect allogeneic T cell responses in both animal models and clinical experiments. The present study gives an overview of the functions of various miRNAs in regulating T cell responses in GVHD. We also provide an outlook on miRNAs and long noncoding RNAs (lncRNAs) potential role in GVHD with the hope of providing a future research direction for expanding their application as the sensitive and noninvasive diagnostic or prognostic biomarkers and also the promising therapeutic targets for improving outcomes after allogeneic HSCT.
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Affiliation(s)
- Mahdi K Vajari
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Moradinasab
- Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wang Z, Heid B, Lu R, Sachdeva M, Edwards MR, Ren J, Cecere TE, Khan D, Jeboda T, Kirsch DG, Reilly CM, Dai R, Ahmed SA. Deletion of microRNA-183-96-182 Cluster in Lymphocytes Suppresses Anti-DsDNA Autoantibody Production and IgG Deposition in the Kidneys in C57BL/6-Fas lpr/lpr Mice. Front Genet 2022; 13:840060. [PMID: 35873462 PMCID: PMC9301314 DOI: 10.3389/fgene.2022.840060] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
Dysregulated miRNAs have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Our previous study reported a substantial increase in three miRNAs located at the miR-183-96-182 cluster (miR-183C) in several autoimmune lupus-prone mice, including MRL/lpr and C57BL/6-lpr (B6/lpr). This study reports that in vitro inhibition of miR-182 alone or miR-183C by specific antagomirs in activated splenocytes from autoimmune-prone MRL/lpr and control MRL mice significantly reduced lupus-related inflammatory cytokines, interferon-gamma (IFNγ), and IL-6 production. To further characterize the role of miR-182 and miR-183C cluster in vivo in lupus-like disease and lymphocyte phenotypes, we used hCD2-iCre to generate B6/lpr mice with conditional deletion of miR-182 or miR-183C in CD2+ lymphocytes (miR-182-/-B6/lpr and miR-183C-/-B6/lpr). The miR-182-/-B6/lpr and miR-183C-/-B6/lpr mice had significantly reduced deposition of IgG immunocomplexes in the kidney when compared to their respective littermate controls, although there appeared to be no remarkable changes in renal pathology. Importantly, we observed a significant reduction of serum anti-dsDNA autoantibodies in miR-183C-/-B6/lpr mice after reaching 24 weeks-of age compared to age-matched miR-183Cfl/flB6/lpr controls. In vitro activated splenocytes from miR-182-/-B6/lpr mice and miR-183C-/-B6/lpr mice showed reduced ability to produce lupus-associated IFNγ. Forkhead box O1(Foxo1), a previously validated miR-183C miRNAs target, was increased in the splenic CD4+ cells of miR-182-/-B6/lpr and miR-183C-/-B6/lpr mice. Furthermore, in vitro inhibition of Foxo1 with siRNA in splenocytes from miR-182-/-B6/lpr and miR-183C-/-B6/lpr mice significantly increased IFNγ expression following anti-CD3/CD28 stimulation, suggesting that miR-182 and miR-183C miRNAs regulate the inflammatory IFNγ in splenocytes via targeting Foxo1. The deletion of either miR-182 alone or the whole miR-183C cluster, however, had no marked effect on the composition of T and B cell subsets in the spleens of B6/lpr mice. There were similar percentages of CD4+, CD8+, CD19+, as well as Tregs, follicular helper T (TFH), germinal center B (GCB), and plasma cells in the miR-183C-/-B6/lpr and miR-182-/-B6/lpr mice and their respective littermate controls, miR-183Cfl/flB6/lpr and miR-182fl/flB6/lpr mice. Together, our data demonstrate a role of miR-183C in the regulation of anti-dsDNA autoantibody production in vivo in B6/lpr mice and the induction of IFNγ in in vitro activated splenocytes from B6/lpr mice.
