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Calvier L, Wasser CR, Solow EB, Wu S, Evers BM, Karp DS, Kounnas MZ, Herz J. Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outcomes. Proc Natl Acad Sci U S A 2025; 122:e2418642122. [PMID: 40073057 DOI: 10.1073/pnas.2418642122] [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: 09/18/2024] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. Furthermore, therapeutic inhibition of Reelin using the CR-50 antibody yielded robust anti-inflammatory effects in multiple preclinical arthritis models, including STA, K/BxN, and collagen-induced arthritis. Notably, CR-50 treatment not only reduced leukocyte infiltration and synovial inflammation but also mitigated pannus formation. Importantly, these benefits were achieved without the gastrointestinal side effects commonly associated with nonsteroidal anti-inflammatory drugs like diclofenac. Our findings position Reelin as a proinflammatory endothelial biomarker and therapeutic target in RA. By modulating endothelial activation and leukocyte recruitment, anti-Reelin strategies offer an alternative approach to attenuate synovial inflammation and joint damage. These results provide a compelling rationale for further exploration of Reelin-targeted therapies as alternatives to conventional immunosuppressive treatments in RA and other chronic inflammatory diseases.
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MESH Headings
- Reelin Protein
- Animals
- Mice
- Humans
- Cell Adhesion Molecules, Neuronal/metabolism
- Cell Adhesion Molecules, Neuronal/genetics
- Extracellular Matrix Proteins/metabolism
- Extracellular Matrix Proteins/genetics
- Signal Transduction
- Nerve Tissue Proteins/metabolism
- Nerve Tissue Proteins/genetics
- LDL-Receptor Related Proteins/metabolism
- LDL-Receptor Related Proteins/genetics
- Serine Endopeptidases/metabolism
- Serine Endopeptidases/genetics
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/drug therapy
- Mice, Knockout
- Male
- Female
- Disease Models, Animal
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/genetics
- Arthritis, Experimental/pathology
- Mice, Inbred C57BL
- Inflammation/metabolism
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Affiliation(s)
- Laurent Calvier
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - Catherine R Wasser
- Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - E Blair Solow
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - Sharon Wu
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - Bret M Evers
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - David S Karp
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | | | - Joachim Herz
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
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Liu Y, Hu H, Chen T, Zhu C, Sun R, Xu J, Liu Y, Dai L, Zhao Y. Exploration and Identification of Potential Biomarkers and Immune Cell Infiltration Analysis in Synovial Tissue of Rheumatoid Arthritis. Int J Rheum Dis 2025; 28:e70137. [PMID: 39953769 DOI: 10.1111/1756-185x.70137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/19/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a prevalent autoimmune disease with synovial inflammation and hyperplasia, which can potentially cause degradation of articular cartilage, ultimately causing joint deformity, and impaired function. However, exact mechanisms underlying RA remain incompletely understood. This study seeks to uncover genomic signatures and potential biomarkers of RA, along with exploring the biological processes involved. METHODS Six microarray datasets from RA patients, osteoarthritis (OA) and healthy controls (HC) of synovial tissue were obtained from the Gene Expression Omnibus (GEO) database for integrated analysis. Differentially expressed genes (DEGs) between groups were identified by "limma" package. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out. Protein-protein interaction (PPI) network was analyzed by STRING and presented by Cytoscape. Weighted gene co-expression network analysis (WGCNA) was conducted to discover and construct the co-expression gene modules correlated with clinical phenotype. CytoHubba and MCODE were utilized for screening hub genes. Additionally, immune cell infiltration analysis was conducted utilizing CIBERSORT algorithm. The correlation of hub genes with immune cells were examined through Pearson Correlation Analysis. RESULTS The overlapped 92 up-regulated genes were determined between RA versus normal controls and RA versus OA, which were primarily enriched in immune response, lymphocyte activation, and chemokine signaling pathway. By integrating WGCNA, Cytohubba and MCODE algorithms, 16 hub genes were identified including CXCL13, ITK, CXCL9, CCR5, CCR7, NKG7, CCR7, and CD52. We validated the diagnostic significance of these markers in RA by qRT-PCR. Moreover, the analysis of immune cell infiltration demonstrated a positive association between these hub genes with B cell naïve, plasma cell, T cells follicular helper, and macrophages M1. The abundance of these cells was markedly greater in RA compared to OA and normal controls. CONCLUSION This research ultimately identified 5 potential diagnostic biomarkers of RA in the synovial tissue, namely NKG7, CD52, ITK, CXCL9, and GZMA. These findings have enhanced our comprehension of RA pathogenesis and identified promising diagnostic and therapeutic targets of RA.
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Affiliation(s)
- Yan Liu
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huifang Hu
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Chen
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenxi Zhu
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Rheumatology and Immunology and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Sun
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiayi Xu
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Liu
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lunzhi Dai
- Department of Rheumatology and Immunology and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Zhao
- Department of Rheumatology and Immunology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Li J, Xiao C, Li C, He J. Tissue-resident immune cells: from defining characteristics to roles in diseases. Signal Transduct Target Ther 2025; 10:12. [PMID: 39820040 PMCID: PMC11755756 DOI: 10.1038/s41392-024-02050-5] [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: 06/04/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 01/19/2025] Open
Abstract
Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.
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Affiliation(s)
- Jia Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Götz T, Cong X, Rauber S, Angeli M, Lang E, Ramming A, Schmidkonz C. A novel Slide-seq based image processing software to identify gene expression at the single cell level. J Pathol Inform 2024; 15:100384. [PMID: 39027045 PMCID: PMC11254742 DOI: 10.1016/j.jpi.2024.100384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/26/2024] [Accepted: 05/27/2024] [Indexed: 07/20/2024] Open
Abstract
Analysis of gene expression at the single-cell level could help predict the effectiveness of therapies in the field of chronic inflammatory diseases such as arthritis. Here, we demonstrate an adopted approach for processing images from the Slide-seq method. Using a puck, which consists of about 50,000 DNA barcode beads, an RNA sequence of a cell is to be read. The pucks are repeatedly brought into contact with liquids and then recorded with a conventional epifluorescence microscope. The image analysis initially consists of stitching the partial images of a sequence recording, registering images from different sequences, and finally reading out the bases. The new method enables the use of an inexpensive epifluorescence microscope instead of a confocal microscope.
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Affiliation(s)
- Th.I. Götz
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
- Department of Industrial Engineering and Health, Technical University of Applied Sciences Amberg-Weiden, Weiden, Germany
| | - X. Cong
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
| | - S. Rauber
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
| | - M. Angeli
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
| | - E.W. Lang
- CIML Group, Biophysics, University of Regensburg, 93040 Regensburg, Germany
| | - A. Ramming
- Department of Internal Medicine, University Hospital Erlangen, Erlangen, Germany
| | - C. Schmidkonz
- Department of Nuclear Medicine, University Hospital Erlangen, 91054 Erlangen, Germany
- Department of Industrial Engineering and Health, Technical University of Applied Sciences Amberg-Weiden, Weiden, Germany
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5
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Al-Nasser MM, Al-Saeedi MJ, Alhowaiti SA, Shinwari Z, Alhamlan FS, Alothaid H, Alkahtani S, Al-Qahtani AA. Combination of Methotrexate and Resveratrol Reduces Pro-Inflammatory Chemokines in Human THP-1 Cells. J Inflamm Res 2024; 17:8085-8098. [PMID: 39507267 PMCID: PMC11539838 DOI: 10.2147/jir.s482503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024] Open
Abstract
Introduction Methotrexate (MTX) is a widely used anti-metabolite drug in cancer therapy, but its efficacy is often hindered by reactive oxygen species (ROS)-induced cellular toxicity. Resveratrol, a natural polyphenol, possesses antioxidant and anticancer properties. Therefore, this in vitro study aimed to investigate the synergistic anti-proliferative and anti-inflammatory effects of MTX and resveratrol in human THP-1 cells. Methods THP-1 cells were differentiated into macrophage-like cells using phorbol 12-myristate 13-acetate. In vitro experiments assessed the impact of various concentrations of MTX and resveratrol on cell viability and proliferation using the MTT assay. Concentration-effect curves were generated to elucidate their relationship. Gene expression was analyzed by RT-qPCR, while chemokine expression was measured via ELISA. Phagocytic and migratory activities were also evaluated. Results Differentiated THP-1 cells were treated with MTX and resveratrol and stimulated with dimethyl sulfoxide (DMSO) and lipopolysaccharide (LPS) as inflammatory stimuli. The combination of MTX and resveratrol exhibited an anti-proliferative effect in THP-1 cells (p = 0.03). The concentration-effect curve revealed IC50 values of 49.15 µg at 24 hours (R = 0.8236) and 2.029e-005 µg at 48 hours (R = 0.97) for MTX, and 20.17 µg at 48 hours (R = 1.000) and 55.38 µg at 96 hours (R = 0.9666) for resveratrol. Co-treatment with MTX and resveratrol significantly reduced mRNA and chemokine expression of CCL2, CCL3, CCL4, CCL5, and CXCL10 (p < 0.05). Moreover, decreased phagocytic and migratory activities were confirmed by phagocytosis and migration assays (p < 0.05). Conclusion The combination of MTX and resveratrol effectively attenuated pro-inflammatory activity in THP-1 cells, as evidenced by the downregulation of mRNA and chemokine expression. These findings suggest that the synergistic effects of MTX and resveratrol hold promise for enhancing cancer therapeutics.
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Affiliation(s)
- Moonerah M Al-Nasser
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mashael J Al-Saeedi
- Department of Infection and Immunity, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Saltana A Alhowaiti
- Department of Infection and Immunity, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Zakia Shinwari
- Therapeutics & Biomarker Discovery for Clinical Applications, Stem Cell & Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fatimah S Alhamlan
- Department of Infection and Immunity, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- Department of Microbiology and Immunology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Hani Alothaid
- Department of Basic Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia
| | - Saad Alkahtani
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed A Al-Qahtani
- Department of Infection and Immunity, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
- Department of Microbiology and Immunology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Hanlon MM, Smith CM, Canavan M, Neto NGB, Song Q, Lewis MJ, O’Rourke AM, Tynan O, Barker BE, Gallagher P, Mullan R, Hurson C, Moran B, Monaghan MG, Pitzalis C, Fletcher JM, Nagpal S, Veale DJ, Fearon U. Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset. SCIENCE ADVANCES 2024; 10:eadj1252. [PMID: 39321281 PMCID: PMC11423874 DOI: 10.1126/sciadv.adj1252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/20/2024] [Indexed: 09/27/2024]
Abstract
This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of patients with rheumatoid arthritis (RA), "individuals at risk" of RA, and healthy controls (HC). Flow cytometric analysis demonstrated the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease activity and treatment response. In-depth RNA sequencing and metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. Single-cell RNA sequencing profiling of 67,908 RA and HC synovial tissue cells identified nine transcriptionally distinct macrophage clusters. IL-1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and are importantly enriched before disease onset. Combined, these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.
