|
1
|
Kajihara R, Long MD, Hoki T, Chen H, Yamauchi T, Kanemaru H, Segal BH, Dy GK, Ito F. Divergent transcriptional states and kinetics of circulating tumor-infiltrating lymphocyte repertoires with highly homologous T-cell receptor sequences in a patient during immunotherapy. J Immunother Cancer 2025; 13:e010092. [PMID: 39863301 PMCID: PMC11784231 DOI: 10.1136/jitc-2024-010092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/12/2024] [Indexed: 01/27/2025] Open
Abstract
Evidence has shown that T-cell receptors (TCRs) that recognize the same epitopes may not be the exact TCR clonotypes but have slightly different TCR sequences. However, the changes in the genomic and transcriptomic signatures of these highly homologous T cells during immunotherapy remain unknown. Here, we examined the evolutionary features in circulating TCR clonotypes observed in tumors (tumor-infiltrating lymphocyte (TIL)-TCRs) by combining single-cell RNA/TCR sequencing of longitudinal blood samples and TCR sequencing of tumor tissue from a patient treated with anti-cytotoxic T-lymphocyte-associated protein 4/programmed cell death protein-1 therapy. We found frequent circulating CD8+ TIL-TCRs with identical complementarity determining region 3 (CDR3)α amino acid sequences but quasi-identical CDR3β and TCR α/β (TRA/TRB) sequences. Despite their sequence similarities, these highly homologous TIL-TCRs responded differently to immunotherapy, and exhibited distinct transcriptional signatures that were uniquely distinguished by the expression of GZMK Overall, the expression of IFNG in CD8+ T-cell subsets including highly homologous TIL-TCRs increased when the patient achieved a response, but gradually decreased as the patient developed acquired resistance. Our findings provide insight into the cross-talk between T cells in the tumor microenvironment and those in the blood, and highlight that CD8+ T cells with highly homologous TCR sequences might display divergent transcriptional states and kinetics in response to immunotherapy.
Collapse
Affiliation(s)
- Ryutaro Kajihara
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Hematology and Immunology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Mark D Long
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Toshifumi Hoki
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Merck Sharp and Dohme Corp, Tokyo, Japan
| | - Hongbin Chen
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA
| | - Takayoshi Yamauchi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Surgery, University of Southern California, Los Angeles, California, USA
| | - Hisashi Kanemaru
- Department of Surgery, University of Southern California, Los Angeles, California, USA
| | - Brahm H Segal
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Grace K Dy
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA
| | - Fumito Ito
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Surgery, University of Southern California, Los Angeles, California, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, USA
| |
Collapse
|
|
2
|
Wen D, Li B, Guo S, Chen L, Chen B. Exploring Pathogenic Genes in Frozen Shoulder through weighted gene co-expression network analysis and Mendelian Randomization. Int J Med Sci 2024; 21:2745-2758. [PMID: 39512681 PMCID: PMC11539380 DOI: 10.7150/ijms.98505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 09/25/2024] [Indexed: 11/15/2024] Open
Abstract
Background: Frozen shoulder (FS) is characterized by the thickening and fibrosis of the joint capsule, leading to joint contracture and a reduction in joint volume. The precise etiology responsible for these pathological changes remains elusive. Therefore, the primary aim of this study was to explore the potential involvement of pathogenic genes in FS and analyze their underlying roles in the disease progression. Methods: Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to investigate co-expressed genes potentially associated with FS. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to elucidate the potential roles of these co-expressed genes. Subsequently, Mendelian randomization (MR) analysis was performed using expression quantitative trait loci datasets for the co-expressed genes, combined with summary statistics from the genome-wide association study of FS, aiming to identify key genes causally associated with FS. The identified key genes were further validated through reverse transcription-quantitative PCR (RT-qPCR). Additionally, a nomogram model and receiver operating characteristic (ROC) curves were established to assess the diagnostic value of the hub genes. Furthermore, the infiltration of immune cells was evaluated using the CIBERSORT algorithm and the relationship between key genes and immune-infiltrating cells was analyzed. Results: 295 overlapping co-expressed genes were identified by intersecting the differentially expressed genes with the hub genes obtained from associated modules identified through WGCNA. Utilizing MR analysis, four key genes, namely ADAMTS1, NR4A2, PARD6G and SMKR1, were found to exhibit positive causal relationships with FS, which were subsequently validated through RT-qPCR analysis. Moreover, the diagnostic value of these four key genes was demonstrated through the development of a nomogram model and the construction of ROC curves. Notably, a causal relationship between ADAMTS1 and immune cell infiltration in FS was observed. Conclusion: Our study suggested genetic predisposition to higher expression levels of ADAMTS1, NR4A2, PARD6G and SMKR1, was associated with an increased risk of FS. Further investigations elucidating the functional roles of these genes will enhance our understanding of the pathogenesis of FS and may facilitate the development of targeted treatment strategies.
Collapse
Affiliation(s)
| | | | | | - Liaobin Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Biao Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| |
Collapse
|
|
3
|
Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B, Sonner JK, Di Liberto G, Mayer C, Binkle-Ladisch L, Rothammer N, Unger L, Raich L, Hadjilaou A, Noli B, Manai AL, Vieira V, Meurs N, Wagner I, Pless O, Cocco C, Stephens SB, Glatzel M, Merkler D, Friese MA. The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis. J Clin Invest 2024; 134:e177692. [PMID: 39145444 PMCID: PMC11324305 DOI: 10.1172/jci177692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 06/11/2024] [Indexed: 08/16/2024] Open
Abstract
A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.
Collapse
Affiliation(s)
- Marcel S. Woo
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lukas C. Bal
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ingo Winschel
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elias Manca
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Biomedical Sciences, NEF-Laboratory, University of Cagliari, Monserrato, Cagliari, Italy
| | - Mark Walkenhorst
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bachar Sevgili
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jana K. Sonner
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Giovanni Di Liberto
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christina Mayer
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lars Binkle-Ladisch
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Rothammer
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lisa Unger
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lukas Raich
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandros Hadjilaou
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Protozoa Immunology, Bernhard-Nocht-Institute for Tropical Medicine (BNITM), Hamburg, Germany
| | - Barbara Noli
- Department of Biomedical Sciences, NEF-Laboratory, University of Cagliari, Monserrato, Cagliari, Italy
| | - Antonio L. Manai
- Department of Biomedical Sciences, NEF-Laboratory, University of Cagliari, Monserrato, Cagliari, Italy
| | - Vanessa Vieira
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nina Meurs
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ingrid Wagner
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Ole Pless
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany
| | - Cristina Cocco
- Department of Biomedical Sciences, NEF-Laboratory, University of Cagliari, Monserrato, Cagliari, Italy
| | - Samuel B. Stephens
- Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doron Merkler
- Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Manuel A. Friese
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
4
|
Ahmed T. Lipid nanoparticle mediated small interfering RNA delivery as a potential therapy for Alzheimer's disease. Eur J Neurosci 2024; 59:2915-2954. [PMID: 38622050 DOI: 10.1111/ejn.16336] [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: 09/18/2023] [Revised: 02/21/2024] [Accepted: 03/14/2024] [Indexed: 04/17/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that exhibits a gradual decline in cognitive function and is prevalent among a significant number of individuals globally. The use of small interfering RNA (siRNA) molecules in RNA interference (RNAi) presents a promising therapeutic strategy for AD. Lipid nanoparticles (LNPs) have been developed as a delivery vehicle for siRNA, which can selectively suppress target genes, by enhancing cellular uptake and safeguarding siRNA from degradation. Numerous research studies have exhibited the effectiveness of LNP-mediated siRNA delivery in reducing amyloid beta (Aβ) levels and enhancing cognitive function in animal models of AD. The feasibility of employing LNP-mediated siRNA delivery as a therapeutic approach for AD is emphasized by the encouraging outcomes reported in clinical studies for other medical conditions. The use of LNP-mediated siRNA delivery has emerged as a promising strategy to slow down or even reverse the progression of AD by targeting the synthesis of tau phosphorylation and other genes linked to the condition. Improvement of the delivery mechanism and determination of the most suitable siRNA targets are crucial for the efficacious management of AD. This review focuses on the delivery of siRNA through LNPs as a promising therapeutic strategy for AD, based on the available literature.
Collapse
Affiliation(s)
- Tanvir Ahmed
- Department of Pharmaceutical Sciences, North South University, Dhaka, Bangladesh
| |
Collapse
|
|
5
|
Zhao S, Wang X, Huang F, Zhou Y, Meng D, Zhao D, Wang J, Zhang H, Wu L, Zhang Y, Zhao L, Zhang L, Song Y, Wang Q. A role of NR4A2 in Graves' disease: regulation of Th17/Treg. Endocrine 2024; 83:432-441. [PMID: 37651006 DOI: 10.1007/s12020-023-03490-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/10/2023] [Indexed: 09/01/2023]
Abstract
PURPOSE This study aimed to explore the molecular pathogenesis of Graves' disease (GD). METHODS The gene expression profile in CD4+ T cells from GD patients and healthy controls were analyzed through mRNA-sequencing. The expression of NR4A2 was determined by quantitative real-time PCR and western blot. The levels of Th17 and Treg were determined by flow cytometry. ELISA was employed to detect the levels of IL-10, IL-17A, IL-17F and IL-22. RESULTS In the CD4+ T cells from GD patients, there were 128 up-regulated and 510 down-regulated genes. Subsequently, we focused on the role of nuclear receptor 4 group A member 2 (NR4A2) in GD. NR4A2 was lowly expressed in the CD4+ T cells from GD patients. Its expression was negatively correlated with free triiodothyronine and tetraiodothyronine, but positively correlated with thyroid stimulating hormone. NR4A2 knockdown decreased the percentage of Treg cells, with a decreased IL-10 level. While its over-expression augmented the Treg differentiation, with an elevated IL-10 level. In addition, knockdown or over-expression of NR4A2 showed no significant influence on Th17 differentiation. CONCLUSION These results indicate that the low level of NR4A2 in GD patients may suppress Treg differentiation, but have no influence on Th17 differentiation, leading to the imbalance of Th17/Treg and contributing to the development of GD. Revealing the role of NR4A2 in GD provides a novel insight for the treatment of GD.
