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Wu CS, Chen CY, Yang CH, Hsu YP, Yu CH, Chen YH, Chen SK. The alterations of molecular repertoire of the RANKL-induced osteoclastogenesis in the M1 macrophage-derived inflammatory milieu. Sci Rep 2025; 15:16137. [PMID: 40341702 PMCID: PMC12062438 DOI: 10.1038/s41598-025-99772-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 04/22/2025] [Indexed: 05/10/2025] Open
Abstract
Inflammation have been linked to bone diseases such as osteoporosis or bone destruction. However, whether M1 inflammatory stimuli exert a stimulatory or inhibitory effect on the differentiation of osteoclasts remained controversial. Also, how inflammatory milieu influence cell proliferation and survival during osteoclastogenesis have not been determined. Here we reported the molecular repertoire alterations of RANKL-stimulated osteoclastogenesis from RAW264.7 at different stages in the inflammatory environments. Adding conditioned medium collected from LPS-stimulated macrophage, which are the primary source of extracellular inflammatory mediators, resulted in a biphasic change in cell number among differentiating preosteoclasts. The inflammatory milieu induced a transient proliferation of preosteoclasts during the initial 48 h, which was followed by a significant decline in cell numbers from the fourth day onwards. Proliferation-related AKT and ERK were transiently activated in the inflammatory environments, which also upregulated the expressions of c-myc, a major transcription factor for osteoclast differentiation, and pro-inflammatory genes, such as Tnf-a and Nos2. Following prolonged exposure to an inflammatory environment, undifferentiated osteoclast precursors undergo apoptosis. Our findings suggest that short-term inflammatory exposure transiently promotes the proliferation and differentiation of preosteoclasts, whereas long-term exposure leads to apoptosis, potentially due to the enhancement of inflammatory signals.
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Affiliation(s)
- Chun-Shan Wu
- Department of Pediatrics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
| | - Ching-Yun Chen
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Chin-Hua Yang
- Department of Radiology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan
- Department of Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-Pao Hsu
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, No. 1492, Zhongshan Road, Taoyuan District, Taoyuan City, 330, Taiwan
| | - Ching-Hsiao Yu
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, No. 1492, Zhongshan Road, Taoyuan District, Taoyuan City, 330, Taiwan
| | - Yu-Hsu Chen
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
- Department of Orthopedic Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, No. 1492, Zhongshan Road, Taoyuan District, Taoyuan City, 330, Taiwan.
- Department of Orthopedics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Shau-Kwaun Chen
- Institute of Neuroscience, National Chengchi University, No. 64, Section 2, Zhinan Road, Wenshan District, Taipei, 11605, Taiwan.
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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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Tamburini B, Di Liberto D, Pratelli G, Rizzo C, Barbera LL, Lauricella M, Carlisi D, Maggio A, Palumbo Piccionello A, D’Anneo A, Caccamo N, Guggino G. Extra Virgin Olive Oil Polyphenol-Enriched Extracts Exert Antioxidant and Anti-Inflammatory Effects on Peripheral Blood Mononuclear Cells from Rheumatoid Arthritis Patients. Antioxidants (Basel) 2025; 14:171. [PMID: 40002358 PMCID: PMC11851824 DOI: 10.3390/antiox14020171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
Rheumatoid arthritis (RA) is a long-term systemic autoimmune disorder that causes joint inflammation, swelling, pain, bone erosion, and deformities. Recent findings emphasize the anti-inflammatory and antioxidant properties of bioactive natural compounds, such as polyphenols extracted from plants and fruits, and their possible synergistic effect when used in combination with current therapies to improve the prognosis and symptoms of inflammatory rheumatic diseases. Here, we report that Sicilian extra virgin olive oil polyphenol-enriched extracts (PE-EVOOs) reduce intracellular reactive oxygen species (ROS) and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β), in peripheral mononuclear cells (PBMCs) obtained from both RA patients and healthy subjects (HSs) treated with lipopolysaccharides (LPS) as a control. HPLC-ESI-MS analysis highlighted that PE-EVOOs are rich in different polyphenolic compounds responsible for many of the observed biological effects. At molecular levels, Western blotting analyses revealed that PE-EVOO treatment is associated with the downregulation of the phosphorylated and active form of the inflammatory transcription factor NF-κB and the pro-inflammatory enzyme cyclooxygenase 2 (COX2). In addition, PE-EVOOs upregulated the transcription factor Nrf2 and its target antioxidant enzyme catalase and manganese superoxide dismutase (MnSOD). Collectively, these results suggest a possible use of PE-EVOOs as potential adjuvants for the treatment of RA.