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Affiliation(s)
- Megan M. Hanlon
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Conor M. Smith
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Mary Canavan
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
- Translational Immunopathology, School of Biochemistry and Immunology and School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Nuno G. B. Neto
- Department of Mechanical and Manufacturing Engineering, Trinity Biomedical Sciences Institute, Dublin, Ireland
| | - Qingxuan Song
- Immunology and Discovery Sciences, Janssen Research and Development, Spring House, PA, USA
| | - Myles J. Lewis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts NIHR BRC and Barts Health NHS Trust, London, UK
| | - Aoife M. O’Rourke
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
- Translational Immunopathology, School of Biochemistry and Immunology and School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Orla Tynan
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Brianne E. Barker
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Phil Gallagher
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ronan Mullan
- Department of Rheumatology, Adelaide and Meath Hospital, Dublin, Ireland
| | - Conor Hurson
- Department of Orthopaedics, St. Vincent’s University Hospital, Dublin, Ireland
| | - Barry Moran
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Michael G. Monaghan
- Department of Mechanical and Manufacturing Engineering, Trinity Biomedical Sciences Institute, Dublin, Ireland
| | - Costantino Pitzalis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London and Barts NIHR BRC and Barts Health NHS Trust, London, UK
- Department of Biomedical Sciences, Humanitas University and Humanitas Research Hospital, Milan, Italy
| | - Jean M. Fletcher
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Sunil Nagpal
- Immunology and Discovery Sciences, Janssen Research and Development, Spring House, PA, USA
| | - Douglas J. Veale
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Ursula Fearon
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
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Pai P, Vijeev A, Phadke S, Shetty MG, Sundara BK. Epi-revolution in rheumatology: the potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention. Inflammopharmacology 2024; 32:2109-2123. [PMID: 38714604 PMCID: PMC11300544 DOI: 10.1007/s10787-024-01486-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 02/16/2024] [Indexed: 05/10/2024]
Abstract
Autoimmune diseases hold significant importance in the realm of medical research, prompting a thorough exploration of potential therapeutic interventions. One crucial aspect of this exploration involves understanding the intricate processes of histone acetylation and deacetylation. Histone acetylation, facilitated by histone acetyl transferases (HATs), is instrumental in rendering DNA transcriptionally active. Conversely, histone deacetylases (HDACs) are responsible for the removal of acetyl groups, influencing gene expression regulation. The upregulation of HDACs, observed in various cancers, has steered attention towards histone deacetylase inhibitors (HDACi) as promising anti-cancer agents. Beyond cancer, HDACi has demonstrated anti-inflammatory properties, prompting interest in their potential therapeutic applications for inflammatory diseases such as rheumatoid arthritis (RA). RA, characterized by the immune system erroneously attacking healthy cells, leads to joint inflammation. Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue growth and suppression of pro-inflammatory cytokines. Furthermore, HDACi may exert protective effects on bone and cartilage, common targets in RA pathology. In-depth investigations through in vivo and histopathology studies contribute to the ongoing discourse on the therapeutic benefits of HDACis in the context of RA treatment.
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Affiliation(s)
- Padmini Pai
- Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Aradhika Vijeev
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sharada Phadke
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Manasa Gangadhar Shetty
- Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Babitha Kampa Sundara
- Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Silveira-Freitas JEP, Campagnolo ML, dos Santos Cortez M, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. Long chikungunya? An overview to immunopathology of persistent arthralgia. World J Virol 2024; 13:89985. [PMID: 38984075 PMCID: PMC11229846 DOI: 10.5501/wjv.v13.i2.89985] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/09/2024] [Accepted: 04/12/2024] [Indexed: 06/24/2024] Open
Abstract
Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Campus Anísio Teixeira, Vitória da Conquista, Bahia 45029-094, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa de Pós-graduação em Biotecnologia, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
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9
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Bakinowska E, Bratborska AW, Kiełbowski K, Ćmil M, Biniek WJ, Pawlik A. The Role of Mesenchymal Stromal Cells in the Treatment of Rheumatoid Arthritis. Cells 2024; 13:915. [PMID: 38891047 PMCID: PMC11171813 DOI: 10.3390/cells13110915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by the formation of a hyperplastic pannus, as well as cartilage and bone damage. The pathogenesis of RA is complex and involves broad interactions between various cells present in the inflamed synovium, including fibroblast-like synoviocytes (FLSs), macrophages, and T cells, among others. Under inflammatory conditions, these cells are activated, further enhancing inflammatory responses and angiogenesis and promoting bone and cartilage degradation. Novel treatment methods for RA are greatly needed, and mesenchymal stromal cells (MSCs) have been suggested as a promising new regenerative and immunomodulatory treatment. In this paper, we present the interactions between MSCs and RA-FLSs, and macrophages and T cells, and summarise studies examining the use of MSCs in preclinical and clinical RA studies.
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Affiliation(s)
- Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | | | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Maciej Ćmil
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Wojciech Jerzy Biniek
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (E.B.); (K.K.); (M.Ć.); (W.J.B.)
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10
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Bashar SJ, Holmes CL, Shelef MA. Macrophage extracellular traps require peptidylarginine deiminase 2 and 4 and are a source of citrullinated antigens bound by rheumatoid arthritis autoantibodies. Front Immunol 2024; 15:1167362. [PMID: 38476240 PMCID: PMC10927735 DOI: 10.3389/fimmu.2024.1167362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 01/29/2024] [Indexed: 03/14/2024] Open
Abstract
Introduction Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis, but the sources of citrullinated antigens as well as which peptidylarginine deiminases (PADs) are required for their production remain incompletely defined. Here, we investigated if macrophage extracellular traps (METs) could be a source of citrullinated proteins bound by APCAs, and if their formation requires PAD2 or PAD4. Methods Thioglycolate-induced peritoneal macrophages from wild-type, PAD2-/-, and PAD4-/- mice or human peripheral blood-derived M1 macrophages were activated with a variety of stimulants, then fixed and stained with DAPI and either anti-citrullinated histone H4 (citH4) antibody or sera from ACPA+ or ACPA- rheumatoid arthritis subjects. METs were visualized by immunofluorescence, confirmed to be extracellular using DNase, and quantified. Results We found that ionomycin and monosodium urate crystals reliably induced murine citH4+ METs, which were reduced in the absence of PAD2 and lost in the absence of PAD4. Also, IgG from ACPA+, but not ACPA-, rheumatoid arthritis sera bound to murine METs, and in the absence of PAD2 or PAD4, ACPA-bound METs were lost. Finally, ionomycin induced human METs that are citH4+ and ACPA-bound. Discussion Thus, METs may contribute to the pool of citrullinated antigens bound by ACPAs in a PAD2- and PAD4-dependent manner, providing new insights into the targets of immune tolerance loss in rheumatoid arthritis.
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Affiliation(s)
- S. Janna Bashar
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
| | - Caitlyn L. Holmes
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
| | - Miriam A. Shelef
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
- William S. Middleton Memorial Veteran’s Hospital, Madison, WI, United States
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11
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Sasaki R, Sakamoto J, Honda Y, Motokawa S, Kataoka H, Origuchi T, Okita M. Low-intensity pulsed ultrasound phonophoresis with diclofenac alleviated inflammation and pain via downregulation of M1 macrophages in rats with carrageenan-induced knee joint arthritis. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2024; 15:100148. [PMID: 38174056 PMCID: PMC10758990 DOI: 10.1016/j.ynpai.2023.100148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 01/05/2024]
Abstract
Objective This study aimed to investigate the effects of low-intensity pulsed ultrasound (LIPUS) phonophoresis with diclofenac on inflammation and pain in the acute phase of carrageenan-induced arthritis in rats. Design 60 male Wistar rats were randomly divided into the arthritis, diclofenac, LIPUS, phonophoresis, and sham-arthritis control groups. LIPUS and transdermal diclofenac gel were applied to the lateral side of the inflamed knee for 7 days, initiated postinjection day 1. In the phonophoresis group, diclofenac gel was rubbed onto the skin, followed by LIPUS application over the medication. Knee joint transverse diameters, pressure pain thresholds (PPTs), and paw withdrawal thresholds (PWT) were evaluated. The number of CD68-, CD11c-, and CD206-positive cells, and IL-1β and COX-2 mRNA expression were analyzed 8 days after injection. Results In the phonophoresis group, the transverse diameter, PPT, PWT significantly recovered at the day 8 compared to those in the LIPUS and diclofenac groups. The number of CD68- and CD11c-positive cells in the phonophoresis group was significantly lower than that in the LIPUS and diclofenac groups, but no significant differences were observed among three groups in CD206-positive cells. IL-1β and COX-2 mRNA levels were lower in the phonophoresis group than in the arthritis group, although there were no differences among the LIPUS, diclofenac, and phonophoresis groups. Conclusion LIPUS phonophoresis with diclofenac is more effective to ameliorate inflammation and pain compared to diclofenac or LIPUS alone, and the mechanism involves the decrease of M1 macrophages.
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Affiliation(s)
- Ryo Sasaki
- Department of Rehabilitation, Juzenkai Hospital, Nagasaki, Japan
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Sakamoto
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Institute of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yuichiro Honda
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Institute of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Satoko Motokawa
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Rehabilitation, Nagasaki Rehabilitation Hospital, Nagasaki, Japan
| | - Hideki Kataoka
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Rehabilitation, Nagasaki Memorial Hospital, Nagasaki, Japan
| | - Tomoki Origuchi
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Institute of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Minoru Okita
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Institute of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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12
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Lu C, Cheng RJ, Zhang Q, Hu Y, Pu Y, Wen J, Zhong Y, Tang Z, Wu L, Wei S, Tsou PS, Fox DA, Li S, Luo Y, Liu Y. Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization. Int Immunopharmacol 2023; 125:111175. [PMID: 37976601 DOI: 10.1016/j.intimp.2023.111175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 10/25/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVE Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood. METHODS CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR. RESULTS We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages. CONCLUSION CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.
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Affiliation(s)
- Chenyang Lu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Rui-Juan Cheng
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiuping Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yidan Hu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yaoyu Pu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ji Wen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yutong Zhong
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhigang Tang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liang Wu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shixiong Wei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, NO. 1 Shuai Fu Yuan, Wang Fu Jing Street, Beijing 100730, China
| | - Pei-Suen Tsou
- Division of Rheumatology, Department of Internal Medicine and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA
| | - David A Fox
- Division of Rheumatology, Department of Internal Medicine and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA
| | - Shasha Li
- Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
| | - Yubin Luo
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China.