Collapse
Affiliation(s)
- Shuiying Zhao
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Xinyu Wang
- Department of Nuclear Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Fengjiao Huang
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Yingying Zhou
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Dongdong Meng
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Di Zhao
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Jiao Wang
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Haohao Zhang
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Lina Wu
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Ying Zhang
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Lin Zhao
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Lixia Zhang
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Yi Song
- Department of Endocrinology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Qingzhu Wang
- Department of Nuclear Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
| |
Collapse
|
|
6
|
Duan S, Li Q, Wang F, Kuang W, Dong Y, Liu D, Wang J, Li W, Chen Q, Zeng X, Li T. Single-Cell Transcriptomes and Immune Repertoires Reveal the Cell State and Molecular Changes in Pemphigus Vulgaris. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:375-388. [PMID: 38117802 DOI: 10.4049/jimmunol.2300312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 10/05/2023] [Indexed: 12/22/2023]
Abstract
The etiology and pathogenesis of pemphigus vulgaris (PV) entail intricate interactions between immune cells and epithelial cells. However, the specific subtypes of immune cells involved in PV, along with their respective roles, remain elusive. Likewise, the precise functions and mechanisms by which glucocorticoids affect cell types within the disease context require further elucidation. To address these knowledge gaps, we performed 5' single-cell RNA sequencing, combined with V(D)J enrichment on buccal mucosal lesions and peripheral blood samples from treatment-naive patients with PV, in conjunction with post-treatment peripheral blood samples obtained after oral prednisone treatment. Our findings suggest that the IL-1α signaling pathway, myeloid APCs, inflammatory CD8+ resident memory T cells, and dysfunctional CD4+ regulatory T cells are involved in the pathogenesis of PV. Part of these findings were validated by immunohistochemical assays and multiplex immunofluorescence assays. Furthermore, our results highlight the significant impact of prednisone treatment on monocytes and mucosal-associated invariant T cells while revealing a limited effect on CD4+ regulatory T cells. Additionally, we present the CDR3 amino acid sequence of BCR related to PV disease and investigate the characteristics of TCR/BCR clonotypes. In conclusion, our study provides a comprehensive understanding of PV, particularly focusing on the mucosal-dominant type, and sheds light on the effects of glucocorticoids within the PV context. These insights hold promise for the development of new therapeutic strategies in this autoimmune disorder.
Collapse
Affiliation(s)
- Shumin Duan
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qionghua Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Fei Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wenjing Kuang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yunmei Dong
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Dan Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jiongke Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wei Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Taiwen Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| |
Collapse
|
|
7
|
Fu J, Wang Z, Martinez M, Obradovic A, Jiao W, Frangaj K, Jones R, Guo XV, Zhang Y, Kuo WI, Ko HM, Iuga A, Bay Muntnich C, Prada Rey A, Rogers K, Zuber J, Ma W, Miron M, Farber DL, Weiner J, Kato T, Shen Y, Sykes M. Plasticity of intragraft alloreactive T cell clones in human gut correlates with transplant outcomes. J Exp Med 2024; 221:e20230930. [PMID: 38091025 PMCID: PMC10720543 DOI: 10.1084/jem.20230930] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/22/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023] Open
Abstract
The site of transition between tissue-resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity, and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single-cell level after human intestinal transplantation. Host-versus-graft (HvG)-reactive T cells were mainly distributed to TRM, effector T (Teff)/TRM, and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to Teff/TRM clusters in association with rejection. By integrating pre- and post-transplantation (Tx) mixed lymphocyte reaction-determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in the human gut, providing novel insight into TRM biology.
Collapse
Affiliation(s)
- Jianing Fu
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Zicheng Wang
- Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA
| | | | - Aleksandar Obradovic
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Wenyu Jiao
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Kristjana Frangaj
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Rebecca Jones
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Xinzheng V. Guo
- Human Immune Monitoring Core, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Ya Zhang
- Human Immune Monitoring Core, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Wan-I Kuo
- Human Immune Monitoring Core, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Huaibin M. Ko
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Alina Iuga
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Constanza Bay Muntnich
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Adriana Prada Rey
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Kortney Rogers
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Julien Zuber
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Wenji Ma
- Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA
| | - Michelle Miron
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Donna L. Farber
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
- Department of Surgery, Columbia University, New York, NY, USA
| | - Joshua Weiner
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
- Department of Surgery, Columbia University, New York, NY, USA
| | - Tomoaki Kato
- Department of Surgery, Columbia University, New York, NY, USA
| | - Yufeng Shen
- Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA
| | - Megan Sykes
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
- Department of Surgery, Columbia University, New York, NY, USA
| |
Collapse
|
|
8
|
Chasman DA, Welch Schwartz R, Vazquez J, Chavarria M, Jenkins ET, Lopez GE, Tyler CT, Stanic AK, Ong IM. Proteogenomic and V(D)J Analysis of Human Decidual T Cells Highlights Unique Transcriptional Programming and Clonal Distribution. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:154-162. [PMID: 37195197 PMCID: PMC10330249 DOI: 10.4049/jimmunol.2200061] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/25/2023] [Indexed: 05/18/2023]
Abstract
Immunological tolerance toward the semiallogeneic fetus is one of many maternal adaptations required for a successful pregnancy. T cells are major players of the adaptive immune system and balance tolerance and protection at the maternal-fetal interface; however, their repertoire and subset programming are still poorly understood. Using emerging single-cell RNA sequencing technologies, we simultaneously obtained transcript, limited protein, and receptor repertoire at the single-cell level, from decidual and matched maternal peripheral human T cells. The decidua maintains a tissue-specific distribution of T cell subsets compared with the periphery. We find that decidual T cells maintain a unique transcriptome programming, characterized by restraint of inflammatory pathways by overexpression of negative regulators (DUSP, TNFAIP3, ZFP36) and expression of PD-1, CTLA-4, TIGIT, and LAG3 in some CD8 clusters. Finally, analyzing TCR clonotypes demonstrated decreased diversity in specific decidual T cell populations. Overall, our data demonstrate the power of multiomics analysis in revealing regulation of fetal-maternal immune coexistence.
Collapse
Affiliation(s)
- Deborah A. Chasman
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
| | - Rene Welch Schwartz
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI
| | - Jessica Vazquez
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Melina Chavarria
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Eryne T. Jenkins
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Gladys E. Lopez
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Chanel T. Tyler
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Aleksandar K. Stanic
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
| | - Irene M. Ong
- Departments of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI
- Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI
- Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI
| |
Collapse
|
|
9
|
Ye Z, Ai X, Yang K, Yang Z, Fei F, Liao X, Qiu Z, Gimple RC, Yuan H, Huang H, Gong Y, Xiao C, Yue J, Huang L, Saulnier O, Wang W, Zhang P, Dai L, Wang X, Wang X, Ahn YH, You C, Xu J, Wan X, Taylor MD, Zhao L, Rich JN, Zhou S. Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma. Cancer Discov 2023; 13:974-1001. [PMID: 36649564 PMCID: PMC10073346 DOI: 10.1158/2159-8290.cd-22-0455] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 11/16/2022] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer. SIGNIFICANCE Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.
Collapse
Affiliation(s)
- Zengpanpan Ye
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Xiaolin Ai
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Zhengnan Yang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Fan Fei
- Department of Neurosurgery, Sichuan People’s Hospital, Chengdu, Sichuan, P. R. China
| | - Xiaoling Liao
- Department of Neurosurgery, Sichuan People’s Hospital, Chengdu, Sichuan, P. R. China
| | - Zhixin Qiu
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ryan C. Gimple
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Huairui Yuan
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Hao Huang
- School of Biological Science and Medical Engineering, Southeast University, Nanjing, P. R. China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P. R. China
| | - Chaoxin Xiao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Jing Yue
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Liang Huang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Olivier Saulnier
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada
| | - Wei Wang
- Department of Gynecology, Huzhou Maternity & Child Health Care Hospital, Huzhou, Zhejiang, P. R. China
| | - Peidong Zhang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, P. R. China
| | - Xin Wang
- Department of Surgery, The Chinese University of Hong Kong. Prince of Wales Hospital, Shatin, N.T., Hong Kong, SAR, P. R. China
| | - Xiuxing Wang
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Young Ha Ahn
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Chao You
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Jianguo Xu
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| | - Xiaoxiao Wan
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael D. Taylor
- Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada
- Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, M5S 3E1, Canada
| | - Linjie Zhao
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
| | - Jeremy N. Rich
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Department of Neurosurgery, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China
| |
Collapse
|
|
10
|
Sato W, Noto D, Araki M, Okamoto T, Lin Y, Yamaguchi H, Kadowaki-Saga R, Kimura A, Kimura Y, Sato N, Ishizuka T, Nakamura H, Miyake S, Yamamura T. First-in-human clinical trial of the NKT cell-stimulatory glycolipid OCH in multiple sclerosis. Ther Adv Neurol Disord 2023; 16:17562864231162153. [PMID: 36993937 PMCID: PMC10041592 DOI: 10.1177/17562864231162153] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 02/20/2023] [Indexed: 03/31/2023] Open
Abstract
Background Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes the damage to the myelin sheath as well as axonal degeneration. Individuals with MS appear to have changes in the numbers and functions of T-cell subsets, leading to an immunological imbalance accompanied by enhanced autoreactivity. In previous preclinical studies, (2 S,3 S,4R)-1-O-(α-D-Galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a synthetic analog of α-galactosylceramide stimulatory for invariant NKT (iNKT) cells, has shown therapeutic or disease-preventive immunoregulatory effects in autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE). Objectives This study is the first-in-human study of oral OCH to evaluate the pharmacokinetics and to examine the effects on immune cells as well as related gene expression profiles. Methods Fifteen healthy volunteers and 13 MS patients who met the study criteria were enrolled. They were divided into five cohorts and received oral administration of various doses of granulated powder of OCH (0.3-30 mg), once per week for 4 or 13 weeks. Plasma OCH concentrations were measured by high-performance liquid chromatography. Frequencies of lymphocyte subsets in peripheral blood were evaluated by flow cytometry, and microarray analysis was performed to determine OCH-induced changes in gene expression. Results Oral OCH was well tolerated, and its bioavailability was found to be sufficient. Six hours after a single dose of OCH, increased frequencies of Foxp3+ regulatory T-cells were observed in some cohorts of healthy subjects and MS patients. Furthermore, gene expression analysis demonstrated an upregulation of several immunoregulatory genes and downregulation of pro-inflammatory genes following OCH administration. Conclusion This study has demonstrated immunomodulatory effects of the iNKT cell-stimulatory drug OCH in human. Safety profiles together with the presumed anti-inflammatory effects of oral OCH encouraged us to conduct a phase II trial.