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Affiliation(s)
- Bartolo Tamburini
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Immunology, University of Palermo, 90127 Palermo, Italy; (B.T.); (N.C.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University Hospital “P. Giaccone”, 90127 Palermo, Italy; (C.R.); (L.L.B.); (G.G.)
| | - Diana Di Liberto
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Biochemistry, University of Palermo, 90127 Palermo, Italy; (D.D.L.); (G.P.); (D.C.)
| | - Giovanni Pratelli
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Biochemistry, University of Palermo, 90127 Palermo, Italy; (D.D.L.); (G.P.); (D.C.)
| | - Chiara Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University Hospital “P. Giaccone”, 90127 Palermo, Italy; (C.R.); (L.L.B.); (G.G.)
| | - Lidia La Barbera
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University Hospital “P. Giaccone”, 90127 Palermo, Italy; (C.R.); (L.L.B.); (G.G.)
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Biochemistry, University of Palermo, 90127 Palermo, Italy; (D.D.L.); (G.P.); (D.C.)
| | - Daniela Carlisi
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Biochemistry, University of Palermo, 90127 Palermo, Italy; (D.D.L.); (G.P.); (D.C.)
| | - Antonella Maggio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (A.P.P.)
| | - Antonio Palumbo Piccionello
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (A.M.); (A.P.P.)
| | - Antonella D’Anneo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy;
| | - Nadia Caccamo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Section of Immunology, University of Palermo, 90127 Palermo, Italy; (B.T.); (N.C.)
| | - Giuliana Guggino
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University Hospital “P. Giaccone”, 90127 Palermo, Italy; (C.R.); (L.L.B.); (G.G.)
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Kodama H, Endo K, Sekiya I. Macrophage depletion in inflamed rat knees prevents the activation of synovial mesenchymal stem cells by weakening Nampt and Spp1 signaling. Inflamm Regen 2024; 44:47. [PMID: 39563425 PMCID: PMC11577658 DOI: 10.1186/s41232-024-00361-2] [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: 06/12/2024] [Accepted: 11/11/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Macrophages and mesenchymal stem cells (MSCs) engage in crucial interplay during inflammation and have significant roles in tissue regeneration. Synovial MSCs, as key players in joint regeneration, are known to proliferate together with macrophages in synovitis. However, the crosstalk between synovial MSCs and macrophages remains unclear. In this study, we investigated changes in the activation of synovial MSCs in inflamed rat knees following selective depletion of macrophages with clodronate liposomes. METHODS Acute inflammation was induced in rat knee joints by injection of carrageenan (day 0). Clodronate liposomes were administered intra-articularly on days 1 and 4 to deplete macrophages, with empty liposomes as a control. Knee joints were collected on day 7 for evaluation by histology, flow cytometry, and colony-forming assays. Concurrently, synovial MSCs were cultured and subjected to proliferation assays, flow cytometry, and chondrogenesis assessments. We also analyzed their crosstalk using single-cell RNA sequencing (scRNA-seq). RESULTS Clodronate liposome treatment significantly reduced CD68-positive macrophage numbers and suppressed synovitis. Immunohistochemistry and flow cytometry showed decreased expression of CD68 (a macrophage marker) and CD44 and CD271 (MSC markers) in the clodronate group, while CD73 expression remained unchanged. The number of colony-forming cells per 1000 nucleated cells and per gram of synovium was significantly lower in the clodronate group than in the control group. Cultured synovial MSCs from both groups showed comparable proliferation, surface antigen expression, and chondrogenic capacity. scRNA-seq identified seven distinct synovial fibroblast (SF) subsets, with a notable decrease in the Mki67+ SF subset, corresponding to synovial MSCs, in the clodronate group. Clodronate treatment downregulated genes related to extracellular matrix organization and anabolic pathways in Mki67+ SF. Cell-cell communication analysis revealed diminished Nampt and Spp1 signaling interaction between macrophages and Mki67+ SF and diminished Ccl7, Spp1, and Csf1 signaling interaction between Mki67+ SF and macrophages in the clodronate group. Spp1 and Nampt promoted the proliferation and/or chondrogenesis of synovial MSCs. CONCLUSIONS Macrophage depletion with clodronate liposomes suppressed synovitis and reduced the number and activity of synovial MSCs, highlighting the significance of macrophage-derived Nampt and Spp1 signals in synovial MSC activation. These findings offer potential therapeutic strategies to promote joint tissue regeneration by enhancing beneficial signals between macrophages and synovial MSCs.