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Nandakumar KS, Fang Q, Wingbro Ågren I, Bejmo ZF. Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis. Int J Mol Sci 2023; 24:15883. [PMID: 37958864 PMCID: PMC10648236 DOI: 10.3390/ijms242115883] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture.
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Affiliation(s)
- Kutty Selva Nandakumar
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
| | - Qinghua Fang
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA;
| | - Isabella Wingbro Ågren
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
| | - Zoe Fuwen Bejmo
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
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14
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Slavick A, Furer V, Polachek A, Tzemach R, Elkayam O, Gertel S. Circulating and Synovial Monocytes in Arthritis and Ex-Vivo Model to Evaluate Therapeutic Modulation of Synovial Monocytes. Immunol Invest 2023; 52:832-855. [PMID: 37615125 DOI: 10.1080/08820139.2023.2247438] [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] [Indexed: 08/25/2023]
Abstract
Monocytes are innate immune cells that play a dual role in protection of host against pathogens and initiation and perpetuation of inflammatory disorders including joint diseases. During inflammation, monocytes migrate from peripheral blood to tissues via chemokine receptors where they produce inflammatory factors. Monocytes are classified into three subsets, namely: classical, intermediate and non-classical, each subset has particular function. Synovium of patients with inflammatory joint diseases, such as rheumatoid arthritis and psoriatic arthritis as well as osteoarthritis, is enriched by monocytes that differ from circulatory ones by distinct subsets distribution. Several therapeutic agents used systemically or locally through intra-articular injections in arthritis management modulate monocyte subsets. This scoping review summarized the existing literature delineating the effect of common therapeutic agents used in arthritis management on circulating and synovial monocytes/macrophages. As certain agents have an inhibitory effect on monocytes, we propose to test their potential to inhibit synovial monocytes via an ex-vivo platform based on cultured synovial fluid mononuclear cells derived from patients with rheumatic diseases. Information obtained from the ex-vivo platform can be applied to explore the therapeutic potential of medications in clinical practice.
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Affiliation(s)
- Adam Slavick
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Victoria Furer
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ari Polachek
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Reut Tzemach
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ori Elkayam
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Smadar Gertel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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15
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Wang Z, Wang M, Xu X, Liu Y, Chen Q, Wu B, Zhang Y. PPARs/macrophages: A bridge between the inflammatory response and lipid metabolism in autoimmune diseases. Biochem Biophys Res Commun 2023; 684:149128. [PMID: 39491979 DOI: 10.1016/j.bbrc.2023.149128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/03/2023] [Accepted: 10/16/2023] [Indexed: 11/05/2024]
Abstract
Autoimmune diseases (AIDs) are a collection of pathologies that arise from autoimmune reactions and lead to the destruction and damage of the body's tissues and cellular components, ultimately resulting in tissue damage and organ dysfunction. The anti-inflammatory effects of the peroxisome proliferator-activated receptor (PPAR), a pivotal regulator of lipid metabolism, are crucial in the context of AIDs. PPAR mitigates AIDs by modulating macrophage polarization and suppressing the inflammatory response. Numerous studies have demonstrated the crucial involvement of lipid metabolism and phenotypic switching in classically activated (M1)/alternatively activated (M2)-like macrophages in the inflammatory pathway of AIDs. However, the precise mechanism by which PPAR, a critical mediator between of lipid metabolism and macrophage polarization, regulates macrophage polarization remains unclear. This review aimed to clarify the role of PPAR and macrophages in the triangular relationship among AIDs, lipid metabolism, and inflammatory response, and aims to summarize the mechanism of the PPAR-mediated macrophage activation and polarization, which impacts the progression and development of AIDs.
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Affiliation(s)
- Zikang Wang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China
| | - Miao Wang
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Xiaoyu Xu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China; Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Yunyan Liu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China
| | - Qian Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China
| | - Bin Wu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China; Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
| | - Ying Zhang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 401334, China; Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
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16
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Lesnak JB, Mazhar K, Price TJ. Neuroimmune Mechanisms Underlying Post-acute Sequelae of SARS-CoV-2 (PASC) Pain, Predictions from a Ligand-Receptor Interactome. Curr Rheumatol Rep 2023; 25:169-181. [PMID: 37300737 PMCID: PMC10256978 DOI: 10.1007/s11926-023-01107-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2023] [Indexed: 06/12/2023]
Abstract
PURPOSE OF REVIEW Individuals with post-acute sequelae of SARS-CoV-2 (PASC) complain of persistent musculoskeletal pain. Determining how COVID-19 infection produces persistent pain would be valuable for the development of therapeutics aimed at alleviating these symptoms. RECENT FINDINGS To generate hypotheses regarding neuroimmune interactions in PASC, we used a ligand-receptor interactome to make predictions about how ligands from PBMCs in individuals with COVID-19 communicate with dorsal root ganglia (DRG) neurons to induce persistent pain. In a structured literature review of -omics COVID-19 studies, we identified ligands capable of binding to receptors on DRG neurons, which stimulate signaling pathways including immune cell activation and chemotaxis, the complement system, and type I interferon signaling. The most consistent finding across immune cell types was an upregulation of genes encoding the alarmins S100A8/9 and MHC-I. This ligand-receptor interactome, from our hypothesis-generating literature review, can be used to guide future research surrounding mechanisms of PASC-induced pain.
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Affiliation(s)
- Joseph B Lesnak
- School for Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, BSB 14.102G, Richardson, TX, 75080, USA
| | - Khadijah Mazhar
- School for Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, BSB 14.102G, Richardson, TX, 75080, USA
| | - Theodore J Price
- School for Behavioral and Brain Sciences and Center for Advanced Pain Studies, University of Texas at Dallas, BSB 14.102G, Richardson, TX, 75080, USA.
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Dharra R, Kumar Sharma A, Datta S. Emerging aspects of cytokine storm in COVID-19: The role of proinflammatory cytokines and therapeutic prospects. Cytokine 2023; 169:156287. [PMID: 37402337 PMCID: PMC10291296 DOI: 10.1016/j.cyto.2023.156287] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/24/2023] [Indexed: 07/06/2023]
Abstract
COVID-19 has claimed millions of lives during the last 3 years since initial cases were reported in Wuhan, China, in 2019. Patients with COVID-19 suffer from severe pneumonia, high fever, acute respiratory distress syndrome (ARDS), and multiple-organ dysfunction, which may also result in fatality in extreme cases. Cytokine storm (CS) is hyperactivation of the immune system, wherein the dysregulated production of proinflammatory cytokines could result in excessive immune cell infiltrations in the pulmonary tissues, resulting in tissue damage. The immune cell infiltration could also occur in other tissues and organs and result in multiple organs' dysfunction. The key cytokines implicated in the onset of disease severity include TNF-α, IFN-γ, IL-6, IL-1β, GM-CSF, and G-CSF. Controlling the CS is critical in treating COVID-19 disease. Therefore, different strategies are employed to mitigate the effects of CS. These include using monoclonal antibodies directed against soluble cytokines or the cytokine receptors, combination therapies, mesenchymal stem cell therapy, therapeutic plasma exchange, and some non-conventional treatment methods to improve patient immunity. The current review describes the role/s of critical cytokines in COVID-19-mediated CS and the respective treatment modalities.
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Affiliation(s)
- Renu Dharra
- CSIR-Institute of Microbial Technology, Sector 39 A, Chandigarh 160036, India
| | - Anil Kumar Sharma
- Department of Bio-Science and Technology, M. M. Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India
| | - Sonal Datta
- Department of Bio-Science and Technology, M. M. Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala 133207, India.
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Álvarez K, Rojas M. Nanoparticles targeting monocytes and macrophages as diagnostic and therapeutic tools for autoimmune diseases. Heliyon 2023; 9:e19861. [PMID: 37810138 PMCID: PMC10559248 DOI: 10.1016/j.heliyon.2023.e19861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 08/16/2023] [Accepted: 09/04/2023] [Indexed: 10/10/2023] Open
Abstract
Autoimmune diseases are chronic conditions that result from an inadequate immune response to self-antigens and affect many people worldwide. Their signs, symptoms, and clinical severity change throughout the course of the disease, therefore the diagnosis and treatment of autoimmune diseases are major challenges. Current diagnostic tools are often invasive and tend to identify the issue at advanced stages. Moreover, the available treatments for autoimmune diseases do not typically lead to complete remission and are associated with numerous side effects upon long-term usage. A promising strategy is the use of nanoparticles that can be used as contrast agents in diagnostic imaging techniques to detect specific cells present at the inflammatory infiltrates in tissues that are not easily accessible by biopsy. In addition, NPs can be designed to deliver drugs to a cell population or tissue. Considering the significant role played by monocytes in the development of chronic inflammatory conditions and their emergence as a target for extracorporeal monitoring and precise interventions, this review focuses on recent advancements in nanoparticle-based strategies for diagnosing and treating autoimmune diseases, with a particular emphasis on targeting monocyte populations.
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Affiliation(s)
- Karen Álvarez
- Grupo de Inmunología Celular e Inmunogenética, Sede de Investigación Universitaria (SIU), Universidad de Antioquia (UDEA), Colombia
| | - Mauricio Rojas
- Grupo de Inmunología Celular e Inmunogenética, Sede de Investigación Universitaria (SIU), Universidad de Antioquia (UDEA), Colombia
- Unidad de Citometría de Flujo, Sede de Investigación Universitaria (SIU), Universidad de Antioquia (UDEA), Colombia
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Hanlon MM, McGarry T, Marzaioli V, Amaechi S, Song Q, Nagpal S, Veale DJ, Fearon U. Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations. Rheumatology (Oxford) 2023; 62:2611-2620. [PMID: 36398893 PMCID: PMC10321118 DOI: 10.1093/rheumatology/keac640] [Citation(s) in RCA: 8] [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: 06/17/2022] [Accepted: 10/28/2022] [Indexed: 07/20/2023] Open
Abstract
OBJECTIVES Myeloid cells with a monocyte/macrophage phenotype are present in large numbers in the RA joint, significantly contributing to disease; however, distinct macrophage functions have yet to be elucidated. This study investigates the metabolic activity of infiltrating polarized macrophages and their impact on pro-inflammatory responses in RA. METHODS CD14+ monocytes from RA and healthy control (HC) bloods were isolated and examined ex vivo or following differentiation into 'M1/M2' macrophages. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, western blot, Seahorse XFe technology, phagocytosis assays and transmission electron microscopy along with RNA-sequencing (RNA-seq) transcriptomic analysis. RESULTS Circulating RA monocytes are hyper-inflammatory upon stimulation, with significantly higher expression of key cytokines compared with HC (P < 0.05) a phenotype which is maintained upon differentiation into mature ex vivo polarized macrophages. This induction in pro-inflammatory mechanisms is paralleled by cellular bioenergetic changes. RA macrophages are highly metabolic, with a robust boost in both oxidative phosphorylation and glycolysis in RA along with altered mitochondrial morphology compared with HC. RNA-seq analysis revealed divergent transcriptional variance between pro- and anti-inflammatory RA macrophages, revealing a role for STAT3 and NAMPT in driving macrophage activation states. STAT3 and NAMPT inhibition results in significant decrease in pro-inflammatory gene expression observed in RA macrophages. Interestingly, NAMPT inhibition specifically restores macrophage phagocytic function and results in reciprocal STAT3 inhibition, linking these two signalling pathways. CONCLUSION This study demonstrates a unique inflammatory and metabolic phenotype of RA monocyte-derived macrophages and identifies a key role for NAMPT and STAT3 signalling in regulating this phenotype.