Collapse
Affiliation(s)
| | | | - Manabu Araki
- Multiple Sclerosis Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Tomoko Okamoto
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Youwei Lin
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Hiromi Yamaguchi
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Ryoko Kadowaki-Saga
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Atsuko Kimura
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Yukio Kimura
- Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Noriko Sato
- Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Takami Ishizuka
- Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Harumasa Nakamura
- Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
| | - Sachiko Miyake
- Department of Immunology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Japan
| | | |
Collapse
|
|
11
|
Baharlooi H, Mansourabadi AH, Minbashi Moeini M, Mohamed Khosroshahi L, Azimi M. Nucleic Acids as Novel Therapeutic Modalities to Address Multiple Sclerosis Onset and Progression. Cell Mol Neurobiol 2022; 42:2611-2627. [PMID: 34694513 PMCID: PMC11421605 DOI: 10.1007/s10571-021-01158-4] [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] [Received: 04/24/2021] [Accepted: 10/17/2021] [Indexed: 02/07/2023]
Abstract
The issue of treating Multiple Sclerosis (MS) begins with disease-modifying treatments (DMTs) which may cause lymphopenia, dyspnea, and many other adverse effects. Consequently, further identification and evaluation of alternative treatments are crucial to monitoring their long-term outcomes and hopefully, moving toward personalized approaches that can be translated into clinical treatments. In this article, we focused on the novel therapeutic modalities that alter the interaction between the cellular constituents contributing to MS onset and progression. Furthermore, the studies that have been performed to evaluate and optimize drugs' efficacy, and particularly, to show their limitations and strengths are also presented. The preclinical trials of novel approaches for multiple sclerosis treatment provide promising prospects to cure the disease with pinpoint precision. Considering the fact that not a single treatment could be effective enough to cover all aspects of MS treatment, additional researches and therapies need to be developed in the future. Since the pathophysiology of MS resembles a jigsaw puzzle, researchers need to put a host of pieces together to create a promising window towards MS treatment. Thus, a combination therapy encompassing all these modules is highly likely to succeed in dealing with the disease. The use of different therapeutic approaches to re-induce self-tolerance in autoreactive cells contributing to MS pathogenesis is presented. A Combination therapy using these tools may help to deal with the clinical disabilities and symptoms of the disease in the future.
Collapse
Affiliation(s)
- Hussein Baharlooi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Moein Minbashi Moeini
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Faculty of Pharmacy, Université Laval, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, Canada
| | | | - Maryam Azimi
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Hemmat highway, Tehran, Iran.
| |
Collapse
|
|
12
|
Raveney BJE, El‐Darawish Y, Sato W, Arinuma Y, Yamaoka K, Hori S, Yamamura T, Oki S. Neuropilin-1 (NRP1) expression distinguishes self-reactive helper T cells in systemic autoimmune disease. EMBO Mol Med 2022; 14:e15864. [PMID: 36069030 PMCID: PMC9549730 DOI: 10.15252/emmm.202215864] [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: 02/10/2022] [Revised: 08/08/2022] [Accepted: 08/15/2022] [Indexed: 02/05/2023] Open
Abstract
Pathogenic T helper cells (Th cells) that respond to self-antigen cannot be easily distinguished from beneficial Th cells. These cells can generate systemic autoimmune disease in response to widely expressed self-antigens. In this study, we have identified neuropilin-1 (NRP1) as a cell surface marker of self-reactive Th cells. NRP1+ Th cells, absent in non-regulatory T cell subsets in normal mice, appeared in models of systemic autoimmune disease and strongly correlated with disease symptoms. NRP1+ Th cells were greatly reduced in Nr4a2 cKO mice, which have reduced self-reactive responses but showed normal responses against exogenous antigens. Transfer of NRP1+ Th cells was sufficient to initiate or accelerate systemic autoimmune disease, and targeting NRP1-expressing Th cells therapeutically ameliorated SLE-like autoimmune symptoms in BXSB-Yaa mice. Peripheral NRP1+ Th cells were significantly increased in human SLE patients. Our data suggest that self-reactive Th cells can be phenotypically distinguished within the Th cell pool. These findings offer a novel approach to identify self-reactive Th cells and target them to treat systemic autoimmune disease.
Collapse
Affiliation(s)
- Ben JE Raveney
- Department of ImmunologyNational Institute of NeuroscienceTokyoJapan
| | - Yosif El‐Darawish
- Department of ImmunologyNational Institute of NeuroscienceTokyoJapan
| | - Wakiro Sato
- Department of ImmunologyNational Institute of NeuroscienceTokyoJapan
| | - Yoshiyuki Arinuma
- Department of Rheumatology and Infectious DiseasesKitasato University School of MedicineSagamiharaJapan
| | - Kunihiro Yamaoka
- Department of Rheumatology and Infectious DiseasesKitasato University School of MedicineSagamiharaJapan
| | - Shohei Hori
- Laboratory for Immunology and MicrobiologyGraduate School of Pharmaceutical Sciences, The University of TokyoTokyoJapan
| | - Takashi Yamamura
- Department of ImmunologyNational Institute of NeuroscienceTokyoJapan
| | - Shinji Oki
- Department of ImmunologyNational Institute of NeuroscienceTokyoJapan
| |
Collapse
|
|
13
|
Aczél T, Benczik B, Ágg B, Körtési T, Urbán P, Bauer W, Gyenesei A, Tuka B, Tajti J, Ferdinandy P, Vécsei L, Bölcskei K, Kun J, Helyes Z. Disease- and headache-specific microRNA signatures and their predicted mRNA targets in peripheral blood mononuclear cells in migraineurs: role of inflammatory signalling and oxidative stress. J Headache Pain 2022; 23:113. [PMID: 36050647 PMCID: PMC9438144 DOI: 10.1186/s10194-022-01478-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients. METHODS We determined miRNA expression of migraineurs' PBMC during (ictal) and between (interictal) headaches compared to age- and sex-matched healthy volunteers. Small RNA sequencing was performed from the PBMC, and mRNA targets of miRNAs were predicted using a network theoretical approach by miRNAtarget.com™. Predicted miRNA targets were investigated by Gene Ontology enrichment analysis and validated by comparing network metrics to differentially expressed mRNA data. RESULTS In the interictal PBMC samples 31 miRNAs were differentially expressed (DE) in comparison to healthy controls, including hsa-miR-5189-3p, hsa-miR-96-5p, hsa-miR-3613-5p, hsa-miR-99a-3p, hsa-miR-542-3p. During headache attacks, the top DE miRNAs as compared to the self-control samples in the interictal phase were hsa-miR-3202, hsa-miR-7855-5p, hsa-miR-6770-3p, hsa-miR-1538, and hsa-miR-409-5p. MiRNA-mRNA target prediction and pathway analysis indicated several mRNAs related to immune and inflammatory responses (toll-like receptor and cytokine receptor signalling), neuroinflammation and oxidative stress, also confirmed by mRNA transcriptomics. CONCLUSIONS We provide here the first evidence for disease- and headache-specific miRNA signatures in the PBMC of migraineurs, which might help to identify novel targets for both prophylaxis and attack therapy.
Collapse
Affiliation(s)
- Timea Aczél
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Bettina Benczik
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Bence Ágg
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Tamás Körtési
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary
| | - Péter Urbán
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Witold Bauer
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Attila Gyenesei
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Bernadett Tuka
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Szeged, Hungary
| | - János Tajti
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
| | - Péter Ferdinandy
- Cardiometabolic and MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - László Vécsei
- MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - József Kun
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, Pécs, Hungary.
- PharmInVivo Ltd., Pécs, Hungary.
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti út 12, 7624, Pécs, Hungary.
| |
Collapse
|
|
14
|
Honkova K, Rossnerova A, Chvojkova I, Milcova A, Margaryan H, Pastorkova A, Ambroz A, Rossner P, Jirik V, Rubes J, Sram RJ, Topinka J. Genome-Wide DNA Methylation in Policemen Working in Cities Differing by Major Sources of Air Pollution. Int J Mol Sci 2022; 23:ijms23031666. [PMID: 35163587 PMCID: PMC8915177 DOI: 10.3390/ijms23031666] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
DNA methylation is the most studied epigenetic mechanism that regulates gene expression, and it can serve as a useful biomarker of prior environmental exposure and future health outcomes. This study focused on DNA methylation profiles in a human cohort, comprising 125 nonsmoking city policemen (sampled twice), living and working in three localities (Prague, Ostrava and Ceske Budejovice) of the Czech Republic, who spent the majority of their working time outdoors. The main characterization of the localities, differing by major sources of air pollution, was defined by the stationary air pollution monitoring of PM2.5, B[a]P and NO2. DNA methylation was analyzed by a genome-wide microarray method. No season-specific DNA methylation pattern was discovered; however, we identified 13,643 differentially methylated CpG loci (DML) for a comparison between the Prague and Ostrava groups. The most significant DML was cg10123377 (log2FC = −1.92, p = 8.30 × 10−4) and loci annotated to RPTOR (total 20 CpG loci). We also found two hypomethylated loci annotated to the DNA repair gene XRCC5. Groups of DML annotated to the same gene were linked to diabetes mellitus (KCNQ1), respiratory diseases (PTPRN2), the dopaminergic system of the brain and neurodegenerative diseases (NR4A2). The most significant possibly affected pathway was Axon guidance, with 86 potentially deregulated genes near DML. The cluster of gene sets that could be affected by DNA methylation in the Ostrava groups mainly includes the neuronal functions and biological processes of cell junctions and adhesion assembly. The study demonstrates that the differences in the type of air pollution between localities can affect a unique change in DNA methylation profiles across the human genome.
Collapse
Affiliation(s)
- Katerina Honkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
- Correspondence: ; Tel.: +420-775-406-170
| | - Andrea Rossnerova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| | - Irena Chvojkova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| | - Alena Milcova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| | - Hasmik Margaryan
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| | - Anna Pastorkova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.P.); (A.A.); (P.R.J.)
| | - Antonin Ambroz
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.P.); (A.A.); (P.R.J.)
| | - Pavel Rossner
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.P.); (A.A.); (P.R.J.)
| | - Vitezslav Jirik
- Centre for Epidemiological Research, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic;
| | - Jiri Rubes
- Veterinary Research Institute, Hudcova 296/70, 621 00 Brno, Czech Republic;
| | - Radim J. Sram
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| | - Jan Topinka
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine CAS, Videnska 1083, 142 20 Prague 4, Czech Republic; (A.R.); (I.C.); (A.M.); (H.M.); (R.J.S.); (J.T.)
| |
Collapse
|
|
15
|
Yoshimizu A, Kinoshita K, Ichihara Y, Kurauchi Y, Seki T, Katsuki H. Hydroxychloroquine improves motor function and affords neuroprotection without inhibition of inflammation and autophagy in mice after intracerebral hemorrhage. J Neuroimmunol 2022; 362:577786. [PMID: 34920280 DOI: 10.1016/j.jneuroim.2021.577786] [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] [Received: 10/19/2021] [Revised: 11/28/2021] [Accepted: 12/06/2021] [Indexed: 01/05/2023]
Abstract
We examined the effect of an immunomodulator hydroxychloroquine, also known as a Nurr1 ligand and an autophagy inhibitor, on a mouse model of intracerebral hemorrhage (ICH). Daily administration of hydroxychloroquine (100 mg/kg, i.p.) from 3 h after induction of ICH alleviated neurological deficits of mice, increased the number of surviving neurons in the hematoma and prevented fragmentation of axon structures in the internal capsule. Unexpectedly, hydroxychloroquine did not inhibit either upregulation of pro-inflammatory mediators or autophagic responses in the brain. Hence, hydroxychloroquine may produce therapeutic effects on ICH primarily via neuroprotection including preservation of the axon tract integrity.