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Affiliation(s)
- Zhuang Wang
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Bettina Heid
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Ran Lu
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Mohit Sachdeva
- Preclinical Lead Immunology, Spark Theraprutics, Philadelphia, PA, United States
| | - Michael R. Edwards
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - JingJing Ren
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Thomas E. Cecere
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Deena Khan
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Taschua Jeboda
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - David G. Kirsch
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States
| | - Christopher M. Reilly
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
- Edward Via College of Osteopathic Medicine, Blacksburg, VA, United States
| | - Rujuan Dai
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - S. Ansar Ahmed
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
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34
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Xie Q, Xue W. IgE-Mediated food allergy: Current diagnostic modalities and novel biomarkers with robust potential. Crit Rev Food Sci Nutr 2022; 63:10148-10172. [PMID: 35587740 DOI: 10.1080/10408398.2022.2075312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Food allergy (FA) is a serious public health issue afflicting millions of people globally, with an estimated prevalence ranging from 1-10%. Management of FA is challenging due to overly restrictive diets and the lack of diagnostic approaches with high accuracy and prediction. Although measurement of serum-specific antibodies combined with patient medical history and skin prick test is a useful diagnostic tool, it is still an imprecise predictor of clinical reactivity with a high false-positive rate. The double-blind placebo-controlled food challenge represents the gold standard for FA diagnosis; however, it requires large healthcare and involves the risk of acute onset of allergic reactions. Improvement in our understanding of the molecular mechanism underlying allergic disease pathology, development of omics-based methods, and advances in bioinformatics have boosted the generation of a number of robust diagnostic biomarkers of FA. In this review, we discuss how traditional diagnostic modalities guide appropriate diagnosis and management of FA in clinical practice, as well as uncover the potential of the latest biomarkers for the diagnosis, monitoring, and prediction of FA. We also raise perspectives for precise and targeted medical intervention to fill the gap in the diagnosis of FA.
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Affiliation(s)
- Qiang Xie
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, P.R. China
| | - Wentong Xue
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, P.R. China
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35
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Rutman AK, Negi S, Saberi N, Khan K, Tchervenkov J, Paraskevas S. Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios. Front Immunol 2022; 13:784374. [PMID: 35281056 PMCID: PMC8906931 DOI: 10.3389/fimmu.2022.784374] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.
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Affiliation(s)
- Alissa K Rutman
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Sarita Negi
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Nasim Saberi
- Department of Surgery, McGill University, Montréal, QC, Canada
| | - Kashif Khan
- Division of Cardiology and Cardiac Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Jean Tchervenkov
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Steven Paraskevas
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
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36
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Behrens G, Heissmeyer V. Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells. Front Immunol 2022; 13:839762. [PMID: 35251035 PMCID: PMC8894612 DOI: 10.3389/fimmu.2022.839762] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/31/2022] [Indexed: 12/18/2022] Open
Abstract
Post-transcriptional gene regulation by RNA-binding proteins (RBPs) is important in the prevention of inflammatory and autoimmune diseases. With respect to T cell activation and differentiation, the RBPs Roquin-1/2 and Regnase-1 play pivotal roles by inducing degradation and/or translational silencing of target mRNAs. These targets encode important proinflammatory mediators and thus Roquin and Regnase-1 functions dampen cellular programs that can lead to inflammation and autoimmune disease. Recent findings demonstrate direct physical interaction of both RBPs. Here, we propose that cooperativity of trans-acting factors may be more generally used to reinforce the regulatory impact on selected targets and promote specific cell fate decisions. We develop this concept for Roquin and Regnase-1 function in resting and activated T cells and discuss the involvement in autoimmunity as well as how the therapeutic potential can be used in anti-tumor therapies.
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Affiliation(s)
- Gesine Behrens
- Institute for Immunology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
| | - Vigo Heissmeyer
- Institute for Immunology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
- Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany
- *Correspondence: Vigo Heissmeyer,
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37
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LMWH-induced miRNA changes in peripheral blood mononuclear cells (PBMCs) in pregnancies with unexplained recurrent pregnancy loss. J Reprod Immunol 2022; 151:103502. [DOI: 10.1016/j.jri.2022.103502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/08/2022] [Accepted: 02/22/2022] [Indexed: 11/20/2022]
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38
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Chirichella M, Bianchi N, Džafo E, Foli E, Gualdrini F, Kenyon A, Natoli G, Monticelli S. RFX transcription factors control a miR-150/PDAP1 axis that restrains the proliferation of human T cells. PLoS Biol 2022; 20:e3001538. [PMID: 35143476 PMCID: PMC8865640 DOI: 10.1371/journal.pbio.3001538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 02/23/2022] [Accepted: 01/13/2022] [Indexed: 01/11/2023] Open
Abstract
Within the immune system, microRNAs (miRNAs) exert key regulatory functions. However, what are the mRNA targets regulated by miRNAs and how miRNAs are transcriptionally regulated themselves remain for the most part unknown. We found that in primary human memory T helper lymphocytes, miR-150 was the most abundantly expressed miRNA, and its expression decreased drastically upon activation, suggesting regulatory roles. Constitutive MIR150 gene expression required the RFX family of transcription factors, and its activation-induced down-regulation was linked to their reduced expression. By performing miRNA pull-down and sequencing experiments, we identified PDGFA-associated protein 1 (PDAP1) as one main target of miR-150 in human T lymphocytes. PDAP1 acted as an RNA-binding protein (RBP), and its CRISPR/Cas-9–mediated deletion revealed that it prominently contributed to the regulation of T-cell proliferation. Overall, using an integrated approach involving quantitative analysis, unbiased genomics, and genome editing, we identified RFX factors, miR-150, and the PDAP1 RBP as the components of a regulatory axis that restrains proliferation of primary human T lymphocytes. MicroRNAs exert key regulatory functions in the immune system, but their targets are largely unknown. This study shows that the ability of primary human T lymphocytes to proliferate in response to T cell receptor activation is modulated by a network comprising miR-150, transcription factors of the RFX family, and the RNA-binding protein PDAP1.