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Affiliation(s)
- Hayato Kodama
- Center for Stem Cell and Regenerative Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan.
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan
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Klimak M, Cimino A, Lenz KL, Springer LE, Collins KH, Harasymowicz NS, Xu N, Pham CTN, Guilak F. Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery. Arthritis Res Ther 2024; 26:190. [PMID: 39501398 PMCID: PMC11539832 DOI: 10.1186/s13075-024-03425-3] [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: 05/08/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner. METHODS For proof-of-concept, we developed "smart" macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection. RESULTS These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA. CONCLUSION These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.
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Affiliation(s)
- Molly Klimak
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
| | - Amanda Cimino
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
| | - Kristin L Lenz
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
| | - Luke E Springer
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
- Division of Rheumatology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Kelsey H Collins
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Natalia S Harasymowicz
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
- Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84108, USA
| | - Nathan Xu
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA
| | - Christine T N Pham
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA
- Division of Rheumatology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Farshid Guilak
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA.
- Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.
- Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA.
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Sun L, Yang K, Wang L, Wu S, Wen D, Wang J. LncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by promoting autophagy through miR-30a-5p/SOCS1 axi. Sci Rep 2024; 14:22608. [PMID: 39349964 PMCID: PMC11442610 DOI: 10.1038/s41598-024-73607-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Accumulated data implicate that long noncoding RNA (lncRNA) plays a pivotal role in rheumatoid arthritis (RA), potentially serving as a competitive endogenous RNA (ceRNA) for microRNAs (miRNAs). The lncRNA myocardial infarction-associated transcript (MIAT) has been demonstrated to regulate inflammation. However, the role of MIAT in the inflammation of RA remains inadequately explored. This study aims to elucidate MIAT's role in the inflammation of lipopolysaccharide (LPS)-induced macrophages and to uncover the underlying molecular mechanisms. We observed heightened MIAT expression in LPS-induced J774A.1 cells and collagen-induced arthritis mouse models, in contrast to the expression pattern of miR-30a-5p. Silencing MIAT resulted in increased expression of the inflammatory cytokines IL-1β and TNF-α. Simultaneously, MIAT interference significantly impeded macrophage autophagy, evidenced by decreased expression of autophagy-related markers LC3-II and Beclin-1, alongside increased levels of p62 in LPS-induced J774A.1 cells. Notably, MIAT functioned as a ceRNA, sponging miR-30a-5p and exerting a negative regulatory influence on its expression. SOCS1 emerged as a target of miR-30a-5p, modulated by MIAT. Mechanistically, inhibiting miR-30a-5p reversed the impact of MIAT deficiency in promoting LPS-induced inflammation, while SOCS1 knockdown countered the cytokine inhibitory effect induced by silencing miR-30a-5p. In summary, this study indicates that lncRNA MIAT suppresses inflammation in LPS-induced J774A.1 macrophages by stimulating autophagy through the miR-30a-5p/SOCS1 axis. This suggests that MIAT holds promise as a potential therapeutic target for RA inflammation.