Collapse
Affiliation(s)
- Ayaka Yoshimizu
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Keita Kinoshita
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Yusei Ichihara
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Yuki Kurauchi
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Takahiro Seki
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
| |
Collapse
|
|
16
|
Fu Z, Dean JW, Xiong L, Dougherty MW, Oliff KN, Chen ZME, Jobin C, Garrett TJ, Zhou L. Mitochondrial transcription factor A in RORγt + lymphocytes regulate small intestine homeostasis and metabolism. Nat Commun 2021; 12:4462. [PMID: 34294718 PMCID: PMC8298438 DOI: 10.1038/s41467-021-24755-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.
Collapse
Affiliation(s)
- Zheng Fu
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Joseph W Dean
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Lifeng Xiong
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | | | - Kristen N Oliff
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Zong-Ming E Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Christian Jobin
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
- Department of Medicine, University of Florida, Gainesville, FL, USA
| | - Timothy J Garrett
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32608, USA
| | - Liang Zhou
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA.
| |
Collapse
|
|
17
|
Magri K, Eftedal I, Petroni Magri V, Matity L, Azzopardi CP, Muscat S, Pace NP. Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving. Front Physiol 2021; 12:660402. [PMID: 34177613 PMCID: PMC8222921 DOI: 10.3389/fphys.2021.660402] [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: 02/02/2021] [Accepted: 05/12/2021] [Indexed: 01/22/2023] Open
Abstract
Decompression sickness (DCS) develops due to inert gas bubble formation in bodily tissues and in the circulation, leading to a wide range of potentially serious clinical manifestations. Its pathophysiology remains incompletely understood. In this study, we aim to explore changes in the human leukocyte transcriptome in divers with DCS compared to closely matched unaffected controls after uneventful diving. Cases (n = 7) were divers developing the typical cutis marmorata rash after diving with a confirmed clinical diagnosis of DCS. Controls (n = 6) were healthy divers who surfaced from a ≥25 msw dive without decompression violation or evidence of DCS. Blood was sampled at two separate time points-within 8 h of dive completion and 40-44 h later. Transcriptome analysis by RNA-Sequencing followed by bioinformatic analysis was carried out to identify differentially expressed genes and relate their function to biological pathways. In DCS cases, we identified enrichment of transcripts involved in acute inflammation, activation of innate immunity and free radical scavenging pathways, with specific upregulation of transcripts related to neutrophil function and degranulation. DCS-induced transcriptomic events were reversed at the second time point following exposure to hyperbaric oxygen. The observed changes are consistent with findings from animal models of DCS and highlight a continuum between the responses elicited by uneventful diving and diving complicated by DCS. This study sheds light on the inflammatory pathophysiology of DCS and the associated immune response. Such data may potentially be valuable in the search for novel treatments targeting this disease.
Collapse
Affiliation(s)
- Kurt Magri
- Hyperbaric Unit, Department of Medicine, Mater Dei Hospital, Msida, Malta
| | - Ingrid Eftedal
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, Trondheim, Norway
- Faculty of Nursing and Health Sciences, Nord University, Bodø, Norway
| | - Vanessa Petroni Magri
- Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Lyubisa Matity
- Hyperbaric Unit, Department of Medicine, Mater Dei Hospital, Msida, Malta
| | | | - Stephen Muscat
- Hyperbaric Unit, Department of Medicine, Mater Dei Hospital, Msida, Malta
| | - Nikolai Paul Pace
- Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| |
Collapse
|
|
18
|
Wang J, Xiang Y, Jiang S, Li H, Caviezel F, Katawatin S, Duangjinda M. Involvement of the VEGF signaling pathway in immunosuppression and hypoxia stress: analysis of mRNA expression in lymphocytes mediating panting in Jersey cattle under heat stress. BMC Vet Res 2021; 17:209. [PMID: 34098948 PMCID: PMC8186226 DOI: 10.1186/s12917-021-02912-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 05/20/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Extreme panting under heat stress threatens dairy cattle milk production. Previous research has revealed that the gas exchange-mediated respiratory drive in critically ill dairy cattle with low O2 saturation induces panting. Vascular endothelial growth factor (VEGF) signaling may play important roles in immunosuppression and oxidative stress during severe respiratory stress responses in heat-stressed cattle. The objectives of this study were to transcriptomically analyze mRNA expression mediating heat-induced respiratory stress-associated panting, evaluate gas exchange, screen hub genes, and verify the expression of proteins encoded by differentially expressed genes in lymphocyte pathways. RESULTS Jersey cattle were naturally heat-exposed. Physiological data were collected for response evaluation, and blood was collected for gas exchange and gene expression assays at 06:00, 10:00 and 14:00 continuously for 1 week. Lymphocytes were isolated from whole-blood samples for mRNA-seq and expression analysis of key pathway genes/proteins. The cattle respiration rates differed with time, averaging 51 bpm at 06:00, 76 bpm at 10:00, and 121 bpm at 14:00 (p < 0.05). Gas exchange analysis showed that both pH and pCO2 differed with time: they were 7.41 and 41 mmHg at 06:00, 7.45 and 37.5 mmHg at 10:00, and 7.49 and 33 mmHg at 14:00, respectively (p < 0.01). Sixteen heat-related differentially expressed genes (DEGs; 13 upregulated and 3 downregulated) were screened between 212 DEGs and 1370 heat stress-affected genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) hub gene functional analysis annotated eleven genes to signal transduction, six genes to the immune response, and five genes to the endocrine response, including both prostaglandin-endoperoxide synthase 2 (PTGS2) and VEGF. Gene Ontology (GO) functional enrichment analysis revealed that oxygen regulation was associated with the phosphorus metabolic process, response to oxygen levels, response to decreased oxygen levels, response to hypoxia and cytokine activity terms. The main signaling pathways were the VEGF, hypoxia inducible factor-1(HIF-1), cytokine-cytokine receptor interaction and TNF pathways. Four genes involved Integrin beta 3 (ITBG3), PTGS2, VEGF, and myosin light chain 9 (MYL9) among the 16 genes related to immunosuppression, oxidative stress, and endocrine dysfunction were identified as participants in the VEGF signaling pathway and oxygenation. CONCLUSION These findings help elucidate the underlying immune and oxygen regulation mechanisms associated with the VEGF signaling pathway in heat-stressed dairy cattle.
Collapse
Affiliation(s)
- Jian Wang
- Faculty of Veterinary Medicine, Southwest University, Chongqing, 400700, China.
| | - Yang Xiang
- Faculty of Veterinary Medicine, Southwest University, Chongqing, 400700, China
| | - Shisong Jiang
- Department of Oncology, Oxford University, Oxford, OX3 7DQ, UK
| | - Hongchang Li
- Faculty of Veterinary Medicine, Southwest University, Chongqing, 400700, China
| | - Flurin Caviezel
- Department of Oncology, Oxford University, Oxford, OX3 7DQ, UK
| | - Suporn Katawatin
- Department of Animal Science, Khon Kaen University, Kaen, 40002, Thailand
| | - Monchai Duangjinda
- Department of Animal Science, Khon Kaen University, Kaen, 40002, Thailand
| |
Collapse
|
|
19
|
Involvement of cytotoxic Eomes-expressing CD4 + T cells in secondary progressive multiple sclerosis. Proc Natl Acad Sci U S A 2021; 118:2021818118. [PMID: 33836594 PMCID: PMC7980371 DOI: 10.1073/pnas.2021818118] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood (n = 44), primary progressive MS (PPMS) patients (n = 25), or healthy controls (n = 42), but Eomes+ Th cells were significantly increased in SPMS (n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases (P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
Collapse
|
|
20
|
Sekiya T, Kagawa S, Masaki K, Fukunaga K, Yoshimura A, Takaki S. Regulation of peripheral Th/Treg differentiation and suppression of airway inflammation by Nr4a transcription factors. iScience 2021; 24:102166. [PMID: 33665581 PMCID: PMC7907427 DOI: 10.1016/j.isci.2021.102166] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/08/2021] [Accepted: 02/04/2021] [Indexed: 12/24/2022] Open
Abstract
Helper T (Th) and regulatory T (Treg) cell differentiation programs promote the eradication of pathogens, while minimizing adverse immune reactions. Here, we found that Nr4a family of nuclear receptors supports Treg cell induction and represses Th1 and Th2 cell differentiation from naive CD4+ T cells. Nr4a factors are transiently induced in CD4+ T cells immediately after antigen stimulation, thereby mediating epigenetic changes. In differentiating Treg cells, Nr4a factors mainly upregulated the early responsive genes in the Treg cell-specifying gene set, either directly or in cooperation with Ets family transcription factors. In contrast, Nr4a factors repressed AP-1 activity by interrupting a positive feedback loop for Batf factor expression, thus suppressing Th2 cell-associated genes. In an allergic airway inflammation model, Nr4a factors suppressed the pathogenesis, mediating oral tolerance. Lastly, pharmacological activation of an engineered Nr4a molecule prevented allergic airway inflammation, indicating that Nr4a factors may be novel therapeutic targets for inflammatory diseases.
Among “Treg signature genes”, Nr4a factors mainly induce early responsive ones Nr4a activate target genes directly or by supporting Ets factors' function Nr4a factors repress Th2-driving positive feedback loop for Batf factor expression Pharmacological activation of Nr4a factors' activity prevented airway inflammation
Collapse
Affiliation(s)
- Takashi Sekiya
- Section of Immune Response Modification, Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.,Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan
| | - Shizuko Kagawa
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Katsunori Masaki
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Koichi Fukunaga
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Satoshi Takaki
- Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan
| |
Collapse
|
|
21
|
Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats. J Neuroinflammation 2021; 18:26. [PMID: 33468172 PMCID: PMC7814630 DOI: 10.1186/s12974-021-02078-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/07/2021] [Indexed: 12/17/2022] Open
Abstract
Background Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. Methods A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. Results The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. Conclusions Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE). Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02078-2.
Collapse
|
|
22
|
Mimouna S, Rollins DA, Shibu G, Tharmalingam B, Deochand DK, Chen X, Oliver D, Chinenov Y, Rogatsky I. Transcription cofactor GRIP1 differentially affects myeloid cell-driven neuroinflammation and response to IFN-β therapy. J Exp Med 2021; 218:e20192386. [PMID: 33045064 PMCID: PMC7555412 DOI: 10.1084/jem.20192386] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 07/29/2020] [Accepted: 09/04/2020] [Indexed: 11/18/2022] Open
Abstract
Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon β (IFN-β) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor-interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell-specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-β. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.