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Affiliation(s)
- Michele Chirichella
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), Bellinzona, Switzerland
| | - Niccolò Bianchi
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), Bellinzona, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Emina Džafo
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), Bellinzona, Switzerland
| | - Elena Foli
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), Bellinzona, Switzerland
| | - Francesco Gualdrini
- IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy
- Humanitas University, Milan, Italy
| | - Amy Kenyon
- IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy
| | - Gioacchino Natoli
- IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy
- Humanitas University, Milan, Italy
| | - Silvia Monticelli
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana (USI), Bellinzona, Switzerland
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39
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Ahmed RF, Shaker OG, Abdelghany HM, Helmy Abdallah N, Elsayed SH, Kamel BA. Role of micro-RNA132 and its long non coding SOX2 in diagnosis of lupus nephritis. Lupus 2022; 31:89-96. [PMID: 35019799 DOI: 10.1177/09612033211067166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND The skin and the kidney are commonly affected in systemic lupus erythematosus (SLE) with similar molecular mechanisms. Although clinical indicators of renal injury in SLE are fairly uncontroversial, few biomarkers are reliable. The role of micro-RNAs (mi-RNAs) in lupus nephritis (LN) pathogenesis has been investigated to help in early diagnosis. PURPOSE The aim of work is to evaluate miRNA132 and SOX2 expressions in SLE Egyptian patients; with and without nephritis, and the relation between miRNA132 and its long non-coding gene SOX2 in both patients groups. RESEARCH DESIGN This is a case-control study involving 100 SLE patients with and without LN (LN and non-LN groups), and 50 age-and sex-matched healthy controls. The study was carried out to detect miRNA132 and SOX2 expression by quantitative Real-Time Polymerase chain reaction methods. The SLE disease activity index (SLEDAI) was assessed. RESULTS SLEDAI increased in LN compared to non-LN. Micro-RNA132 expression was significantly increased in patient groups compared to controls (p<0.01) and increased in LN more than non-LN group (p<0.001). SOX2 significantly decreased in patient groups compared to controls (p<0.001), and was more in LN compared to non-LN group (p<0.001). There was a negative correlation between miRNA132 and SOX2 expression in both patient groups (p<0.001). CONCLUSION miRNA132 and SOX2 may play a role in SLE activity and help in the early non-invasive diagnosis of LN.
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Affiliation(s)
- Rasha F Ahmed
- Department of Medical Biochemistry, 68786Faculty of Medicine , Minia University, Egypt
| | | | - Hend M Abdelghany
- Department of Medical Biochemistry, 68786Faculty of Medicine , Minia University, Egypt
| | - Nilly Helmy Abdallah
- Department of Internal Medicine, Faculty of Medicine, 158406BeniSuef University, Egypt
| | - Samar Hisham Elsayed
- Department of Medical Biochemistry, 68786Faculty of Medicine , Minia University, Egypt
| | - Bothina Ahmed Kamel
- Department of Medical Biochemistry, 68786Faculty of Medicine , Minia University, Egypt
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40
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Zhou X, Dai H, Jiang H, Rui H, Liu W, Dong Z, Zhang N, Zhao Q, Feng Z, Hu Y, Hou F, Zheng Y, Liu B. MicroRNAs: Potential mediators between particulate matter 2.5 and Th17/Treg immune disorder in primary membranous nephropathy. Front Pharmacol 2022; 13:968256. [PMID: 36210816 PMCID: PMC9532747 DOI: 10.3389/fphar.2022.968256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/29/2022] [Indexed: 11/19/2022] Open
Abstract
Primary membranous nephropathy (PMN), is an autoimmune glomerular disease and the main reason of nephrotic syndrome in adults. Studies have confirmed that the incidence of PMN increases yearly and is related to fine air pollutants particulate matter 2.5 (PM2.5) exposure. These imply that PM2.5 may be associated with exposure to PMN-specific autoantigens, such as the M-type receptor for secretory phospholipase A2 (PLA2R1). Emerging evidence indicates that Th17/Treg turns to imbalance under PM2.5 exposure, but the molecular mechanism of this process in PMN has not been elucidated. As an important indicator of immune activity in multiple diseases, Th17/Treg immune balance is sensitive to antigens and cellular microenvironment changes. These immune pathways play an essential role in the disease progression of PMN. Also, microRNAs (miRNAs) are susceptible to external environmental stimulation and play link role between the environment and immunity. The contribution of PM2.5 to PMN may induce Th17/Treg imbalance through miRNAs and then produce epigenetic affection. We summarize the pathways by which PM2.5 interferes with Th17/Treg immune balance and attempt to explore the intermediary roles of miRNAs, with a particular focus on the changes in PMN. Meanwhile, the mechanism of PM2.5 promoting PLA2R1 exposure is discussed. This review aims to clarify the potential mechanism of PM2.5 on the pathogenesis and progression of PMN and provide new insights for the prevention and treatment of the disease.