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Affiliation(s)
- Linqian Sun
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Kun Yang
- Medical Research Center, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liqin Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Si Wu
- Department of Infectious Disease, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Dawei Wen
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Jibo Wang
- Department of Rheumatology & Clinical Immunology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Kulakova K, Lawal TR, Mccarthy E, Floudas A. The Contribution of Macrophage Plasticity to Inflammatory Arthritis and Their Potential as Therapeutic Targets. Cells 2024; 13:1586. [PMID: 39329767 PMCID: PMC11430612 DOI: 10.3390/cells13181586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/06/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024] Open
Abstract
Inflammatory arthritis are common chronic inflammatory autoimmune diseases characterised by progressive, destructive inflammation of the joints leading to a loss of function and significant comorbidities; importantly, there are no cures and only 20% of patients achieve drug-free remission for over 2 years. Macrophages play a vital role in maintaining homeostasis, however, under the wrong environmental cues, become drivers of chronic synovial inflammation. Based on the current "dogma", M1 macrophages secrete pro-inflammatory cytokines and chemokines, promoting tissue degradation and joint and bone erosion which over time lead to accelerated disease progression. On the other hand, M2 macrophages secrete anti-inflammatory mediators associated with wound healing, tissue remodelling and the resolution of inflammation. Currently, four subtypes of M2 macrophages have been identified, namely M2a, M2b, M2c and M2d. However, more subtypes may exist due to macrophage plasticity and the ability for repolarisation. Macrophages are highly plastic, and polarisation exists as a continuum with diverse intermediate phenotypes. This plasticity is achieved by a highly amenable epigenome in response to environmental stimuli and shifts in metabolism. Initiating treatment during the early stages of disease is important for improved prognosis and patient outcomes. Currently, no treatment targeting macrophages specifically is available. Such therapeutics are being investigated in ongoing clinical trials. The repolarisation of pro-inflammatory macrophages towards the anti-inflammatory phenotype has been proposed as an effective approach in targeting the M1/M2 imbalance, and in turn is a potential therapeutic strategy for IA diseases. Therefore, elucidating the mechanisms that govern macrophage plasticity is fundamental for the success of novel macrophage targeting therapeutics.
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Affiliation(s)
- Karina Kulakova
- School of Biotechnology, Dublin City University, D09 V209 Dublin, Ireland; (K.K.)
- Life Sciences Institute, Dublin City University, D09 V209 Dublin, Ireland
| | - Tope Remilekun Lawal
- School of Biotechnology, Dublin City University, D09 V209 Dublin, Ireland; (K.K.)
| | - Eoghan Mccarthy
- Department of Rheumatology, Beaumont Hospital, D09 V2N0 Dublin, Ireland
- Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland
| | - Achilleas Floudas
- School of Biotechnology, Dublin City University, D09 V209 Dublin, Ireland; (K.K.)
- Life Sciences Institute, Dublin City University, D09 V209 Dublin, Ireland
- Medical School, University of Ioannina, 45110 Ioannina, Greece
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Klimak M, Cimino A, Lenz K, Springer L, Collins K, Harasymowicz N, Xu N, Pham C, Guilak F. Engineered Self-Regulating Macrophages for Targeted Anti-inflammatory Drug Delivery. RESEARCH SQUARE 2024:rs.3.rs-4385938. [PMID: 38854124 PMCID: PMC11160898 DOI: 10.21203/rs.3.rs-4385938/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Background Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner. Methods For proof-of-concept, we developed "smart" macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection. Results These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA. Conclusion These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.