Collapse
Affiliation(s)
- Sanda Mimouna
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
| | - David A. Rollins
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY
| | - Gayathri Shibu
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY
| | - Bowranigan Tharmalingam
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
| | - Dinesh K. Deochand
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
| | - Xi Chen
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY
| | - David Oliver
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
| | - Yurii Chinenov
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
| | - Inez Rogatsky
- The David Z. Rosensweig Genomics Center, Hospital for Special Surgery Research Institute, New York, NY
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY
| |
Collapse
|
|
23
|
Amiri A, Barreto G, Sathyapalan T, Sahebkar A. siRNA Therapeutics: Future Promise for Neurodegenerative Diseases. Curr Neuropharmacol 2021; 19:1896-1911. [PMID: 33797386 PMCID: PMC9185778 DOI: 10.2174/1570159x19666210402104054] [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: 11/06/2020] [Revised: 01/29/2021] [Accepted: 03/30/2021] [Indexed: 11/22/2022] Open
Abstract
Neurodegenerative diseases (ND), as a group of central nervous system (CNS) disorders, are among the most prominent medical problems of the 21st century. They are often associated with considerable disability, motor dysfunction and dementia and are more common in the aged population. ND imposes a psychologic, economic and social burden on the patients and their families. Currently, there is no effective treatment for ND. Since many ND result from the gain of function of a mutant allele, small interference RNA (siRNA) can be a potential therapeutic agent for ND management. Based on the RNA interference (RNAi) approach, siRNA is a powerful tool for modulating gene expression through gene silencing. However, there are some obstacles in the clinical application of siRNA, including unfavorable immune response, off-target effects, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system. Since there are some issues related to siRNA delivery routes, in this review, we focus on the application of siRNA in the management of ND treatment from 2000 to 2020.
Collapse
Affiliation(s)
| | | | | | - Amirhossein Sahebkar
- Address correspondence to this author at the Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Tel: 985118002288; Fax: 985118002287; E-mails: ;
| |
Collapse
|
|
24
|
Kurd NS, He Z, Louis TL, Milner JJ, Omilusik KD, Jin W, Tsai MS, Widjaja CE, Kanbar JN, Olvera JG, Tysl T, Quezada LK, Boland BS, Huang WJ, Murre C, Goldrath AW, Yeo GW, Chang JT. Early precursors and molecular determinants of tissue-resident memory CD8 + T lymphocytes revealed by single-cell RNA sequencing. Sci Immunol 2020; 5:eaaz6894. [PMID: 32414833 PMCID: PMC7341730 DOI: 10.1126/sciimmunol.aaz6894] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 04/16/2020] [Indexed: 01/06/2023]
Abstract
During an immune response to microbial infection, CD8+ T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we used single-cell RNA sequencing to examine the gene expression patterns of individual CD8+ T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional heterogeneity within the siIEL CD8+ T cell population at several stages of differentiation, representing functionally distinct TRM cell subsets and a subset of TRM cell precursors within the tissue early in infection. Together, these findings may inform strategies to optimize CD8+ T cell responses to protect against microbial infection and cancer.
Collapse
Affiliation(s)
- Nadia S Kurd
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Zhaoren He
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Division of Biologic Sciences, University of California San Diego, La Jolla, CA, USA
| | - Tiani L Louis
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - J Justin Milner
- Division of Biologic Sciences, University of California San Diego, La Jolla, CA, USA
| | - Kyla D Omilusik
- Division of Biologic Sciences, University of California San Diego, La Jolla, CA, USA
| | - Wenhao Jin
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Matthew S Tsai
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | | | - Jad N Kanbar
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jocelyn G Olvera
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Tiffani Tysl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Lauren K Quezada
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Brigid S Boland
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Wendy J Huang
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cornelis Murre
- Division of Biologic Sciences, University of California San Diego, La Jolla, CA, USA
| | - Ananda W Goldrath
- Division of Biologic Sciences, University of California San Diego, La Jolla, CA, USA
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
- Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA
| | - John T Chang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Division of Gastroenterology, VA San Diego Healthcare System, San Diego, CA, USA
| |
Collapse
|
|
25
|
Wang X, Ni L, Wan S, Zhao X, Ding X, Dejean A, Dong C. Febrile Temperature Critically Controls the Differentiation and Pathogenicity of T Helper 17 Cells. Immunity 2020; 52:328-341.e5. [PMID: 32049050 DOI: 10.1016/j.immuni.2020.01.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/02/2019] [Accepted: 01/19/2020] [Indexed: 02/06/2023]
Abstract
Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation in vitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C-39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities in vivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both in vitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases.
Collapse
Affiliation(s)
- Xiaohu Wang
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
| | - Lu Ni
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Siyuan Wan
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiaohong Zhao
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xiao Ding
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
| | - Anne Dejean
- Nuclear Organization and Oncogenesis Laboratory, Department of Cell Biology and Infection, INSERM U993, Institute Pasteur, Paris 75015, France
| | - Chen Dong
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing 100084, China.
| |
Collapse
|
|
26
|
Lee KH, Ahn BS, Cha D, Jang WW, Choi E, Park S, Park JH, Oh J, Jung DE, Park H, Park JH, Suh Y, Jin D, Lee S, Jang YH, Yoon T, Park MK, Seong Y, Pyo J, Yang S, Kwon Y, Jung H, Lim CK, Hong JB, Park Y, Choi E, Shin JI, Kronbichler A. Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: A comprehensive review. Autoimmun Rev 2020; 19:102469. [PMID: 31918027 DOI: 10.1016/j.autrev.2020.102469] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 12/21/2022]
Abstract
Autoimmune diseases are clinical syndromes that result from pathogenic inflammatory responses driven by inadequate immune activation by T- and B-cells. Although the exact mechanisms of autoimmune diseases are still elusive, genetic factors also play an important role in the pathogenesis. Recently, with the advancement of understanding of the immunological and molecular basis of autoimmune diseases, gene modulation has become a potential approach for the tailored treatment of autoimmune disorders. Gene modulation can be applied to regulate the levels of interleukins (IL), tumor necrosis factor (TNF), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interferon-γ and other inflammatory cytokines by inhibiting these cytokine expressions using short interfering ribonucleic acid (siRNA) or by inhibiting cytokine signaling using small molecules. In addition, gene modulation delivering anti-inflammatory cytokines or cytokine antagonists showed effectiveness in regulating autoimmunity. In this review, we summarize the potential target genes for gene or immunomodulation in autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD) and multiple sclerosis (MS). This article will give a new perspective on understanding immunopathogenesis of autoimmune diseases not only in animals but also in human. Emerging approaches to investigate cytokine regulation through gene modulation may be a potential approach for the tailored immunomodulation of some autoimmune diseases near in the future.
Collapse
Affiliation(s)
- Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung Soo Ahn
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dohyeon Cha
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Woo Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eugene Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soohyun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyeong Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junseok Oh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Da Eun Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Heeryun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ju Ha Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngsong Suh
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dongwan Jin
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Siyeon Lee
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Hwan Jang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tehwook Yoon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min-Kyu Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoonje Seong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jihoon Pyo
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sunmo Yang
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youngin Kwon
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunjean Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chae Kwang Lim
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Beom Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeoeun Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eunjin Choi
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
27
|
Odagiu L, May J, Boulet S, Baldwin TA, Labrecque N. Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology. Front Endocrinol (Lausanne) 2020; 11:624122. [PMID: 33597928 PMCID: PMC7883379 DOI: 10.3389/fendo.2020.624122] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
The nuclear orphan receptors NR4A1, NR4A2, and NR4A3 are immediate early genes that are induced by various signals. They act as transcription factors and their activity is not regulated by ligand binding and are thus regulated via their expression levels. Their expression is transiently induced in T cells by triggering of the T cell receptor following antigen recognition during both thymic differentiation and peripheral T cell responses. In this review, we will discuss how NR4A family members impact different aspects of the life of a T cell from thymic differentiation to peripheral response against infections and cancer.
Collapse
Affiliation(s)
- Livia Odagiu
- Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada
| | - Julia May
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Salix Boulet
- Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
| | - Troy A. Baldwin
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Troy A. Baldwin, ; Nathalie Labrecque,
| | - Nathalie Labrecque
- Laboratory of Immunology, Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada
- Département de Médecine, Université de Montréal, Montreal, QC, Canada
- *Correspondence: Troy A. Baldwin, ; Nathalie Labrecque,
| |
Collapse
|
|
28
|
Oki S. Eomes-expressing T-helper cells as potential target of therapy in chronic neuroinflammation. Neurochem Int 2019; 130:104348. [DOI: 10.1016/j.neuint.2018.11.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 11/29/2022]
|
|
29
|
Grabarek BO, Wcisło-Dziadecka D, Bednarek K, Kruszniewska-Rajs C, Gola J. Assessment of transcriptional activity genes associated with the IL-17 signaling pathway in skin fibroblasts under the influence of adalimumab. Dermatol Ther 2019; 32:e13112. [PMID: 31605567 DOI: 10.1111/dth.13112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/04/2019] [Accepted: 10/04/2019] [Indexed: 01/17/2023]
Abstract
It is believed that IL-17 is involved in the signaling pathways of nuclear factor κB (NFκB) and mitogen-activated kinases (MAPKs). Adalimumab, a full anti-TNF-α monoclonal antibody, was used for treatment of moderate to severe psoriasis. This study aimed to investigate the effect of adalimumab on changes in the expression of genes associated with IL-17 signaling pathways in normal human dermal fibroblast (NHDF) culture. NHDFs treated with adalimumab at 2, 8, and 24 hr were compared with those of control. Microarray technique and PANTHER program were used to determine the expression of genes. The number of mRNA IDs differentiating the culture displayed on adalimumab in comparison with the control culture (-3.0 < FC > + 3.0) was as follows: H-2-32 mRNA ID, H-8-3 mRNA ID, H-2 and H-8-47 mRNA ID, H-8 and H-24-1 mRNA ID. Analysis by the PANTHER program indicated that adalimumab significantly affects the six signaling pathways and 19 biological processes associated with IL-17. The strongest changes in the expression profile concerned pathway genes associated with the chemokine and cytokine signaling pathway, the gonadotropin-releasing hormone receptor pathway, and the CCKR signaling map.