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Affiliation(s)
- Xiaoshan Zhou
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Haoran Dai
- Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Hanxue Jiang
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hongliang Rui
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,Beijing Institute of Chinese Medicine, Beijing, China
| | - Wenbin Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhaocheng Dong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Na Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Qihan Zhao
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zhendong Feng
- Pinggu Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Yuehong Hu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Fanyu Hou
- School of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yang Zheng
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Baoli Liu
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
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41
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Samiei H, Ajam F, Gharavi A, Abdolmaleki S, Kokhaei P, Mohammadi S, Memarian A. Simultaneous disruption of circulating miR-21 and cytotoxic T lymphocytes (CTLs): Prospective diagnostic and prognostic markers for esophageal squamous cell carcinoma (ESCC). J Clin Lab Anal 2022; 36:e24125. [PMID: 34799871 PMCID: PMC8761409 DOI: 10.1002/jcla.24125] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) as the most prominent type of esophageal cancer (EC) in developing countries encompasses a substantial contribution of cancer-related mortalities and morbidities. Cytotoxic T lymphocytes (CTLs) are the major subset of effector T cells against cancer. However, the microRNAs involved in the development and regulation of CTLs could be disrupted in cancers such as EC. METHODS Here, we evaluated the population of IL-10, TGF-β, IFN-γ, and IL-17a-producing CD3+CD8+ T cells, their association with the circulating levels of miR-21 and miR-29b, and their diagnostic and/or prognostic (after 160 weeks of follow-up) utilities in 34 ESCC patients (12 newly diagnosed: ND, 24 under-treatment: UT) and 34 matched healthy donors. RESULTS The population of IL-10 and TGF-β-producing CTLs (CD8+ Tregs) were considerably expanded, in addition to the overexpression of miR-21 in both groups (ND and UT) of ESCC patients, while the frequency of Tc17 and CD8+ Treg cells increased only in UT patients. The expression means of TGF-β and IL-10 in CTLs were considered to be excellent biomarkers (1 ≥ area under the curve: AUC ≥0.9) in distinguishing ESCC patients and associated subgroups from healthy subjects. Moreover, the lower expressions of TGF-β, IL-17a, IL-10, and IFN-γ in CTLs were associated with ESCC better prognosis. CONCLUSIONS The association between the impaired function of CD3+ CD8+ T cell subsets and miR-21 expression could be introduced as novel therapeutic targets and powerful diagnostic and prognostic markers for ESCC.
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Affiliation(s)
- Hadiseh Samiei
- Immunology DepartmentFaculty of MedicineSemnan University of Medical SciencesSemnanIran
| | - Faezeh Ajam
- Immunology DepartmentFaculty of MedicineGolestan University of Medical SciencesGorganIran
| | - Abdolsamad Gharavi
- Digestive Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Sara Abdolmaleki
- Clinical Immunology LaboratoryDeziani Specialized and Advanced ClinicGolestan University of Medical SciencesGorganIran
| | - Parviz Kokhaei
- Immune and Gene Therapy LaboratoryCancer Centre KarolinskaDepartment of Oncology and PathologyKarolinska InstituteStockholmSweden
- Cancer Research Center and Department of ImmunologySemnan University of Medical SciencesSemnanIran
| | - Saeed Mohammadi
- Stem Cell Research CenterGolestan University of Medical SciencesGorganIran
- Infectious Diseases Research CenterGolestan University of Medical SciencesGorganIran
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
- Department of ImmunologySchool of MedicineGolestan University of Medical SciencesGorganIran
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42
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Xu Y, Wu J, Yuan X, Liu W, Pan J, Xu B. MicroRNA-155 contributes to host immunity against Toxoplasma gondii. Parasite 2021; 28:83. [PMID: 34907898 PMCID: PMC8672677 DOI: 10.1051/parasite/2021082] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 11/26/2021] [Indexed: 11/14/2022] Open
Abstract
Toxoplasma gondii is well known to infect almost all avian and mammalian species including humans, with worldwide distribution. This protozoan parasite can cause serious toxoplasmosis, posing with a risk to public health. The role of microRNAs in the pathogenesis of T. gondii has not been well described. The aim of the present study was to investigate the role of microRNA-155 (miR-155) in mediating innate and adaptive immune responses during T. gondii infection in mice models. The survival and parasite burden in T. gondii-infected miR-155−/− and wild-type (WT) C57BL6 mice were compared. In these two mouse models, ELISA tests were used for analysis of Th1-associated, Th2-associated, and Th17-associated cytokines, and flow cytometry was used for analysis of the subpopulations of NK, NKT, CD8+T, CD4+T cells and regulatory T cells (Tregs), as well as Ly6Chi inflammatory monocytes and dendritic cells. The lack of miR-155 led to increased parasite burden and decreased survival of infected mice in contrast to WT mice. Innate and adaptive immune responses were reduced in the absence of miR-155, along with decreased proinflammatory mediators, Th-1-associated and Th-2-associated cytokines and accumulation of lymphocyte subpopulations. Also, CD8+ T cell exhaustion was also worsened in the absence of miR-155 via targeting of SHIP-1 and SOCS1, showing as up-regulated recruitment of Tregs and expression of PD-1, and down-regulated expression of IFN-γ and TNF-α in CD8+ T cells. Our results show that miR-155 is a critical immune regulator for the control of T. gondii infection, suggesting that miR-155 can be explored as a potential molecular target for boosting immunity against T. gondii.