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Affiliation(s)
- Megan M Hanlon
- Molecular Rheumatology Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | | | | | - Success Amaechi
- Molecular Rheumatology Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Qingxuan Song
- Immunology and Discovery Sciences, Janssen Research & Development, Philadelphia, PA, USA
| | - Sunil Nagpal
- Immunology and Discovery Sciences, Janssen Research & Development, Philadelphia, PA, USA
| | - Douglas J Veale
- EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin, Ireland
| | - Ursula Fearon
- Correspondence to: Ursula Fearon, Molecular Rheumatology Research Group, School of Medicine, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin D02 R590, Dublin, Ireland. E-mail:
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Nakamachi Y, Uto K, Hayashi S, Okano T, Morinobu A, Kuroda R, Kawan S, Saegusa J. Exosomes derived from synovial fibroblasts from patients with rheumatoid arthritis promote macrophage migration that can be suppressed by miR-124-3p. Heliyon 2023; 9:e14986. [PMID: 37151687 PMCID: PMC10161379 DOI: 10.1016/j.heliyon.2023.e14986] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023] Open
Abstract
Objectives Exosomes are potent vehicles for intercellular communication. Rheumatoid arthritis (RA) is a chronic systemic disease of unknown etiology. Local administration of miR-124 precursor to rats with adjuvant-induced arthritis suppresses systemic arthritis and bone destruction. Thus, exosomes may be involved in this disease. We aimed to determine the role of exosomes in the pathology of RA. Methods Fibroblast-like synoviocytes (FLS) were collected from patients with RA and osteoarthritis (OA). miR-124-3p mimic was transfected into the RA FLS (RA miR-124 FLS). Exosomes were collected from the culture medium by ultracentrifugation. Macrophages were produced from THP-1 cells. MicroRNAs in the exosomes were analyzed using real-time PCR. Proteomics analysis was performed using nanoscale liquid chromatography-tandem mass spectrometry. Macrophage migration was evaluated using a Transwell migration assay. SiRNA was used to knockdown proteins of interest. Results MicroRNAs in the RA FLS, RA miR-124 FLS, and OA FLS exosomes were similar. Proteomics analysis revealed that pentraxin 3 (PTX3) levels were higher in RA FLS exosomes than in RA miR-124 FLS and OA FLS exosomes, and proteasome 20S subunit beta 5 (PSMB5) levels were lower in RA FLS exosomes than in RA miR-124 FLS and OA FLS exosomes. The RA FLS exosomes promoted and the RA miR-124 FLS exosomes suppressed macrophage migration. PTX3-silenced RA FLS exosomes suppressed and PSMB5-silenced OA FLS exosomes promoted macrophage migration. Conclusions RA FLS exosomes promote macrophage migration via PTX3 and PSMB5, and miR-124-3p suppresses this migration.
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21
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Weivoda MM, Bradley EW. Macrophages and Bone Remodeling. J Bone Miner Res 2023; 38:359-369. [PMID: 36651575 PMCID: PMC10023335 DOI: 10.1002/jbmr.4773] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023]
Abstract
Bone remodeling in the adult skeleton facilitates the removal and replacement of damaged and old bone to maintain bone quality. Tight coordination of bone resorption and bone formation during remodeling crucially maintains skeletal mass. Increasing evidence suggests that many cell types beyond osteoclasts and osteoblasts support bone remodeling, including macrophages and other myeloid lineage cells. Herein, we discuss the origin and functions for macrophages in the bone microenvironment, tissue resident macrophages, osteomacs, as well as newly identified osteomorphs that result from osteoclast fission. We also touch on the role of macrophages during inflammatory bone resorption. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | - Elizabeth W. Bradley
- Department of Orthopedics and Stem Cell Institute, University of Minnesota, Minneapolis, MN
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22
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Yousaf H, Khan MIU, Ali I, Munir MU, Lee KY. Emerging role of macrophages in non-infectious diseases: An update. Biomed Pharmacother 2023; 161:114426. [PMID: 36822022 DOI: 10.1016/j.biopha.2023.114426] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/23/2023] Open
Abstract
In the past three decades, a huge body of evidence through various research studies conducted on animal models, has demonstrated that the macrophages are centralized of all the leukocytes involved in diseases and, particularly, their role in non-infectious diseases has been studied extensively for which they have also been referred to as the "double-edged swords". The most versatile of all immunocytes, macrophages play a key role in health and diseases. Various experimental models have demonstrated the conventional paradigms such as the M1/M2 dichotomy, which is not as obvious and presents a complex characterization of the macrophages in the disease immunology. In human diseases, this M1-M2 continuum shows a complex web of mechanisms, which are majorly divided into the pro-inflammatory roles (derived mainly by the cytokines: IL-1, IL-6, IL-12, IL-23, and tumor necrosis factor) and anti-inflammatory roles (CCl-17, CCl-22, CCL-2, transforming growth factor (TGF), and interleukin-10), which are involved in the wound healing and pathogen-suppression. The conventional division of these macrophages as M1 and M2 is derived from the opposing functions of these macrophages; where M1 is involved in the tissue damage and pro-inflammatory roles and M2 promotes cell proliferation and the resolution of inflammation. Both these pathways down-regulate each other in diseases through a plethora of enzymatic and cytokine mediators.
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Affiliation(s)
- Hassan Yousaf
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore, Lahore, Pakistan
| | - Malik Ihsan Ullah Khan
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore, Lahore, Pakistan.
| | - Iftikhar Ali
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Muhammad Usman Munir
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University Sakaka, Aljouf 72388, Saudi Arabia
| | - Ka Yiu Lee
- Swedish Winter Sports Research Centre, Department of Health Sciences, Mid Sweden University, Ostersund, Sweden.
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23
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Vitale A, Alivernini S, Caporali R, Cassone G, Bruno D, Cantarini L, Lopalco G, Rossini M, Atzeni F, Favalli EG, Conti F, Gremese E, Iannone F, Ferraccioli GF, Lapadula G, Sebastiani M. From Bench to Bedside in Rheumatoid Arthritis from the "2022 GISEA International Symposium". J Clin Med 2023; 12:jcm12020527. [PMID: 36675455 PMCID: PMC9863451 DOI: 10.3390/jcm12020527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
While precision medicine is still a challenge in rheumatic disease, in recent years many advances have been made regarding pathogenesis, the treatment of inflammatory arthropathies, and their interaction. New insight into the role of inflammasome and synovial tissue macrophage subsets as predictors of drug response give hope for future tailored therapeutic strategies and a personalized medicine approach in inflammatory arthropathies. Here, we discuss the main pathogenetic mechanisms and therapeutic approaches towards precision medicine in rheumatoid arthritis from the 2022 International GISEA/OEG Symposium.
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Affiliation(s)
- Antonio Vitale
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease Clinic, University of Siena, 53100 Siena, SI, Italy
| | - Stefano Alivernini
- Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, RM, Italy
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, RM, Italy
| | - Roberto Caporali
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, 20122 Milano, MI, Italy
- Department of Clinical Sciences and Community Health, Research Center for Pediatric and Adult Rheumatic Diseases (RECAP.RD), University of Milan, 20122 Milano, MI, Italy
| | - Giulia Cassone
- Rheumatology Unit, Azienda Ospedaliera Policlinico di Modena, University of Modena and Reggio Emilia, 41121 Modena, MO, Italy
| | - Dario Bruno
- Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, RM, Italy
| | - Luca Cantarini
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease Clinic, University of Siena, 53100 Siena, SI, Italy
| | - Giuseppe Lopalco
- Rheumatology Unit, Department of Emergency Surgery and Organ Transplantations, University of Bari, 70121 Bari, BA, Italy
| | - Maurizio Rossini
- Rheumatology Unit, University of Verona, Policlinico G.B. Rossi, Piazzale A. Scuro, 37134 Verona, VR, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, 98122 Messina, ME, Italy
| | - Ennio Giulio Favalli
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, 20122 Milano, MI, Italy
- Department of Clinical Sciences and Community Health, Research Center for Pediatric and Adult Rheumatic Diseases (RECAP.RD), University of Milan, 20122 Milano, MI, Italy
| | - Fabrizio Conti
- Lupus Clinic, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza University of Rome, 00185 Roma, RM, Italy
| | - Elisa Gremese
- Immunology Research Core Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, RM, Italy
- Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 20123 Milano, MI, Italy
| | - Florenzo Iannone
- Rheumatology Unit, Department of Emergency Surgery and Organ Transplantations, University of Bari, 70121 Bari, BA, Italy
| | | | - Giovanni Lapadula
- Rheumatology Unit, Department of Emergency Surgery and Organ Transplantations, University of Bari, 70121 Bari, BA, Italy
| | - Marco Sebastiani
- Rheumatology Unit, Azienda Ospedaliera Policlinico di Modena, University of Modena and Reggio Emilia, 41121 Modena, MO, Italy
- Correspondence:
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24
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Prajapati P, Doshi G. An Update on the Emerging Role of Wnt/β-catenin, SYK, PI3K/AKT, and GM-CSF Signaling Pathways in Rheumatoid Arthritis. Curr Drug Targets 2023; 24:1298-1316. [PMID: 38083893 DOI: 10.2174/0113894501276093231206064243] [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: 08/07/2023] [Revised: 10/14/2023] [Accepted: 11/14/2023] [Indexed: 01/06/2024]
Abstract
Rheumatoid arthritis is an untreatable autoimmune disorder. The disease is accompanied by joint impairment and anomalies, which negatively affect the patient's quality of life and contribute to a decline in manpower. To diagnose and treat rheumatoid arthritis, it is crucial to understand the abnormal signaling pathways that contribute to the disease. This understanding will help develop new rheumatoid arthritis-related intervention targets. Over the last few decades, researchers have given more attention to rheumatoid arthritis. The current review seeks to provide a detailed summary of rheumatoid arthritis, highlighting the basic description of the disease, past occurrences, the study of epidemiology, risk elements, and the process of disease progression, as well as the key scientific development of the disease condition and multiple signaling pathways and enumerating the most current advancements in discovering new rheumatoid arthritis signaling pathways and rheumatoid arthritis inhibitors. This review emphasizes the anti-rheumatoid effects of these inhibitors [for the Wnt/β-catenin, Phosphoinositide 3-Kinases (PI3K/AKT), Spleen Tyrosine Kinase (SYK), and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling pathways], illustrating their mechanism of action through a literature search, current therapies, and novel drugs under pre-clinical and clinical trials.