Collapse
Affiliation(s)
- Beniamin Oskar Grabarek
- Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Cracow Branch, Poland.,Katowice School of Technology, The University of Science and Arts in Katowice, Poland.,Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
| | - Dominika Wcisło-Dziadecka
- Department of Cosmetology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
| | - Kinga Bednarek
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
| | - Celina Kruszniewska-Rajs
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
| | - Joanna Gola
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Poland
| |
Collapse
|
|
30
|
Trudler D, Levy‐Barazany H, Nash Y, Samuel L, Sharon R, Frenkel D. Alpha synuclein deficiency increases CD4
+
T‐cells pro‐inflammatory profile in a Nurr1‐dependent manner. J Neurochem 2019; 152:61-71. [DOI: 10.1111/jnc.14871] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 01/25/2023]
Affiliation(s)
- Dorit Trudler
- Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
- Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel
| | - Hilit Levy‐Barazany
- Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
| | - Yuval Nash
- Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
- Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel
| | - Liron Samuel
- Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
| | - Ronit Sharon
- Faculty of Medicine Biochemistry and Molecular Biology IMRIC The Hebrew University Jerusalem Jerusalem Israel
| | - Dan Frenkel
- Department of Neurobiology George S. Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel
- Sagol School of Neuroscience Tel Aviv University Tel Aviv Israel
| |
Collapse
|
|
31
|
Extrapituitary prolactin promotes generation of Eomes-positive helper T cells mediating neuroinflammation. Proc Natl Acad Sci U S A 2019; 116:21131-21139. [PMID: 31570595 PMCID: PMC6800326 DOI: 10.1073/pnas.1906438116] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
We have previously demonstrated that induction of pathogenic eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) is associated with transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE). In the late phase of EAE, B cells and non-B cell antigen-presenting cells (APCs) recruited to the central nervous system strikingly up-regulate prolactin (PRL). The PRL-producing APCs have the potential to promote generation of Eomes+ Th cells from naïve T cells in an MHC class II-restricted manner, and therapies inhibitory for PRL production suppress the induction of Eomes+ Th cells and ameliorate clinical signs of EAE. Our study highlights the unexpected role of extrapituitary PRL in the development of persistent neuroinflammation. Induction of eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) has recently been correlated with the transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Moreover, these cells’ pathogenic role has been experimentally proven in EAE. While exploring how the pathogenic Eomes+ Th cells are generated during the course of EAE, we unexpectedly found that B cells and MHC class II+ myeloid cells isolated from the late EAE lesions strikingly up-regulated the expression of prolactin (PRL). We demonstrate that such PRL-producing cells have a unique potential to induce Eomes+ Th cells from naïve T cells ex vivo, and that anti-MHC class II antibody could block this process. Furthermore, PRL levels in the cerebrospinal fluid were significantly increased in the late phase of EAE, and blocking the production of PRL by bromocriptine or Zbtb20-specific siRNA significantly reduced the numbers of Eomes+ Th cells in the central nervous system (CNS) and ameliorated clinical signs in the later phase of EAE. The PRL dependency of Eomes+ Th cells was confirmed in a series of in vitro and ex vivo experiments. Collectively, these results indicate that extrapituitary PRL plays a crucial role in the CNS inflammation mediated by pathogenic Eomes+ Th cells. Cellular interactions involving PRL-producing immune cells could be considered as a therapeutic target for the prevention of chronic neuroinflammation.
Collapse
|
|
32
|
Song CH, Joo HM, Han SH, Kim JI, Nam SY, Kim JY. Low-dose ionizing radiation attenuates mast cell migration through suppression of monocyte chemoattractant protein-1 (MCP-1) expression by Nr4a2. Int J Radiat Biol 2019; 95:1498-1506. [PMID: 31287373 DOI: 10.1080/09553002.2019.1642535] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Purpose: The aim of this study was to investigate whether low-dose ionizing radiation attenuates mast cell migration by modulating migration-associated signaling pathways and the expression of chemotactic cytokines.Materials and methods: IgE-sensitized RBL-2H3 mast cells were exposed with ionizing radiation at 0.01, 0.05, 0.1, or 0.5 Gy using a 137Cs γ-irradiator and stimulated with 2,4-dinitrophenol-human serum albumin. Cell migration was determined using a transwell assay system, F-actin distribution using Alex Fluor 488-conjugated phalloidin, expression of various signaling proteins by Western blotting, mRNA expression by RT-PCR.Results: Low-dose ionizing radiation significantly suppressed mast cell migration induced by IgE-mediated mast cell activation. Furthermore, low-dose ionizing radiation altered cell morphology, as reflected by changes in F-actin distribution, and inhibited the activation of PI3K, Btk, Rac1, and Cdc42. These effects were mediated by Nr4a2, an immune-modulating factor. Knockdown of Nr4a2 reduced mast cell migration, inhibited the PI3K and Btk signaling pathways, and reduced expression of the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1). We further demonstrated that direct blockade of MCP-1 using neutralizing antibodies inhibits mast cell migration.Conclusion: Low-dose ionizing radiation inhibits mast cell migration through the regulation production of MCP-1 by Nr4a2 in the activated mast cell system.
Collapse
Affiliation(s)
- Chin-Hee Song
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| | - Hae Mi Joo
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| | - So Hyun Han
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| | - Jeong-In Kim
- Radiation Emergency Medical Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| | - Seon Young Nam
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| | - Ji Young Kim
- Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., Ltd, Seoul, Republic of Korea
| |
Collapse
|
|
33
|
DGAT1 inhibits retinol-dependent regulatory T cell formation and mediates autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2019; 116:3126-3135. [PMID: 30718413 DOI: 10.1073/pnas.1817669116] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The balance of effector versus regulatory T cells (Tregs) controls inflammation in numerous settings, including multiple sclerosis (MS). Here we show that memory phenotype CD4+ T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis (EAE), a widely studied animal model of MS, expressed high levels of mRNA for Dgat1 encoding diacylglycerol-O-acyltransferase-1 (DGAT1), an enzyme that catalyzes triglyceride synthesis and retinyl ester formation. DGAT1 inhibition or deficiency attenuated EAE, with associated enhanced Treg frequency; and encephalitogenic, DGAT1-/- in vitro-polarized Th17 cells were poor inducers of EAE in adoptive recipients. DGAT1 acyltransferase activity sequesters retinol in ester form, preventing synthesis of retinoic acid, a cofactor for Treg generation. In cultures with T cell-depleted lymphoid tissues, retinol enhanced Treg induction from DGAT1-/- but not from WT T cells. The WT Treg induction defect was reversed by DGAT1 inhibition. These results demonstrate that DGAT1 suppresses retinol-dependent Treg formation and suggest its potential as a therapeutic target for autoimmune inflammation.
Collapse
|
|
34
|
|
|
35
|
Cyclic AMP-Responsive Element-Binding Protein (CREB) is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation. EBioMedicine 2017; 25:165-174. [PMID: 29050947 PMCID: PMC5704088 DOI: 10.1016/j.ebiom.2017.10.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 09/30/2017] [Accepted: 10/09/2017] [Indexed: 12/12/2022] Open
Abstract
The molecular mechanisms that govern differential T cell development into pro-inflammatory Th17 vs. regulatory T (Treg) cells remain unclear. Here, we show that selective deletion of CREB in T cells or Th17 cells impaired Th17 cell differentiation in vitro and in vivo, and led to resistance to autoimmune diseases. Mechanistically, CREB, activated by CD3-PKC-ϴ signaling, plays a key role in regulating Th17 cell differentiation, at least in part through directly binding to the Il17-Il17f gene locus. Unexpectedly, although dispensable for FOXP3 expression and for the homeostasis and suppressive function of thymus-derived Treg cells, CREB negatively regulates the survival of TGF-β-induced Treg cells, and deletion of CREB resulted in increased FOXP3 + Treg cells in the intestine and protection in a colitis model. Thus, CREB is critical in autoimmune diseases by promoting Th17 cell and inhibiting de novo Treg cell generation.
CREB is critical for autoimmunity. CREB plays a T cell- and Th17 cell-instrinsic role in controlling IL-17 expression and Th17 cell differentiation. CREB is dispensable for FOXP3 expression and the homeostasis of nTreg cells. CREB negatively regulates the survival of iTreg cells. The balance of Th17 and Treg cells dictates development of numerous autoimmune and inflammatory diseases, and targeting Th17 cell-related pathways has been proved to be effective in treatment of related diseases. Here, we identified CREB as a critical transcription factor in regulating the differentiation of Th17 cells and survival of Treg cells in both in vitro experimental systems and mouse models of autoimmune diseases. The findings in this study might be useful for developing therapeutics against Th17 cell-related immune diseases.
Collapse
|
|
36
|
Takahashi H, Tsuboi H, Asashima H, Hirota T, Kondo Y, Moriyama M, Matsumoto I, Nakamura S, Sumida T. cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome. Clin Exp Immunol 2017. [PMID: 28621822 DOI: 10.1111/cei.13000] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up-regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4+ T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4-RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4+ T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17)-polarized CD4+ T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-β, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4+ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4+ T cells of SS patients, which could play a critical role in the pathogenesis of SS.
Collapse
Affiliation(s)
- H Takahashi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - H Tsuboi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - H Asashima
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - T Hirota
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Y Kondo
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - M Moriyama
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - I Matsumoto
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - S Nakamura
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - T Sumida
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| |
Collapse
|
|
37
|
Hosokawa K, Kajigaya S, Keyvanfar K, Qiao W, Xie Y, Townsley DM, Feng X, Young NS. T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways. THE JOURNAL OF IMMUNOLOGY 2017. [PMID: 28630090 DOI: 10.4049/jimmunol.1601299] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder originating from hematopoietic stem cells and is a life-threating disease characterized by intravascular hemolysis, bone marrow (BM) failure, and venous thrombosis. The etiology of PNH is a somatic mutation in the phosphatidylinositol glycan class A gene (PIG-A) on the X chromosome, which blocks synthesis of the glycolipid moiety and causes deficiency in GPI-anchored proteins. PNH is closely related to aplastic anemia, in which T cells mediate destruction of BM. To identify aberrant molecular mechanisms involved in immune targeting of hematopoietic stem cells in BM, we applied RNA-seq to examine the transcriptome of T cell subsets (CD4+ naive, CD4+ memory, CD8+ naive, and CD8+ memory) from PNH patients and healthy control subjects. Differentially expressed gene analysis in four different T cell subsets from PNH and healthy control subjects showed distinct transcriptional profiles, depending on the T cell subsets. By pathway analysis, we identified novel signaling pathways in T cell subsets from PNH, including increased gene expression involved in TNFR, IGF1, NOTCH, AP-1, and ATF2 pathways. Dysregulation of several candidate genes (JUN, TNFAIP3, TOB1, GIMAP4, GIMAP6, TRMT112, NR4A2, CD69, and TNFSF8) was validated by quantitative real-time RT-PCR and flow cytometry. We have demonstrated molecular signatures associated with positive and negative regulators in T cells, suggesting novel pathophysiologic mechanisms in PNH. These pathways may be targets for new strategies to modulate T cell immune responses in BM failure.