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Affiliation(s)
- Yanan Xu
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
| | - Junhua Wu
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
| | - Xiaoqi Yuan
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
| | - Wenyuan Liu
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
| | - Jiewen Pan
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
| | - Binbin Xu
- Ningbo Women and Children's Hospital, Ningbo, Zhejiang, PR China
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Cao Y, Wang Z, Yan Y, Ji L, He J, Xuan B, Shen C, Ma Y, Jiang S, Ma D, Tong T, Zhang X, Gao Z, Zhu X, Fang JY, Chen H, Hong J. Enterotoxigenic Bacteroidesfragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p. Gastroenterology 2021; 161:1552-1566.e12. [PMID: 34371001 DOI: 10.1053/j.gastro.2021.08.003] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/20/2021] [Accepted: 08/02/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. METHODS microRNA sequencing was used to detect the differentially expressed microRNAs in both ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit 8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo. RESULTS ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF-down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC. CONCLUSIONS Exosomal miR-149-3p derived from ETBF-treated cells facilitated T-helper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. Targeting the ETBF/miR-149-3p pathway presents a promising approach to treat patients with intestinal inflammation and CRC with a high amount of ETBF.
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MESH Headings
- Animals
- Bacteroides fragilis/pathogenicity
- Cell Differentiation
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/microbiology
- Colitis, Ulcerative/pathology
- Colon/metabolism
- Colon/microbiology
- Colon/pathology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/microbiology
- Colorectal Neoplasms/pathology
- Crohn Disease/genetics
- Crohn Disease/metabolism
- Crohn Disease/microbiology
- Crohn Disease/pathology
- Disease Models, Animal
- Exosomes/genetics
- Exosomes/metabolism
- Exosomes/microbiology
- HCT116 Cells
- Histone Acetyltransferases/genetics
- Histone Acetyltransferases/metabolism
- Host-Pathogen Interactions
- Humans
- Methyltransferases/genetics
- Methyltransferases/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Mice
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Affiliation(s)
- Yingying Cao
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenhua Wang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuqing Yan
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Linhua Ji
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie He
- Department of Gastroenterology and Guangzhou Key Laboratory of Digestive Disease, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Baoqin Xuan
- State Key Laboratory for Oncogenes and Related Genes; Shanghai Cancer Institute; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chaoqin Shen
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanru Ma
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shanshan Jiang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Ma
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tianying Tong
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xinyu Zhang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ziyun Gao
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoqiang Zhu
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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44
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Gao C, Cai X, Cao M, Fu Q, Yang N, Liu X, Wang B, Li C. Comparative analysis of the miRNA-mRNA regulation networks in turbot (Scophthalmus maximus L.) following Vibrio anguillarum infection. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 124:104164. [PMID: 34129850 DOI: 10.1016/j.dci.2021.104164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/06/2021] [Accepted: 06/06/2021] [Indexed: 06/12/2023]
Abstract
MicroRNAs could not only regulate posttranscriptional silencing of target genes in eukaryotic organisms, but also have positive effect on their target genes as well. These microRNAs have been reported to be involved in mucosal immune responses to pathogen infection in teleost. Therefore, we constructed the immune-related miRNA-mRNA networks in turbot intestine following Vibrio anguillarum infection. In our results, 1550 differentially expressed (DE) genes and 167 DE miRNAs were identified. 113 DE miRNAs targeting 89 DE mRNAs related to immune response were used to construct miRNA-mRNA interaction networks. Functional analysis showed that target genes were associated with synthesis and degradation of ketone bodies, mucin type O-Glycan biosynthesis, homologous recombination, biotin metabolism, and intestinal immune network for IgA production that were equivalent to the function of IgT and IgM in fish intestine. Finally, 10 DE miRNAs and 7 DE mRNAs were selected for validating the accuracy of high-throughput sequencing results by qRT-PCR. The results of this study will provide valuable information for the elucidation of the regulation mechanisms of miRNA-mRNA interactions involved in disease resistance in teleost mucosal immune system.