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Affiliation(s)
- Pradyuman Prajapati
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India
| | - Gaurav Doshi
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India
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25
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Jiang SZ, To JL, Hughes MR, McNagny KM, Kim H. Platelet signaling at the nexus of innate immunity and rheumatoid arthritis. Front Immunol 2022; 13:977828. [PMID: 36505402 PMCID: PMC9732516 DOI: 10.3389/fimmu.2022.977828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/03/2022] [Indexed: 11/26/2022] Open
Abstract
Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation of the synovial tissues and progressive destruction of bone and cartilage. The inflammatory response and subsequent tissue degradation are orchestrated by complex signaling networks between immune cells and their products in the blood, vascular endothelia and the connective tissue cells residing in the joints. Platelets are recognized as immune-competent cells with an important role in chronic inflammatory diseases such as RA. Here we review the specific aspects of platelet function relevant to arthritic disease, including current knowledge of the molecular crosstalk between platelets and other innate immune cells that modulate RA pathogenesis.
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Affiliation(s)
- Steven Z. Jiang
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Jeffrey L. To
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
| | - Michael R. Hughes
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Kelly M. McNagny
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Hugh Kim
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada
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26
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Sigalov AB. Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis. Int J Mol Sci 2022; 23:ijms23168857. [PMID: 36012120 PMCID: PMC9408405 DOI: 10.3390/ijms23168857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/04/2022] [Accepted: 08/07/2022] [Indexed: 11/16/2022] Open
Abstract
The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA.
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27
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Anchi P, Chilvery S, Tekalkar S, bolla L, Rao Gajula SN, Sonti R, Godugu C. Nimbolide loaded sustained release microparticles as single-dose formulations for effective management of arthritis. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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28
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Multi-omics profiling of collagen-induced arthritis mouse model reveals early metabolic dysregulation via SIRT1 axis. Sci Rep 2022; 12:11830. [PMID: 35821263 PMCID: PMC9276706 DOI: 10.1038/s41598-022-16005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/04/2022] [Indexed: 11/24/2022] Open
Abstract
Rheumatoid arthritis (RA) is characterized by joint infiltration of immune cells and synovial inflammation which leads to progressive disability. Current treatments improve the disease outcome, but the unmet medical need is still high. New discoveries over the last decade have revealed the major impact of cellular metabolism on immune cell functions. So far, a comprehensive understanding of metabolic changes during disease development, especially in the diseased microenvironment, is still limited. Therefore, we studied the longitudinal metabolic changes during the development of murine arthritis by integrating metabolomics and transcriptomics data. We identified an early change in macrophage pathways which was accompanied by oxidative stress, a drop in NAD+ level and induction of glucose transporters. We discovered inhibition of SIRT1, a NAD-dependent histone deacetylase and confirmed its dysregulation in human macrophages and synovial tissues of RA patients. Mining this database should enable the discovery of novel metabolic targets and therapy opportunities in RA.
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29
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Kurowska-Stolarska M, Alivernini S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat Rev Rheumatol 2022; 18:384-397. [PMID: 35672464 DOI: 10.1038/s41584-022-00790-8] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2022] [Indexed: 02/07/2023]
Abstract
Synovial tissue macrophages (STMs) were principally recognized as having a pro-inflammatory role in rheumatoid arthritis (RA), serving as the main producers of pathogenic tumour necrosis factor (TNF). Recent advances in single-cell omics have facilitated the discovery of distinct STM populations, providing an atlas of discrete phenotypic clusters in the context of healthy and inflamed joints. Interrogation of the functions of distinct STM populations, via ex vivo and experimental mouse models, has re-defined our understanding of STM biology, opening up new opportunities to better understand the pathology of the arthritic joint. These works have identified STM subpopulations that form a protective lining barrier within the synovial membrane and actively participate in the remission of RA. We discuss how distinct functions of STM clusters shape the synovial tissue environment in health, during inflammation and in disease remission, as well as how an increased understanding of STM heterogeneity might aid the prediction of clinical outcomes and inform novel treatments for RA.
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Affiliation(s)
- Mariola Kurowska-Stolarska
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK.
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Stefano Alivernini
- Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), Glasgow, UK.
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.
- Immunology Research Core Facility, Gemelli Science and Technology Park (GSTeP), Rome, Italy.
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30
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Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity. Cells 2022; 11:cells11101663. [PMID: 35626700 PMCID: PMC9140143 DOI: 10.3390/cells11101663] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/05/2022] [Accepted: 05/13/2022] [Indexed: 11/19/2022] Open
Abstract
Immune cells undergo different metabolic pathways or immunometabolisms to interact with various antigens. Immunometabolism links immunological and metabolic processes and is critical for innate and adaptive immunity. Although metabolic reprogramming is necessary for cell differentiation and proliferation, it may mediate the imbalance of immune homeostasis, leading to the pathogenesis and development of some diseases, such as autoimmune diseases. Here, we discuss the effects of metabolic changes in autoimmune diseases, exerted by the leading actors of innate immunity, and their role in autoimmunity pathogenesis, suggesting many immunotherapeutic approaches.
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31
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Knab K, Chambers D, Krönke G. Synovial Macrophage and Fibroblast Heterogeneity in Joint Homeostasis and Inflammation. Front Med (Lausanne) 2022; 9:862161. [PMID: 35547214 PMCID: PMC9081642 DOI: 10.3389/fmed.2022.862161] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/14/2022] [Indexed: 11/23/2022] Open
Abstract
The synovial tissue is an immunologically challenging environment where, under homeostatic conditions, highly specialized subsets of immune-regulatory macrophages and fibroblasts constantly prevent synovial inflammation in response to cartilage- and synovial fluid-derived danger signals that accumulate in response to mechanical stress. During inflammatory joint diseases, this immune-regulatory environment becomes perturbed and activated synovial fibroblasts and infiltrating immune cells start to contribute to synovial inflammation and joint destruction. This review summarizes our current understanding of the phenotypic and molecular characteristics of resident synovial macrophages and fibroblasts and highlights their crosstalk during joint homeostasis and joint inflammation, which is increasingly appreciated as vital to understand the molecular basis of prevalent inflammatory joint diseases such as rheumatoid arthritis.
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Affiliation(s)
- Katharina Knab
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
| | - David Chambers
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
| | - Gerhard Krönke
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
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32
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Xi X, Ye Q, Fan D, Cao X, Wang Q, Wang X, Zhang M, Xu Y, Xiao C. Polycyclic Aromatic Hydrocarbons Affect Rheumatoid Arthritis Pathogenesis via Aryl Hydrocarbon Receptor. Front Immunol 2022; 13:797815. [PMID: 35392076 PMCID: PMC8981517 DOI: 10.3389/fimmu.2022.797815] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by symmetrical synovial inflammation of multiple joints with the infiltration of pro-inflammatory immune cells and increased cytokines (CKs) levels. In the past few years, numerous studies have indicated that several factors could affect RA, such as mutations in susceptibility genes, epigenetic modifications, age, and race. Recently, environmental factors, particularly polycyclic aromatic hydrocarbons (PAHs), have attracted increasing attention in RA pathogenesis. Therefore, exploring the specific mechanisms of PAHs in RA is vitally critical. In this review, we summarize the recent progress in understanding the mechanisms of PAHs and aryl hydrocarbon receptors (AHRs) in RA. Additionally, the development of therapeutic drugs that target AHR is also reviewed. Finally, we discuss the challenges and perspectives on AHR application in the future.
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Affiliation(s)
- Xiaoyu Xi
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Qinbin Ye
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Danping Fan
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Xiaoxue Cao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Qiong Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Xing Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Mengxiao Zhang
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Yuan Xu
- Department of Traditional Chinese Medicine (TCM) Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China.,Department of Emergency, China-Japan Friendship Hospital, Beijing, China
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33
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Kim YJ, Lee JY, Yang MJ, Cho HJ, Kim MY, Kim L, Hwang JH. Therapeutic effect of intra-articular injected 3'-sialyllactose on a minipig model of rheumatoid arthritis induced by collagen. Lab Anim Res 2022; 38:8. [PMID: 35314005 PMCID: PMC8939226 DOI: 10.1186/s42826-022-00119-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 03/16/2022] [Indexed: 12/03/2022] Open
Abstract
Background Rheumatoid arthritis (RA) is a chronic inflammatory disease of joint, but there is no known cure. 3′-sialyllactose (3′-SL) is an oligosaccharide that is abundant in breast milk of mammals, and has anti-inflammatory properties. However, the efficacy of 3′-SL on RA remains unclear. The objective of the present study was to evaluate the therapeutic effect of 3′-SL after it was directly injected into the knee joint cavity of a RA minipig model.
Results Minipig RA model was induced by intra-articular injection of bovine type II collagen emulsified with complete or incomplete Freund’s adjuvant into left knee joint. In clinical assessment, lameness and swelling of the hindlimb and increased knee joint width were observed in all animals. After the onset of arthritis, 3′-SL (0, 2, 10, and 50 mg/kg) was directly administered to the left knee joint cavity once a week for 4 weeks. Compared to the vehicle control group, no significant difference in macroscopic observation of the synovial pathology or the expression of inflammation-related genes (IL-1β, TNF-α, and COX2) in the synovial membrane of the knee joint was found. In microscopic observation, cell cloning of the articular cartilage was significantly reduced in proportion to the concentration of 3′-SL administered.
Conclusions Our results suggest that intra-articular injected 3′-SL had a therapeutic effect on collagen-induced arthritis at the cellular level with potential as a medication for RA. Supplementary Information The online version contains supplementary material available at 10.1186/s42826-022-00119-2.