Collapse
Affiliation(s)
- Kohei Hosokawa
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Sachiko Kajigaya
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Keyvan Keyvanfar
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Wangmin Qiao
- Beijing Genomics Institute-Shenzhen, Shenzhen 518083, China
| | - Yanling Xie
- Beijing Genomics Institute-Shenzhen, Shenzhen 518083, China
| | - Danielle M Townsley
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Xingmin Feng
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Neal S Young
- Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and
| |
Collapse
|
|
38
|
Mottaghitalab F, Rastegari A, Farokhi M, Dinarvand R, Hosseinkhani H, Ou KL, Pack DW, Mao C, Dinarvand M, Fatahi Y, Atyabi F. Prospects of siRNA applications in regenerative medicine. Int J Pharm 2017; 524:312-329. [PMID: 28385649 DOI: 10.1016/j.ijpharm.2017.03.092] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 03/14/2017] [Accepted: 03/31/2017] [Indexed: 12/18/2022]
Abstract
Small interfering RNA (siRNA) has established its reputation in the field of tissue engineering owing to its ability to silence the proteins that inhibit tissue regeneration. siRNA is capable of regulating cellular behavior during tissue regeneration processes. The concept of using siRNA technology in regenerative medicine derived from its ability to inhibit the expression of target genes involved in defective tissues and the possibility to induce the expression of tissue-inductive factors that improve the tissue regeneration process. To date, siRNA has been used as a suppressive biomolecule in different tissues, such as nervous tissue, bone, cartilage, heart, kidney, and liver. Moreover, various delivery systems have been applied in order to deliver siRNA to the target tissues. This review will provide an in-depth discussion on the development of siRNA and their delivery systems and mechanisms of action in different tissues.
Collapse
Affiliation(s)
- Fatemeh Mottaghitalab
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Rastegari
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Farokhi
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Rassoul Dinarvand
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Hosseinkhani
- Innovation Center for Advanced Technology, Matrix, Inc., New York, NY 10029, USA
| | - Keng-Liang Ou
- Research Center for Biomedical Devices and Prototyping Production, Research Center for Biomedical Implants and Microsurgery Devices, Taipei Medical University, Taipei, Taiwan
| | - Daniel W Pack
- Department of Chemical & Materials Engineering and Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States
| | - Chuanbin Mao
- Department of Chemistry & Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, United States; School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China
| | - Meshkat Dinarvand
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Atyabi
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
39
|
Rodríguez-Calvo R, Tajes M, Vázquez-Carrera M. The NR4A subfamily of nuclear receptors: potential new therapeutic targets for the treatment of inflammatory diseases. Expert Opin Ther Targets 2017; 21:291-304. [PMID: 28055275 DOI: 10.1080/14728222.2017.1279146] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Prolonged inflammatory response contributes to the pathogenesis of chronic disease-related disturbances. Among nuclear receptors (NRs), the orphan NR4A subfamily, which includes Nur77 (NR4A1), Nurr1 (NR4A2) and NOR1 (NR4A3), has recently emerged as a therapeutic target for the treatment of inflammation. Areas covered: This review focuses on the capacity of NR4A receptors to counter-regulate the development of the inflammatory response, with a special focus on the molecular transrepression mechanisms. Expert opinion: Recent studies have highlighted the role of NR4A receptors as significant regulators of the inflammatory response. NR4A receptors are rapidly induced by inflammatory stimuli, thus suggesting that they are required for the initiation of inflammation. Nevertheless, NR4A anti-inflammatory properties indicate that this acute regulation could be a protective reaction aimed at resolving inflammation in the later stages. Therefore, NR4A receptors are involved in a negative feedback mechanism to maintain the inflammatory balance. However, the underlying mechanisms are not entirely clear. Only a small number of NR4A-target genes have been identified, and the transcriptional repression mechanisms are only beginning to emerge. Despite further research is needed to fully understand the role of NR4A receptors in inflammation, these NRs should be considered as targets for new therapeutic approaches to inflammatory diseases.
Collapse
Affiliation(s)
- Ricardo Rodríguez-Calvo
- a Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Pere Virgili Health Research Institute (IISPV) and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Medicine and Health Sciences , Rovira i Virgili University , Reus , Spain
| | - Marta Tajes
- b Heart Diseases Biomedical Research Group, Inflammatory and Cardiovascular Disorders Program , Hospital del Mar Medical Research Institute (IMIM), Parc de Salut Mar , Barcelona , Spain
| | - Manuel Vázquez-Carrera
- c Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Pediàtrica-Hospital Sant Joan de Déu, and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, Diagonal 643 , University of Barcelona , Barcelona , Spain
| |
Collapse
|
|
40
|
Sato F, Omura S, Jaffe S, Tsunoda I. Role of CD4+ T Cells in the Pathophysiology of Multiple Sclerosis. MULTIPLE SCLEROSIS 2016. [PMCID: PMC7150304 DOI: 10.1016/b978-0-12-800763-1.00004-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although the precise etiology of MS remains unclear, CD4+ T cells have been proposed to play not only effector but also regulatory roles in MS. CD4+ T cells can be divided into four subsets: pro-inflammatory helper T (Th) 1 and Th17 cells, anti-inflammatory Th2 cells and regulatory T cells (Tregs). The roles of CD4+ T cells in MS have been clarified by either “loss-of-function” or “gain-of-function” methods, which have been carried out mainly in autoimmune and viral models of MS: experimental autoimmune encephalomyelitis and Theiler's murine encephalomyelitis virus infection, respectively. Observations in MS patients were consistent with the mechanisms found in the MS models, that is, increased pro-inflammatory Th1 and Th17 activity is associated with disease exacerbation, while anti-inflammatory Th2 cells and Tregs appear to play a protective role.
Collapse
|
|
41
|
Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation. Nat Commun 2015; 6:8437. [PMID: 26436530 DOI: 10.1038/ncomms9437] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/20/2015] [Indexed: 11/09/2022] Open
Abstract
Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4(+) T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes(+) CD4(+) T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes(+) CD4(+) T cells.
Collapse
|
|
42
|
Mahajan S, Saini A, Chandra V, Nanduri R, Kalra R, Bhagyaraj E, Khatri N, Gupta P. Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis. J Biol Chem 2015; 290:18304-14. [PMID: 25953901 DOI: 10.1074/jbc.m115.638064] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Indexed: 01/22/2023] Open
Abstract
The orphan nuclear receptor Nr4a2 is known to modulate both inflammatory and metabolic processes, but the mechanism by which it regulates innate inflammatory homeostasis has not been adequately addressed. This study shows that exposure to ligands for Toll-like receptors (TLRs) robustly induces Nr4a2 and that this induction is tightly regulated by the PI3K-Akt signaling axis. Interestingly, exogenous expression of Nr4a2 in macrophages leads to their alternative phenotype with induction of genes that are prototypical M2 markers. Moreover, Nr4a2 transcriptionally activates arginase 1 expression by directly binding to its promoter. Adoptive transfer experiments revealed that increased survival of animals in endotoxin-induced sepsis is Nr4a2-dependent. Thus our data identify a previously unknown role for Nr4a2 in the regulation of macrophage polarization.
Collapse
Affiliation(s)
- Sahil Mahajan
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Ankita Saini
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Vemika Chandra
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Ravikanth Nanduri
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Rashi Kalra
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Ella Bhagyaraj
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Neeraj Khatri
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| | - Pawan Gupta
- From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India
| |
Collapse
|
|
43
|
Merino-Zamorano C, Hernández-Guillamon M, Jullienne A, Le Béhot A, Bardou I, Parés M, Fernández-Cadenas I, Giralt D, Carrera C, Ribó M, Vivien D, Ali C, Rosell A, Montaner J. NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke. Stroke 2014; 46:477-84. [PMID: 25503547 DOI: 10.1161/strokeaha.114.006826] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND PURPOSE Despite the effectiveness of recombinant tissue-type plasminogen activator (r-tPA) during the acute phase of ischemic stroke, the therapy remains limited by a narrow time window and the occurrence of occasional vascular side effects, particularly symptomatic hemorrhages. Our aim was to investigate the mechanisms underlying the endothelial damage resulting from r-tPA treatment in ischemic-like conditions. METHODS Microarray analyses were performed on cerebral endothelial cells submitted to r-tPA treatment during oxygen and glucose deprivation to identify novel biomarker candidates. Validation was then performed in vivo in a mouse model of thromboembolic stroke and culminated in an analysis in a clinical cohort of patients with ischemic stroke treated with thrombolysis. RESULTS The transcription factor NURR1 (NR4A2) was identified as a downstream target induced by r-tPA during oxygen and glucose deprivation. Silencing NURR1 expression reversed the endothelial-toxicity induced by the combined stimuli, a protective effect attributable to reduced levels of proinflammatory mediators, such as nuclear factor-kappa-beta 2 (NF-κ-B2), interleukin 1 alpha (IL1α), intercellular adhesion molecule 1 (ICAM1), SMAD family member 3 (SMAD3), colony stimulating factor 2 (granulocyte-macrophage; CSF2). The detrimental effect of delayed thrombolysis, in conditions in which NURR1 gene expression was enhanced, was confirmed in the preclinical stroke model. Finally, we determined that patients with stroke who had a symptomatic hemorrhagic transformation after r-tPA treatment exhibited higher baseline serum NURR1 levels than did patients with an asymptomatic or absence of cerebral bleedings. CONCLUSIONS Our results suggest that NURR1 upregulation by r-tPA during ischemic stroke is associated with endothelial dysfunction and inflammation and the enhancement of hemorrhagic complications associated to thrombolysis.