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Affiliation(s)
- Chengbin Gao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China; Centre for Sustainable Aquatic Ecosystems, Harry Butler Institute, Murdoch University, 90 South St, Murdoch, Perth, 6150, Australia
| | - Xin Cai
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China; Centre for Sustainable Aquatic Ecosystems, Harry Butler Institute, Murdoch University, 90 South St, Murdoch, Perth, 6150, Australia
| | - Min Cao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Qiang Fu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Ning Yang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xiaoli Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Beibei Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
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45
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Lone W, Bouska A, Sharma S, Amador C, Saumyaranjan M, Herek TA, Heavican TB, Yu J, Lim ST, Ong CK, Slack GW, Savage KJ, Rosenwald A, Ott G, Cook JR, Feldman AL, Rimsza LM, McKeithan TW, Greiner TC, Weisenburger DD, Melle F, Motta G, Pileri S, Vose JM, Chan WC, Iqbal J. Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma. Clin Cancer Res 2021; 27:6039-6053. [PMID: 34426436 DOI: 10.1158/1078-0432.ccr-21-0573] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/15/2021] [Accepted: 08/19/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. EXPERIMENTAL DESIGN We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. RESULTS Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. CONCLUSIONS Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
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Affiliation(s)
- Waseem Lone
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Alyssa Bouska
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sunandini Sharma
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Catalina Amador
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Mallick Saumyaranjan
- Institute of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Tyler A Herek
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Tayla B Heavican
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jiayu Yu
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Soon Thye Lim
- Division of Medical Oncology, National Cancer Centre Singapore/Duke-National University of Singapore (NUS) Medical School, Singapore
| | - Choon Kiat Ong
- Division of Medical Oncology, National Cancer Centre Singapore/Duke-National University of Singapore (NUS) Medical School, Singapore
| | - Graham W Slack
- Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Kerry J Savage
- Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Andreas Rosenwald
- Institute of Pathology, University of Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - James R Cook
- Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lisa M Rimsza
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona
| | - Timothy W McKeithan
- Department of Pathology, City of Hope National Medical Center, Duarte, California
| | - Timothy C Greiner
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | | | | | | | | | - Julie M Vose
- Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, California
| | - Javeed Iqbal
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
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46
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Gajanayaka N, Dong SXM, Ali H, Iqbal S, Mookerjee A, Lawton DA, Caballero RE, Cassol E, Cameron DW, Angel JB, Crawley AM, Kumar A. TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR- and JNK-MAPK-Activated p70S6K Pathway. THE JOURNAL OF IMMUNOLOGY 2021; 207:2310-2324. [PMID: 34551966 DOI: 10.4049/jimmunol.2001191] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 08/18/2021] [Indexed: 12/18/2022]
Abstract
IFN-γ, a proinflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-γ production by murine macrophages, IFN-γ production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-γ and IL-12- and IL-18-stimulated monocyte-derived macrophages (M0) produce significant levels of IFN-γ. Further stimulation of IL-12/IL-18-primed macrophages or M1 macrophages with agonists for TLR-2, TLR-3, or TLR-4 significantly enhanced IFN-γ production in contrast to the similarly stimulated M0, M2a, M2b, and M2c macrophages. Similarly, M1 macrophages generated from COVID-19-infected patients' macrophages produced IFN-γ that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-γ production, suggesting that differentiation with IFN-γ plays a key role in IFN-γ induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4-induced IFN-γ production in M1 macrophages. Our results show that TLR-4-induced IFN-γ production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of PI3K, the mammalian target of rapamycin complex 1/2 (mTORC1/2), and the JNK MAPK pathways. These results suggest that M1-derived IFN-γ may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC1/2, PI3K, and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.