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Affiliation(s)
- Young June Kim
- Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeollabukdo, 56212, Republic of Korea
| | - Ju-Young Lee
- Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeollabukdo, 56212, Republic of Korea
| | - Mi-Jin Yang
- Pathology Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeollabukdo, 56212, Republic of Korea
| | - Hyun Jin Cho
- Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeollabukdo, 56212, Republic of Korea
| | - Min-Young Kim
- GeneChem Inc. A-501, 187 Techno 2-ro, Yuseong-gu, Daejeon, 34025, Republic of Korea
| | - Lila Kim
- GeneChem Inc. A-501, 187 Techno 2-ro, Yuseong-gu, Daejeon, 34025, Republic of Korea
| | - Jeong Ho Hwang
- Animal Model Research Group, Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeollabukdo, 56212, Republic of Korea.
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Chen J, Zhu G, Sun Y, Wu Y, Wu B, Zheng W, Ma X, Zheng Y. 7-deacetyl-gedunin suppresses proliferation of Human rheumatoid arthritis synovial fibroblast through activation of Nrf2/ARE signaling. Int Immunopharmacol 2022; 107:108557. [PMID: 35247778 DOI: 10.1016/j.intimp.2022.108557] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an chronic autoimmune disease and characterized by high incidence. However, there is no effective therapies for RA. Therefore, it is urgent to discover new drugs for RA treatment. Nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) can effectively protect against arthritic inflammatory diseases through diverse stages, such as regulating redox balance, detoxification, metabolism and inflammation. Dimethyl fumarate (DMF), targets the Nrf2 pathway, was approved by FDA for the clinical treatment of multiple sclerosis (MS), which is another autoimmune disease. The latest report shown that DMF ameliorates complete Freund's adjuvant-induced arthritis in rats through activation of the Nrf2/HO-1 signaling pathway. Hence, Nrf2 serves as an important target for inflammation interference and oxidative stress of macrophages and RASFs in RA; therefore, it can be adopted as an effective therapeutic approach in the future. Rheumatoid arthritis synovial fibroblasts (RASFs) play crucial roles in the RA pathogenesis. Our results revealed that 7-deacetyl-gedunin (7-d-GDN), derived from fruits of Toona sinensis (A. Juss.) Roem, significantly inhibited RASFs proliferation in dose- and time- dependent manners and inhibited cell viability in MH7A cells, which is a kind of immortal cell line from joints of patients with RA. Additionally, 7-d-GDN remarkably down-regulated MMP-1/3/9/13 in RASFs, IL-6 and IL-33 in MH7A cells. Besides, 7-d-GDN sharply inhibited reactive oxygen species (ROS) in RASFs. Further mechanistic study demonstrated that 7-d-GDN induced heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1(NQO1), which all participated in suppressing of oxidative stress. Additionally, 7-d-GDN increased sequestosome 1 (SQSTM1, p62), causing down-regulating Kelch-like ECH-associated protein 1 (Keap1), which resulting in NF-E2-related factor 2 (Nrf2) cytoplasm accumulation and subsequently translocation into nucleus. Collectively, 7-d-GDN exerts the anti-inflammatory effect through regulating anti-oxidative enzymes via p62/ Nrf2/ARE signaling. All suggest that the potential of 7-d-GDN in suppression of inflammation, especially antagonizing RA severity. Our works support for drugs discovery in RA treatment.
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Affiliation(s)
- JianYu Chen
- Department of Pharmacology, School of Pharmacy, Fujian University of Traditional Chinese Medicine, No.1,Huatuo Road, Min hou shang jie, Fuzhou 350122, China
| | - GuoYuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China
| | - YiBin Sun
- Department of Pharmacology, School of Pharmacy, Fujian University of Traditional Chinese Medicine, No.1,Huatuo Road, Min hou shang jie, Fuzhou 350122, China
| | - YueChan Wu
- LiuHe Township Health Center, No.63, LiuHe Road, Qi Chun Liu He, Huang Gang 436328, China
| | - BaoKun Wu
- AIM Explorer Life Sciences Co., Ltd., Gemdale Viseem MinHang Technology & Industrial Park, No. 1288, Zhongchun Road, Minhang, ShangHai 201108, China
| | - WanTing Zheng
- Department of Pharmacology, School of Pharmacy, Fujian University of Traditional Chinese Medicine, No.1,Huatuo Road, Min hou shang jie, Fuzhou 350122, China
| | - XueQin Ma
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan 750004, China.
| | - YanFang Zheng
- Department of Pharmacology, School of Pharmacy, Fujian University of Traditional Chinese Medicine, No.1,Huatuo Road, Min hou shang jie, Fuzhou 350122, China.
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Zhang C, Huang W, Huang C, Zhou C, Tang Y, Wei W, Li Y, Tang Y, Luo Y, Zhou Q, Chen W. VHPKQHR Peptide Modified Ultrasmall Paramagnetic Iron Oxide Nanoparticles Targeting Rheumatoid Arthritis for T1-Weighted Magnetic Resonance Imaging. Front Bioeng Biotechnol 2022; 10:821256. [PMID: 35295653 PMCID: PMC8918785 DOI: 10.3389/fbioe.2022.821256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/14/2022] [Indexed: 11/18/2022] Open
Abstract
Magnetic resonance imaging (MRI) could be the ideal diagnostic modality for early rheumatoid arthritis (RA). Vascular cell adhesion molecule-1 (VCAM-1) is highly expressed in synovial locations in patients with RA, which could be a potential target protein for RA diagnosis. The peptide VHPKQHR (VHP) has a high affinity to VCAM-1. To make the contrast agent to target RA at an early stage, we used VHP and ultrasmall paramagnetic iron oxide (USPIO) to synthesize UVHP (U stands for USPIO) through a chemical reaction with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide. The size of UVHP was 6.7 nm; the potential was −27.7 mV, and the r2/r1 value was 1.73. Cytotoxicity assay exhibited that the cell survival rate was higher than 80% at even high concentrations of UVHP (Fe concentration 200 µg/mL), which showed the UVHP has low toxicity. Compared with no TNF-α stimulation, VCAM-1 expression was increased nearly 3-fold when mouse aortic endothelial cells (MAECs) were stimulated with 50 ng/mL TNF-α; cellular Fe uptake was increased very significantly with increasing UVHP concentration under TNF-α treatment; cellular Fe content was 17 times higher under UVHP with Fe concentration 200 µg/mL treating MAECs. These results indicate that UVHP can target overexpression of VCAM-1 at the cellular level. RA mice models were constructed with adjuvant-induced arthritis. In vivo MRI and biodistribution results show that the signal intensity of knee joints was increased significantly and Fe accumulation in RA model mice compared with normal wild-type mice after injecting UVHP 24 h. These results suggest that we have synthesized a simple, low-cost, and less toxic contrast agent UVHP, which targeted VCAM-1 for early-stage RA diagnosis and generates high contrast in T1-weighted MRI.
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Affiliation(s)
- Chunyu Zhang
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Wentao Huang
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Chen Huang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Chengqian Zhou
- Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
| | - Yukuan Tang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Wei Wei
- Institution of GuangDong Cord Blood Bank, Guangzhou, China
| | - Yongsheng Li
- Institution of GuangDong Cord Blood Bank, Guangzhou, China
| | - Yukuan Tang
- Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Guangzhou, China
- *Correspondence: Yukuan Tang, ; Yu Luo, ; Quan Zhou, ; Wenli Chen,
| | - Yu Luo
- Shanghai Engineering Technology Research Center for Pharmaceutical Intelligent Equipment, Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, China
- *Correspondence: Yukuan Tang, ; Yu Luo, ; Quan Zhou, ; Wenli Chen,
| | - Quan Zhou
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Yukuan Tang, ; Yu Luo, ; Quan Zhou, ; Wenli Chen,
| | - Wenli Chen
- MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
- Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China
- *Correspondence: Yukuan Tang, ; Yu Luo, ; Quan Zhou, ; Wenli Chen,
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Laranjeira P, Pedrosa M, Duarte C, Pedreiro S, Antunes B, Ribeiro T, dos Santos F, Martinho A, Fardilha M, Domingues MR, Abecasis M, Pereira da Silva JA, Paiva A. Human Bone Marrow Mesenchymal Stromal/Stem Cells Regulate the Proinflammatory Response of Monocytes and Myeloid Dendritic Cells from Patients with Rheumatoid Arthritis. Pharmaceutics 2022; 14:pharmaceutics14020404. [PMID: 35214136 PMCID: PMC8880255 DOI: 10.3390/pharmaceutics14020404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/15/2022] Open
Abstract
Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients.
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Affiliation(s)
- Paula Laranjeira
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto, Bloco de Celas, 3000-075 Coimbra, Portugal;
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Polo 1, 1.° Piso, FMUC, Rua Larga, 3004-504 Coimbra, Portugal
| | - Mónia Pedrosa
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Signal Transduction Laboratory, Center of Cellular Biology, SACS and Department of Biology, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
- Enzifarma—Diagnostica e Farmacêutica, S.A., Estrada da Luz, n.° 90, 2° F, 1600-160 Lisbon, Portugal
| | - Cátia Duarte
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal
| | - Susana Pedreiro
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
| | - Brígida Antunes
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
| | - Tânia Ribeiro
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
| | - Francisco dos Santos
- Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Lote 4A, 3060-197 Cantanhede, Portugal; ; (B.A.); (T.R.); (F.d.S.)
- Stemlab SA, Biocant Park, Núcleo 04, Lote 2, 3060-197 Cantanhede, Portugal
| | - António Martinho
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
| | - Margarida Fardilha
- Signal Transduction Laboratory, Center of Cellular Biology, SACS and Department of Biology, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
- Laboratory of Signal Transduction, Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - M. Rosário Domingues
- Mass Spectrometry Centre, LAQV REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal;
- Centre for Environmental and Marine Studies (CESAM), Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal
| | - Manuel Abecasis
- Serviço de Transplantação de Progenitores Hematopoiéticos (UTM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal;
- Instituto Português do Sangue e da Transplantação—CEDACE, Alameda das Linhas de Torres, 117, 1769-001 Lisbon, Portugal
| | - José António Pereira da Silva
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Rheumatology Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, 3000-075 Coimbra, Portugal
| | - Artur Paiva
- Flow Cytometry Unit, Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, Av. Bissaya Barreto, Bloco de Celas, 3000-075 Coimbra, Portugal;
- Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal, Quinta da Vinha Moura, São Martinho do Bispo, 3041-861 Coimbra, Portugal; (M.P.); (S.P.); (A.M.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; (C.D.); (J.A.P.d.S.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Rua 5 de Outubro, 3046-854 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-488-700
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Simmons DP, Nguyen HN, Gomez-Rivas E, Jeong Y, Jonsson AH, Chen AF, Lange JK, Dyer GS, Blazar P, Earp BE, Coblyn JS, Massarotti EM, Sparks JA, Todd DJ, Rao DA, Kim EY, Brenner MB. SLAMF7 engagement superactivates macrophages in acute and chronic inflammation. Sci Immunol 2022; 7:eabf2846. [PMID: 35148199 PMCID: PMC8991457 DOI: 10.1126/sciimmunol.abf2846] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.