Collapse
Affiliation(s)
- Cristina Merino-Zamorano
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Mar Hernández-Guillamon
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.).
| | - Amandine Jullienne
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Audrey Le Béhot
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Isabelle Bardou
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Mireia Parés
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Israel Fernández-Cadenas
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Dolors Giralt
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Caty Carrera
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Marc Ribó
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Denis Vivien
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Carine Ali
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Anna Rosell
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| | - Joan Montaner
- From the Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain (C.M.-Z., M.H.-G., M.P., I.F.-C., D.G., C.C., A.R., J.M.); INSERM UMR-S U919, GIP Cyceron, University of Caen, Caen, France (A.J., A.L.B., I.B., D.V., C.A.); and Neurovascular Unit, Department of Neurology, Vall d'Hebron Hospital, Barcelona, Spain (M.R., J.M.)
| |
Collapse
|
|
44
|
Kacperska MJ, Jastrzebski K, Tomasik B, Walenczak J, Konarska-Krol M, Glabinski A. Selected extracellular microRNA as potential biomarkers of multiple sclerosis activity--preliminary study. J Mol Neurosci 2014; 56:154-63. [PMID: 25487315 PMCID: PMC4382531 DOI: 10.1007/s12031-014-0476-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 11/26/2014] [Indexed: 11/30/2022]
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Four distinct disease courses are known, although approximately 90% of patients are diagnosed with the relapsing-remitting form (RRMS). The name "multiple sclerosis" pertains to the underlying pathology: the presence of demyelinating plaques in the CNS, in particular in the periventricular region, corpus callosum, cervical spine, and the cerebellum. There are ongoing efforts to discover biomarkers that would allow for an unequivocal diagnosis, assess the activity of inflammatory and neurodegenerative processes, or warn of disease progression. At present, small noncoding RNA particles-microRNA (miRNA, miR) seem to be particularly noteworthy, as they take part in posttranscriptional regulation of expression of various genes. Changes in composition as well as function of miRNA found in body fluids of MS patients are subjects of research, in the hope they prove accurate markers of MS activity. This preliminary study aims to evaluate the expression of selected extracellular microRNA particles (miRNA-let-7a, miRNA-92a, miRNA-684a) in patients experiencing MS relapse and remission, with healthy volunteers serving as a control group and to evaluate the correlation between miRNA expression and selected clinical parameters of those patients. Thirty-seven patients suffering from MS formed two examined groups: 20 patients undergoing relapse and 17 in remission. Thirty healthy volunteers formed the control group. All patients who were subjects to peripheral blood sampling had been hospitalized in the Department of Neurology and Stroke(1). Four milliliters of venous whole blood had been collected into EDTA tubes. The basis for the selection of the three particular miRNA investigated in this study (miRNA-let-7a, miRNA-92a, miRNA-684a) was a preliminary bioinformatic analysis of data compiled from several medical databases, including Ovid MEDLINE®, Embase, Cochrane Database of Systematic Reviews (CDSR), miRWalk, and miRBase. The isolation of extracellular microRNA from plasma was carried out using miRNeasy Mini Kit (Qiagen) reagents. The reverse transcription was carried out with TaqMan® MicroRNA Reverse Transcription Kit (Applied Biosystems), as per manufacturers' instructions. Standard microRNA TaqMan® tests (Applied Biosystems) were used for miRNA quantification. The qPCR were performed on a 7900 HT Fast Real-Time PCR System (Applied Biosystems) and analyzed using Sequence Detection System 2.3 software. In addition, all patients at the Department of Neurology and Stroke undergo a routine complete blood count with differential. The main objective of this study was to evaluate the expression of selected microRNA (has-miR-let-7a, miR-92a, and miR-648a) in the plasma of patients with MS during a relapse as well as in remission and attempt to correlate the acquired data with clinically relevant parameters of the disease. Finding such correlations may potentially lead to the use of miRNA as a biomarker of MS, which could help diagnose the disease and assess its severity and the efficacy of treatment. The difference in the expression of has-miR-let-7a in the remission group and the control group was statistically significant (p = 0.002). Similarly, the expression of miRNA-648a in patients in remission was significantly different from the expression in the control group (p = 0.02). Analysis of the correlation between the expression of miRNA-92a and the severity of the disease as measured by the EDSS scale in patients undergoing relapse showed significant negative linear correlation (r = -0.54, p = 0.01). Higher miR-648a expression correlated with more frequent flare-ups in the joint group of patients in remission and relapse (p = 0.03). This study is one of the few that demonstrate significantly changed expression of selected extracellular miRNA in plasma of MS patients and correlate those findings with clinical parameters. These observations may suggest that some miRNA subsets may be potential biomarkers for MS activity.
Collapse
|
|
45
|
Shu SA, Wang J, Tao MH, Leung PSC. Gene Therapy for Autoimmune Disease. Clin Rev Allergy Immunol 2014; 49:163-76. [DOI: 10.1007/s12016-014-8451-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
46
|
Yan J, Fu Q, Cheng L, Zhai M, Wu W, Huang L, Du G. Inflammatory response in Parkinson's disease (Review). Mol Med Rep 2014; 10:2223-33. [PMID: 25215472 DOI: 10.3892/mmr.2014.2563] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 07/01/2014] [Indexed: 11/05/2022] Open
Abstract
Parkinson's disease (PD) is one of the most common age‑related neurodegenerative diseases, which results from a number of environmental and inherited factors. PD is characterized by the slow progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. The nigrostriatal DA neurons are particularly vulnerable to inflammatory attack. Neuroinflammation is an important contributor to the pathogenesis of age‑related neurodegenerative disorders, such as PD, and as such anti‑inflammatory agents are becoming a novel therapeutic focus. This review will discuss the current knowledge regarding inflammation and review the roles of intracellular inflammatory signaling pathways, which are specific inflammatory mediators in PD. Finally, possible therapeutic strategies are proposed, which may downregulate inflammatory processes and inhibit the progression of PD.
Collapse
Affiliation(s)
- Junqiang Yan
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Qizhi Fu
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Liniu Cheng
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Mingming Zhai
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Wenjuan Wu
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Lina Huang
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Ganqin Du
- Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| |
Collapse
|
|
47
|
Advances in siRNA delivery to T-cells: potential clinical applications for inflammatory disease, cancer and infection. Biochem J 2013; 455:133-47. [DOI: 10.1042/bj20130950] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The specificity of RNAi and its ability to silence ‘undruggable’ targets has made inhibition of gene expression in T-cells with siRNAs an attractive potential therapeutic strategy for the treatment of inflammatory disease, cancer and infection. However, delivery of siRNAs into primary T-cells represents a major hurdle to their use as potential therapeutic agents. Recent advances in siRNA delivery through the use of electroporation/nucleofection, viral vectors, peptides/proteins, nanoparticles, aptamers and other agents have now enabled efficient gene silencing in primary T-cells both in vitro and in vivo. Overcoming such barriers in siRNA delivery offers exciting new prospects for directly targeting T-cells systemically with siRNAs, or adoptively transferring T-cells back into patients following ex vivo manipulation with siRNAs. In the present review, we outline the challenges in delivering siRNAs into primary T-cells and discuss the mechanism and therapeutic opportunities of each delivery method. We emphasize studies that have exploited RNAi-mediated gene silencing in T-cells for the treatment of inflammatory disease, cancer and infection using mouse models. We also discuss the potential therapeutic benefits of manipulating T-cells using siRNAs for the treatment of human diseases.
Collapse
|
|
48
|
Raveney BJE, Oki S, Yamamura T. Nuclear receptor NR4A2 orchestrates Th17 cell-mediated autoimmune inflammation via IL-21 signalling. PLoS One 2013; 8:e56595. [PMID: 23437182 PMCID: PMC3578929 DOI: 10.1371/journal.pone.0056595] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Accepted: 01/11/2013] [Indexed: 12/12/2022] Open
Abstract
IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.
Collapse
MESH Headings
- Animals
- Autoimmune Diseases/chemically induced
- Autoimmune Diseases/immunology
- Autoimmune Diseases/metabolism
- Autoimmunity/genetics
- Autoimmunity/immunology
- Cell Differentiation/immunology
- Encephalomyelitis, Autoimmune, Experimental/chemically induced
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Gene Expression Regulation
- Humans
- Inflammation/immunology
- Inflammation/pathology
- Interleukins/administration & dosage
- Interleukins/genetics
- Interleukins/metabolism
- Mice
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Signal Transduction
- T-Lymphocytes, Helper-Inducer/cytology
- T-Lymphocytes, Helper-Inducer/immunology
- Th17 Cells/immunology
- Th17 Cells/metabolism
Collapse
Affiliation(s)
- Ben J. E. Raveney
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Shinji Oki
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Takashi Yamamura
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
49
|
Han YF, Cao GW. Role of nuclear receptor NR4A2 in gastrointestinal inflammation and cancers. World J Gastroenterol 2012; 18:6865-73. [PMID: 23322982 PMCID: PMC3531668 DOI: 10.3748/wjg.v18.i47.6865] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 08/27/2012] [Accepted: 09/12/2012] [Indexed: 02/06/2023] Open
Abstract
NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily. It was originally considered to be essential in the generation and maintenance of dopaminergic neurons, and associated with neurological disorders such as Parkinson’s disease. Recently, NR4A2 has been found to play a critical role in some inflammatory diseases and cancer. NR4A2 can be efficiently trans-activated by some proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and vascular endothelial growth factor (VEGF). The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells. NR4A2 can trans-activate Foxp3, a hallmark specifically expressed in regulatory T (Treg) cells, and plays a critical role in the differentiation, maintenance, and function of Treg cells. NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions. High density of Foxp3+ Treg cells is significantly associated with gastrointestinal inflammation, tumor immune escape, and disease progression. NR4A2 is produced at high levels in CD133+ colorectal carcinoma (CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E2 in a cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent manner in CRC cells. The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer. NR4A2 trans-activates osteopontin, a direct target of the Wnt/β-catenin pathway associated with CRC invasion, metastasis, and poor prognosis. Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation, migration and in vivo angiogenesis. Taken together, NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer, especially CRC, and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.
Collapse
|
|
50
|
Mori K, Kaneko YS, Nakashima A, Nagasaki H, Nagatsu T, Nagatsu I, Ota A. Subventricular zone under the neuroinflammatory stress and Parkinson's disease. Cell Mol Neurobiol 2012; 32:777-85. [PMID: 22189676 PMCID: PMC11498532 DOI: 10.1007/s10571-011-9783-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 12/08/2011] [Indexed: 12/20/2022]
Abstract
This review summarizes the effects of neuroinflammatory stress on the subventricular zone (SVZ), where new neurons are constitutively produced in the adult brain, especially focusing on the relation with Parkinson's disease (PD), because the SVZ is under the control of dopaminergic afferents from the substantia nigra (SN). In Lewy bodies-positive-PD, microglia is known to phagocytoze aggregated α-synuclein, resulting in the release of inflammatory cytokines. The neurogenesis in the SVZ should be affected in PD brain by the neuroinflammatory process. The administration of lipopolysaccaharide is available as an alternative model for microglia-induced loss of dopaminergic neurons and also the impairment of stem cell maintenance. Therefore, the research on the neuroinflammatory process in the SVZ gives us a hint to prevent the outbreak of PD or at least slow the disease process.
Collapse
Affiliation(s)
- Keiji Mori
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Yoko S. Kaneko
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Akira Nakashima
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Hiroshi Nagasaki
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Toshiharu Nagatsu
- Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Ikuko Nagatsu
- Department of Anatomy, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| | - Akira Ota
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192 Japan
| |
Collapse
|