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Affiliation(s)
- Niranjala Gajanayaka
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Simon Xin Min Dong
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Hamza Ali
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Faculty of Applied Medical Sciences, Taibah University, Medina, Kingdom of Saudi Arabia
| | - Salma Iqbal
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ananda Mookerjee
- Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - David A Lawton
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ramon Edwin Caballero
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Edana Cassol
- Department of Biology, Carleton University, Ottawa, Ontario, Canada
| | - Donald William Cameron
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Jonathan B Angel
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Angela M Crawley
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Biology, Carleton University, Ottawa, Ontario, Canada.,Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Center for Infection, Immunity, and Inflammation, Faculty of Medicine, University of Ottawa, Ontario, Canada; and
| | - Ashok Kumar
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; .,Apoptosis Research Center, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.,Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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47
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Nicolet BP, Zandhuis ND, Lattanzio VM, Wolkers MC. Sequence determinants as key regulators in gene expression of T cells. Immunol Rev 2021; 304:10-29. [PMID: 34486113 PMCID: PMC9292449 DOI: 10.1111/imr.13021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/09/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022]
Abstract
T cell homeostasis, T cell differentiation, and T cell effector function rely on the constant fine-tuning of gene expression. To alter the T cell state, substantial remodeling of the proteome is required. This remodeling depends on the intricate interplay of regulatory mechanisms, including post-transcriptional gene regulation. In this review, we discuss how the sequence of a transcript influences these post-transcriptional events. In particular, we review how sequence determinants such as sequence conservation, GC content, and chemical modifications define the levels of the mRNA and the protein in a T cell. We describe the effect of different forms of alternative splicing on mRNA expression and protein production, and their effect on subcellular localization. In addition, we discuss the role of sequences and structures as binding hubs for miRNAs and RNA-binding proteins in T cells. The review thus highlights how the intimate interplay of post-transcriptional mechanisms dictate cellular fate decisions in T cells.
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Affiliation(s)
- Benoit P. Nicolet
- Department of HematopoiesisSanquin Research and Landsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
| | - Nordin D. Zandhuis
- Department of HematopoiesisSanquin Research and Landsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
| | - V. Maria Lattanzio
- Department of HematopoiesisSanquin Research and Landsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
| | - Monika C. Wolkers
- Department of HematopoiesisSanquin Research and Landsteiner LaboratoryAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Oncode InstituteUtrechtThe Netherlands
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48
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Rajendiran A, Klemm P, Schippers A, Scheufen A, Schwarz T, Peitz J, Brandenburg LO, Wagner N, Consolaro A, Raggi F, Bosco MC, Luedde T, Foell D, Denecke B, Horneff G, Ohl K, Tenbrock K. miR-23a contributes to T cellular redox metabolism in juvenile idiopathic oligoarthritis. Rheumatology (Oxford) 2021; 61:2694-2703. [PMID: 34559194 DOI: 10.1093/rheumatology/keab709] [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: 05/06/2021] [Revised: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of unknown origin. The regulation of inflammatory processes involves multiple cellular steps including mRNA transcription and translation. Different miRNAs tightly control these processes. We aimed to determine the roles of specific miRNAs within JIA pathogenesis. METHODS We performed a global miRNA expression analysis in parallel in cells from the arthritic joint and peripheral blood of oligoarticular JIA patients and healthy controls. QRT-PCR analysis was used to verify expression of miRNA in T cells. Ex vivo experiments and flow cytometric analyses were used to analyze proliferation and redox metabolism. RESULTS Global miRNA expression analysis demonstrated a different composition of miRNA expression at the site of inflammation compared with peripheral blood. Bioinformatic analysis of predicted miRNA target genes suggest a huge overrepresentation of genes involved in metabolic and oxidative stress pathways in the inflamed joint. Despite enhanced ROS levels within the local inflammatory milieu, JIA T cells are hyperproliferative and reveal an overexpression of miR-23a, which is an inhibitor of PPIF, the regulator of mitochondrial ROS escape. Mitochondrial ROS escape is diminished in JIA T cells resulting in their prolonged survival. CONCLUSION Our data suggest that miRNA dependent mitochondrial ROS shuttling might be a mechanism that contributes to T cell regulation in JIA at the site of inflammation.