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Affiliation(s)
- Daimon P. Simmons
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Hung N. Nguyen
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Emma Gomez-Rivas
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Yunju Jeong
- Harvard Medical School, Boston, MA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - A. Helena Jonsson
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Antonia F. Chen
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Jeffrey K. Lange
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - George S. Dyer
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Philip Blazar
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Brandon E. Earp
- Harvard Medical School, Boston, MA
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA
| | - Jonathan S. Coblyn
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Elena M. Massarotti
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Jeffrey A. Sparks
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Derrick J. Todd
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | | | - Deepak A. Rao
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Edy Y. Kim
- Harvard Medical School, Boston, MA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Michael B. Brenner
- Harvard Medical School, Boston, MA
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Degboé Y, Poupot R, Poupot M. Repolarization of Unbalanced Macrophages: Unmet Medical Need in Chronic Inflammation and Cancer. Int J Mol Sci 2022; 23:1496. [PMID: 35163420 PMCID: PMC8835955 DOI: 10.3390/ijms23031496] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Monocytes and their tissue counterpart macrophages (MP) constitute the front line of the immune system. Indeed, they are able to rapidly and efficiently detect both external and internal danger signals, thereby activating the immune system to eradicate the disturbing biological, chemical, or physical agents. They are also in charge of the control of the immune response and account for the repair of the damaged tissues, eventually restoring tissue homeostasis. The balance between these dual activities must be thoroughly controlled in space and time. Any sustained unbalanced response of MP leads to pathological disorders, such as chronic inflammation, or favors cancer development and progression. In this review, we take advantage of our expertise in chronic inflammation, especially in rheumatoid arthritis, and in cancer, to highlight the pivotal role of MP in the physiopathology of these disorders and to emphasize the repolarization of unbalanced MP as a promising therapeutic strategy to control these diseases.
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Affiliation(s)
- Yannick Degboé
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31024 Toulouse, France;
- Département de Rhumatologie, CHU Toulouse, 31029 Toulouse, France
| | - Rémy Poupot
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31024 Toulouse, France;
| | - Mary Poupot
- Centre de Recherche en Cancérologie de Toulouse, Université Toulouse, INSERM, UPS, 31037 Toulouse, France;
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Vafaei S, Wu X, Tu J, Nematollahi-mahani SN. The Effects of Crocin on Bone and Cartilage Diseases. Front Pharmacol 2022; 12:830331. [PMID: 35126154 PMCID: PMC8807478 DOI: 10.3389/fphar.2021.830331] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 12/28/2021] [Indexed: 12/16/2022] Open
Abstract
Crocin, the main biologically active carotenoid of saffron, generally is derived from the dried trifid stigma of Crocus sativus L. Many studies have demonstrated that crocin has several therapeutic effects on biological systems through its anti-oxidant and anti-inflammatory properties. The wide range of crocin activities is believed to be because of its ability to anchor to many proteins, triggering some cellular pathways responsible for cell proliferation and differentiation. It also has therapeutic potentials in arthritis, osteoarthritis, rheumatoid arthritis, and articular pain probably due to its anti-inflammatory properties. Anti-apoptotic effects, as well as osteoclast inhibition effects of crocin, have suggested it as a natural substance to treat osteoporosis and degenerative disease of bone and cartilage. Different mechanisms underlying crocin effects on bone and cartilage repair have been investigated, but remain to be fully elucidated. The present review aims to undertake current knowledge on the effects of crocin on bone and cartilage degenerative diseases with an emphasis on its proliferative and differentiative properties in mesenchymal stem cells.
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Affiliation(s)
- Shayan Vafaei
- Department of Anatomical Science, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Xuming Wu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Jiajie Tu
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, China
- *Correspondence: Jiajie Tu, ; Seyed Noureddin Nematollahi-mahani,
| | - Seyed Noureddin Nematollahi-mahani
- Department of Anatomical Science, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- *Correspondence: Jiajie Tu, ; Seyed Noureddin Nematollahi-mahani,
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Zhang H, Liu J, Zhang P, Li D, Feng G, Huandike M, Sun S, Chai L, Zhou J. Herbal Formula Longteng Decoction Promotes the Regression of Synovial Inflammation in Collagen-Induced Arthritis Mice by Regulating Type 2 Innate Lymphocytes. Front Pharmacol 2021; 12:778845. [PMID: 35002715 PMCID: PMC8735860 DOI: 10.3389/fphar.2021.778845] [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: 09/17/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
The etiology and pathogenesis of rheumatoid arthritis (RA) have not yet been fully elucidated, with greater adverse drug effects in traditional treatment of RA. It is particularly necessary to develop and study Chinese herbal formula as a supplement and alternative drug for the treatment of RA. The traditional Chinese medicine compound Longteng Decoction (LTD), as an empirical prescription in the treatment of RA in Dongzhimen Hospital of Beijing University of Chinese Medicine, has been widely used in clinic. Type 2 innate lymphocytes (ILC2s) have specific transcription factors and signature cytokines that are very similar to Th cells, which have been proved to be necessary in addressing RA inflammation, and are potential targets for RA prevention and treatment. Our previous studies have confirmed that LTD can intervene in the differentiation of peripheral blood Th17 and Treg cells, reduce joint pain index and swelling degree, shorten the time of morning stiffness, reduce ESR, and inhibit joint inflammation. However, it is unclear whether LTD can promote the regression of RA synovial inflammation by regulating the immune response mechanism of ILC2s.Therefore, our team established a collagen-induced arthritis mouse model and conducted an experimental study with LTD as the intervention object. The results showed that joint swelling, synovial inflammatory infiltration, and articular cartilage destruction were alleviated in CIA mice after intervention with LTD. The proliferation and differentiation of Th17 inflammatory cells and the secretion of proinflammatory cytokines (IL-17 and IFN-γ) were inhibited. In addition, LTD can also activate ILC2s to secrete the anti-inflammatory cytokine IL-4, activate the STAT6 signaling pathway, and act synergistic with Treg cells to inhibit the infiltration of type M1 macrophages in synovial tissue and promote its transformation to M2 phenotype. Taken together, these results confirm that LTD can be used as an adjunct or alternative to RA therapy by modulating the ILC2s immune response network and slowing down the inflammatory process of synovial tissue.
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Affiliation(s)
- Huijie Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Juan Liu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Pingxin Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Dongyang Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guiyu Feng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Meiyier Huandike
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Song Sun
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Limin Chai
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jingwei Zhou
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Department of Rheumatology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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Zhao J, Guo S, Schrodi SJ, He D. Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications. Front Immunol 2021; 12:790122. [PMID: 34899757 PMCID: PMC8660630 DOI: 10.3389/fimmu.2021.790122] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and inflammatory cytokine inhibitors (ICI), typically associated with differentiated clinical effects and characteristics. Personalized responsiveness is observed to the standard treatment due to the pathophysiological heterogeneity in rheumatoid arthritis, resulting in an overall poor prognosis. Understanding the role of individual variation in cellular and molecular mechanisms related to rheumatoid arthritis will considerably improve clinical care and patient outcomes. In this review, we discuss the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis. We provide emphasized description of the heterogeneity derived from mast cells, monocyte cell, macrophage fibroblast-like synoviocytes and, interactions within immune cells and with inflammatory cytokines, as well as the potential as a new therapeutic target to develop a novel treatment approach. Finally, we summarize the latest clinical trials of treatment options for rheumatoid arthritis and provide a suggestive framework for implementing preclinical and clinical experimental results into clinical practice.
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Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Steven J. Schrodi
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
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Zhang XP, Ma JD, Mo YQ, Jing J, Zheng DH, Chen LF, Wu T, Chen CT, Zhang Q, Zou YY, Lin JZ, Xu YH, Zou YW, Yang ZH, Ling L, Miossec P, Dai L. Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at 1 Year in Active Rheumatoid Arthritis. Front Immunol 2021; 12:778480. [PMID: 34887865 PMCID: PMC8650215 DOI: 10.3389/fimmu.2021.778480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/02/2021] [Indexed: 11/30/2022] Open
Abstract
Objectives This study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA). Methods Active RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year. Results Among 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Conclusions This novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA.
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Affiliation(s)
- Xue-Pei Zhang
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian-Da Ma
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ying-Qian Mo
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jun Jing
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dong-Hui Zheng
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Le-Feng Chen
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tao Wu
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chu-Tao Chen
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qian Zhang
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yao-Yao Zou
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian-Zi Lin
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yan-Hui Xu
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yao-Wei Zou
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ze-Hong Yang
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Li Ling
- Department of Medical Statistics, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Pierre Miossec
- Department of Clinical Immunology and Rheumatology, Immunogenomics and Inflammation Research Unit, University of Lyon and Hospices Civils de Lyon, Lyon, France
| | - Lie Dai
- Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Wang Y, Wu H, Deng R. Angiogenesis as a potential treatment strategy for rheumatoid arthritis. Eur J Pharmacol 2021; 910:174500. [PMID: 34509462 DOI: 10.1016/j.ejphar.2021.174500] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 08/04/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022]
Abstract
Angiogenesis is an early and key event in the pathogenesis of rheumatoid arthritis (RA) and is crucial for the proliferation of synovial tissue and the formation of pannus. This process is regulated by both angiogenesis-stimulating factors and angiogenesis inhibitors, the basis for the "on-off hypothesis of angiogenesis." In RA, inflammation, immune imbalance, and hypoxia can further turn on the switch for blood vessel formation and induce angiogenesis. The new vasculature can recruit white blood cells, induce immune imbalance, and aggravate inflammation. At the same time, it also can provide oxygen and nutrients for the proliferating synovial tissue, which can accelerate the process of RA. The current therapies for RA mainly target the inflammatory response of autoimmune activation. Although these therapies have been greatly improved, there are still many patients whose RA is difficult to treat or who do not fully respond to treatment. Therefore, new innovative therapies are still urgently needed. This review covers the mechanism of synovial angiogenesis in RA, including the detailed process of angiogenesis and the relationship between inflammation, immune imbalance, hypoxia, and synovial angiogenesis, respectively. At the same time, in the context of the development of angiogenesis inhibition therapy for cancer, we also discuss similar treatment strategies for RA, especially the combination of targeted angiogenesis inhibition therapy and immunotherapy.