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Affiliation(s)
- Anandhi Rajendiran
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | - Patricia Klemm
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | - Anastasia Schippers
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | - Anja Scheufen
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | - Tobias Schwarz
- Dept of Pediatric Rheumatology St. Josef-Stift Sendenhorst, Sendenhorst, Germany
| | - Joachim Peitz
- Asklepios Children's Hospital Sankt Augustin, Sankt Augustin, Germany
| | - Lars-Ove Brandenburg
- Institute of Anatomy and Cell Biology, Medical Faculty, RWTH Aachen, Germany.,Institute of Anatomy, Rostock University Medical Center Rostock, Germany
| | - Norbert Wagner
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | | | - Federica Raggi
- Laboratory of Molecular Biology, IRCSS, Instituto Gaslini, Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, IRCSS, Instituto Gaslini, Genova, Italy
| | - Tom Luedde
- Dept of Medicine III, RWTH Aachen, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University of Münster, Germany
| | - Bernd Denecke
- Interdisciplinary center for clinical research Aachen, Medical Faculty, RWTH Aachen, Germany
| | - Gerd Horneff
- Asklepios Children's Hospital Sankt Augustin, Sankt Augustin, Germany.,Dept. of Pediatrics, University of Cologne, Cologne, Germant
| | - Kim Ohl
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
| | - Klaus Tenbrock
- Dept of Pediatrics, Pediatric Rheumatology, Medical Faculty, RWTH Aachen, Germany
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49
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Alcohol induced impairment/abnormalities in brain: Role of MicroRNAs. Neurotoxicology 2021; 87:11-23. [PMID: 34478768 DOI: 10.1016/j.neuro.2021.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 08/12/2021] [Accepted: 08/28/2021] [Indexed: 12/21/2022]
Abstract
Alcohol is a highly toxic substance and has teratogenic properties that can lead to a wide range of developmental disorders. Excessive use of alcohol can change the structural and functional aspects of developed brain and other organs. Which can further lead to significant health, social and economic implications in many countries of the world. Convincing evidence support the involvement of microRNAs (miRNAs) as important post-transcriptional regulators of gene expression in neurodevelopment and maintenance. They also show differential expression following an injury. MiRNAs are the special class of small non coding RNAs that can modify the gene by targeting the mRNA and fine tune the development of cells to organs. Numerous pieces of evidences have shown the relationship between miRNA, alcohol and brain damage. These studies also show how miRNA controls different cellular mechanisms involved in the development of alcohol use disorder. With the increasing number of research studies, the roles of miRNAs following alcohol-induced injury could help researchers to recognize alternative therapeutic methods to treat/cure alcohol-induced brain damage. The present review summarizes the available data and brings together the important miRNAs, that play a crucial role in alcohol-induced brain damage, which will help in better understanding complex mechanisms. Identifying these miRNAs will not only expand the current knowledge but can lead to the identification of better targets for the development of novel therapeutic interventions.
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Hoefig KP, Reim A, Gallus C, Wong EH, Behrens G, Conrad C, Xu M, Kifinger L, Ito-Kureha T, Defourny KAY, Geerlof A, Mautner J, Hauck SM, Baumjohann D, Feederle R, Mann M, Wierer M, Glasmacher E, Heissmeyer V. Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. Nat Commun 2021; 12:5208. [PMID: 34471108 PMCID: PMC8410761 DOI: 10.1038/s41467-021-25345-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 07/28/2021] [Indexed: 01/01/2023] Open
Abstract
Post-transcriptional gene regulation in T cells is dynamic and complex as targeted transcripts respond to various factors. This is evident for the Icos mRNA encoding an essential costimulatory receptor that is regulated by several RNA-binding proteins (RBP), including Roquin-1 and Roquin-2. Here, we identify a core RBPome of 798 mouse and 801 human T cell proteins by utilizing global RNA interactome capture (RNA-IC) and orthogonal organic phase separation (OOPS). The RBPome includes Stat1, Stat4 and Vav1 proteins suggesting unexpected functions for these transcription factors and signal transducers. Based on proximity to Roquin-1, we select ~50 RBPs for testing coregulation of Roquin-1/2 targets by induced expression in wild-type or Roquin-1/2-deficient T cells. Besides Roquin-independent contributions from Rbms1 and Cpeb4 we also show Roquin-1/2-dependent and target-specific coregulation of Icos by Celf1 and Igf2bp3. Connecting the cellular RBPome in a post-transcriptional context, we find contributions from multiple RBPs to the prototypic regulation of mRNA targets by individual trans-acting factors. An extensive RNA binding protein atlas (RBPome) for primary T cells would be a useful resource. Here the authors use two different methods to characterise the mouse and human T cell RBPome and show regulation of Roquin-1/2 dependent and independent pathways.
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Affiliation(s)
- Kai P Hoefig
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Alexander Reim
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany
| | - Christian Gallus
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany
| | - Elaine H Wong
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Gesine Behrens
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Christine Conrad
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Meng Xu
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Lisa Kifinger
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Taku Ito-Kureha
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Kyra A Y Defourny
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.,Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Arie Geerlof
- Institute of Structural Biology, Helmholtz Center Munich, Neuherberg, Germany
| | - Josef Mautner
- Research Unit Gene Vectors, Helmholtz Center Munich & Children's Hospital, TU Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Center Munich, Munich, Germany
| | - Dirk Baumjohann
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.,Medical Clinic III for Oncology, Immuno-Oncology and Rheumatology University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany
| | - Michael Wierer
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany. .,Proteomics Research Infrastructure, University of Copenhagen, Copenhagen, Denmark.
| | - Elke Glasmacher
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany. .,Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany.
| | - Vigo Heissmeyer
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany. .,Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.
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