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Affiliation(s)
- Yan Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China
| | - Hong Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China.
| | - Ran Deng
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China
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Van Raemdonck K, Umar S, Palasiewicz K, Volin MV, Elshabrawy HA, Romay B, Tetali C, Ahmed A, Amin MA, Zomorrodi RK, Sweiss N, Shahrara S. Interleukin-34 Reprograms Glycolytic and Osteoclastic Rheumatoid Arthritis Macrophages via Syndecan 1 and Macrophage Colony-Stimulating Factor Receptor. Arthritis Rheumatol 2021; 73:2003-2014. [PMID: 33982895 PMCID: PMC8568622 DOI: 10.1002/art.41792] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 04/27/2021] [Indexed: 11/07/2022]
Abstract
OBJECTIVE In rheumatoid arthritis (RA), elevated serum interleukin-34 (IL-34) levels are linked with increased disease severity. IL-34 binds to 2 receptors, macrophage colony-stimulating factor receptor (M-CSFR) and syndecan 1, which are coexpressed in RA macrophages. Expression of both IL-34 and syndecan 1 is strikingly elevated in the RA synovium, yet their mechanisms of action remain undefined. This study was undertaken to investigate the mechanism of action of IL-34 in RA. METHODS To characterize the significance of IL-34 in immunometabolism, its mechanism of action was elucidated in joint macrophages, fibroblasts, and T effector cells using RA and preclinical models. RESULTS Intriguingly, syndecan 1 activated IL-34-induced M-CSFR phosphorylation and reprogrammed RA naive cells into distinctive CD14+CD86+GLUT1+ M34 macrophages that expressed elevated levels of IL-1β, CXCL8, and CCL2. In murine M34 macrophages, the inflammatory phenotype was accompanied by potentiated glycolytic activity, exhibited by transcriptional up-regulation of GLUT1, c-Myc, and hypoxia-inducible factor 1α (HIF-1α) and amplified pyruvate and l-lactate secretion. Local expression of IL-34 provoked arthritis by expanding the glycolytic F4/80-positive, inducible nitric oxide synthase (iNOS)-positive macrophage population, which in turn attracted fibroblasts and polarized Th1/Th17 cells. The cross-talk between murine M34 macrophages and Th1/Th17 cells broadened the inflammatory and metabolic phenotypes, resulting in the expansion of IL-34 pathogenicity. Consequently, IL-34-instigated joint inflammation was alleviated in RAG-/- mice compared to wild-type mice. Syndecan 1 deficiency attenuated IL-34-induced arthritis by interfering with joint glycolytic M34 macrophage and osteoclast remodeling. Similarly, inhibition of glycolysis by 2-deoxy-d-glucose reversed the joint swelling and metabolic rewiring triggered by IL-34 via HIF-1α and c-Myc induction. CONCLUSION IL-34 is a novel endogenous factor that remodels hypermetabolic M34 macrophages and facilitates their cross-regulation with T effector cells to advance inflammatory bone destruction in RA.
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Affiliation(s)
- Katrien Van Raemdonck
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Karol Palasiewicz
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Michael V. Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL 60515, USA
| | - Hatem A. Elshabrawy
- Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA
| | - Bianca Romay
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Chandana Tetali
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Azam Ahmed
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - M. Asif Amin
- Division of Rheumatology, Clinical Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Ryan K. Zomorrodi
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Nadera Sweiss
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL 60612, USA
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Mesenchymal Stem Cell-Based Therapy for Rheumatoid Arthritis. Int J Mol Sci 2021; 22:ijms222111592. [PMID: 34769021 PMCID: PMC8584240 DOI: 10.3390/ijms222111592] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have great potential to differentiate into various types of cells, including but not limited to, adipocytes, chondrocytes and osteoblasts. In addition to their progenitor characteristics, MSCs hold unique immunomodulatory properties that provide new opportunities in the treatment of autoimmune diseases, and can serve as a promising tool in stem cell-based therapy. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that deteriorates quality and function of the synovium membrane, resulting in chronic inflammation, pain and progressive cartilage and bone destruction. The mechanism of RA pathogenesis is associated with dysregulation of innate and adaptive immunity. Current conventional treatments by steroid drugs, antirheumatic drugs and biological agents are being applied in clinical practice. However, long-term use of these drugs causes side effects, and some RA patients may acquire resistance to these drugs. In this regard, recently investigated MSC-based therapy is considered as a promising approach in RA treatment. In this study, we review conventional and modern treatment approaches, such as MSC-based therapy through the understanding of the link between MSCs and the innate and adaptive immune systems. Moreover, we discuss recent achievements in preclinical and clinical studies as well as various strategies for the enhancement of MSC immunoregulatory properties.
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Kondo N, Kuroda T, Kobayashi D. Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis. Int J Mol Sci 2021; 22:ijms222010922. [PMID: 34681582 PMCID: PMC8539723 DOI: 10.3390/ijms222010922] [Citation(s) in RCA: 221] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.
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Affiliation(s)
- Naoki Kondo
- Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan;
| | - Takeshi Kuroda
- Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishi-ku, Niigata City 950-2181, Japan
- Correspondence: ; Tel.: +81-25-262-6244; Fax: +81-25-262-7517
| | - Daisuke Kobayashi
- Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City 951-8510, Japan;
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Kemble S, Croft AP. Critical Role of Synovial Tissue-Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation. Front Immunol 2021; 12:715894. [PMID: 34539648 PMCID: PMC8446662 DOI: 10.3389/fimmu.2021.715894] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/17/2021] [Indexed: 12/11/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.
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Affiliation(s)
| | - Adam P. Croft
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom
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Ingegnoli F, Coletto LA, Scotti I, Compagnoni R, Randelli PS, Caporali R. The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How? Front Med (Lausanne) 2021; 8:705382. [PMID: 34422862 PMCID: PMC8377390 DOI: 10.3389/fmed.2021.705382] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/07/2021] [Indexed: 11/13/2022] Open
Abstract
In the majority of joint diseases, changes in the organization of the synovial architecture appear early. Synovial tissue analysis might provide useful information for the diagnosis, especially in atypical and rare joint disorders, and might have a value in case of undifferentiated inflammatory arthritis, by improving disease classification. After patient selection, it is crucial to address the dialogue between the clinician and the pathologist for adequately handling the sample, allowing identifying histological patterns depending on the clinical suspicion. Moreover, synovial tissue analysis gives insight into disease progression helping patient stratification, by working as an actionable and mechanistic biomarker. Finally, it contributes to an understanding of joint disease pathogenesis holding promise for identifying new synovial biomarkers and developing new therapeutic strategies. All of the indications mentioned above are not so far from being investigated in everyday clinical practice in tertiary referral hospitals, thanks to the great feasibility and safety of old and more recent techniques such as ultrasound-guided needle biopsy and needle arthroscopy. Thus, even in rheumatology clinical practice, pathobiology might be a key component in the management and treatment decision-making process. This review aims to examine some essential and crucial points regarding why, when, where, and how to perform a synovial biopsy in clinical practice and research settings and what information you might expect after a proper patient selection.
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Affiliation(s)
- Francesca Ingegnoli
- Division of Clinical Rheumatology, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milano, Italy
| | - Lavinia Agra Coletto
- Division of Clinical Rheumatology, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milano, Italy
| | - Isabella Scotti
- Division of Clinical Rheumatology, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milano, Italy
| | - Riccardo Compagnoni
- 1° Clinica Ortopedica, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milano, Italy
| | - Pietro Simone Randelli
- 1° Clinica Ortopedica, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Laboratory of Applied Biomechanics, Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milano, Italy
| | - Roberto Caporali
- Division of Clinical Rheumatology, ASST Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milano, Italy.,Department of Clinical Sciences & Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Research Center for Environmental Health, Università degli Studi di Milano, Milano, Italy
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Wu X, Sun M, Yang Z, Lu C, Wang Q, Wang H, Deng C, Liu Y, Yang Y. The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases. Front Cell Dev Biol 2021; 9:686548. [PMID: 34490243 PMCID: PMC8416662 DOI: 10.3389/fcell.2021.686548] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/23/2021] [Indexed: 12/15/2022] Open
Abstract
Chemokine is a structure-related protein with a relatively small molecular weight, which can target cells to chemotaxis and promote inflammatory response. Inflammation plays an important role in aging. C-C chemokine receptor 9 (CCR9) and its ligand C-C chemokine ligand 25 (CCL25) are involved in the regulating the occurrence and development of various diseases, which has become a research hotspot. Early research analysis of CCR9-deficient mouse models also confirmed various physiological functions of this chemokine in inflammatory responses. Moreover, CCR9/CCL25 has been shown to play an important role in a variety of inflammation-related diseases, such as cardiovascular disease (CVD), rheumatoid arthritis, hepatitis, inflammatory bowel disease, asthma, etc. Therefore, the purpose of this review gives an overview of the recent advances in understanding the roles of CCR9/CCL25 in inflammation and inflammation-associated diseases, which will contribute to the design of future experimental studies on the potential of CCR9/CCL25 and advance the research of CCR9/CCL25 as pharmacological inflammatory targets.
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Affiliation(s)
- Xue Wu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Meng Sun
- Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhi Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Chenxi Lu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Qiang Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Haiying Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yonglin Liu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
| | - Yang Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Shenmu, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
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Li X, Tang X, Wang Y, Chai C, Zhao Z, Zhang H, Peng Y, Wu L. CS-semi5 Inhibits NF-κB Activation to Block Synovial Inflammation, Cartilage Loss and Bone Erosion Associated With Collagen-Induced Arthritis. Front Pharmacol 2021; 12:655101. [PMID: 34305585 PMCID: PMC8298759 DOI: 10.3389/fphar.2021.655101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects 1% of the population. CS-semi5 is a semisynthetic chondroitin sulfate. In this study, CS-semi5 was shown to have positive effects on a model of collagen-induced arthritis (CIA). CS-semi5 treatment had obvious effects on weight loss and paw swelling in CIA mice. Post-treatment analysis revealed that CS-semi5 alleviated three main pathologies (i.e., synovial inflammation, cartilage erosion and bone loss) in a dose-dependent manner. Further study showed that CS-semi5 could effectively reduce TNF-α and IL-1β production in activated macrophages via the NF-κB pathway. CS-semi5 also blocked RANKL-trigged osteoclast differentiation from macrophages. Therefore, CS-semi5 may effectively ameliorate synovial inflammation, cartilage erosion and bone loss in RA through NF-κB deactivation.
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Affiliation(s)
- Xiang Li
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaonan Tang
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yufei Wang
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Changwei Chai
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhehui Zhao
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haijing Zhang
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Peng
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianqiu Wu
- Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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