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Xu H, Wang Y, Rong X, Wang D, Xie J, Huang Z, Zeng W, Fu X, Li J, Zhou Z. Ingenious Synergy of a Pathology-Specific Biomimetic Multifunctional Nanoplatform for Targeted Therapy in Rheumatoid Arthritis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2305197. [PMID: 37914665 DOI: 10.1002/smll.202305197] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/11/2023] [Indexed: 11/03/2023]
Abstract
Based on the pathological characteristics of rheumatoid arthritis, including the overproduction of reactive oxygen species (ROS), inflammatory responses, and osteoclast differentiation, a biomimetic multifunctional nanomedicine (M-M@I) is designed. Iguratimod (IGU) is loaded, which inhibits inflammatory responses and osteoclast differentiation, into mesoporous polydopamine (MPDA), which scavenges ROS. Subsequently, the nanoparticles are coated with a cell membrane of macrophages to achieve actively targeted delivery of the nanoparticles to inflamed joints. It is shown that the M-M@I nanoparticles are taken up well by lipopolysaccharide-induced RAW 264.7 macrophages or bone marrow-derived macrophages (BMDMs). In vitro, the M-M@I nanoparticles effectively scavenge ROS, downregulate genes related to inflammation promotion and osteoclast differentiation, and reduce the proinflammatory cytokines and osteoclast-related enzymes. They also reduce the polarization of macrophages to a pro-inflammatory M1 phenotype and inhibit differentiation into osteoclasts. In mice with collagen-induced arthritis, the M-M@I nanoparticles accumulate at arthritic sites and circulate longer, significantly mitigating arthritis symptoms and bone destruction. These results suggest that the pathology-specific biomimetic multifunctional nanoparticles are effective against rheumatoid arthritis, and they validate the approach of developing multifunctional therapies that target various pathological processes simultaneously.
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Affiliation(s)
- Hong Xu
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuemin Wang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
| | - Xiao Rong
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Duan Wang
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinwei Xie
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zeyu Huang
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Weinan Zeng
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaoxue Fu
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianshu Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu, 610041, China
| | - Zongke Zhou
- Department of Orthopedic Surgery and Orthopedic Research Institution, West China Hospital, Sichuan University, Chengdu, 610041, China
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Li M, Kim YM, Koh JH, Park J, Kwon HM, Park JH, Jin J, Park Y, Kim D, Kim WU. Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5. J Clin Invest 2024; 134:e167835. [PMID: 38426494 PMCID: PMC10904059 DOI: 10.1172/jci167835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/05/2024] [Indexed: 03/02/2024] Open
Abstract
Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern-triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.
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Affiliation(s)
- Meiling Li
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu-Mi Kim
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
| | - Jung Hee Koh
- Division of Rheumatology, Department of Internal Medicine, Uijeoungbu St.Mary’s hospital, the Catholic University of Korea, Uijeoungbu, Republic of Korea
| | - Jihyun Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - H. Moo Kwon
- School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jong-Hwan Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea
| | - Jingchun Jin
- Department of Immunology of Yanbian University Hospital, Yanji, Jilin Province, China
- Key Laboratory of Science and Technology Department (Jilin Province), Cancer Research Center, Yanji, Jilin Province, China
| | - Youngjae Park
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Donghyun Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Endemic Diseases, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Wan-Uk Kim
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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11
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Klimak M, Guilak F. Genetically engineered macrophages derived from iPSCs for self-regulating delivery of anti-inflammatory biologic drugs. J Tissue Eng Regen Med 2024; 2024:6201728. [PMID: 38571695 PMCID: PMC10990417 DOI: 10.1155/2024/6201728] [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] [Indexed: 04/05/2024]
Abstract
In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (TNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an auto-regulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.
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Affiliation(s)
- Molly Klimak
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA
- Shriners Hospitals for Children – St. Louis, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA
- Center of Regenerative Medicine, Washington University, St. Louis, MO 63110, USA
| | - Farshid Guilak
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, USA
- Shriners Hospitals for Children – St. Louis, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA
- Center of Regenerative Medicine, Washington University, St. Louis, MO 63110, USA
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12
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Xie R, Pal V, Yu Y, Lu X, Gao M, Liang S, Huang M, Peng W, Ozbolat IT. A comprehensive review on 3D tissue models: Biofabrication technologies and preclinical applications. Biomaterials 2024; 304:122408. [PMID: 38041911 PMCID: PMC10843844 DOI: 10.1016/j.biomaterials.2023.122408] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/09/2023] [Accepted: 11/22/2023] [Indexed: 12/04/2023]
Abstract
The limitations of traditional two-dimensional (2D) cultures and animal testing, when it comes to precisely foreseeing the toxicity and clinical effectiveness of potential drug candidates, have resulted in a notable increase in the rate of failure during the process of drug discovery and development. Three-dimensional (3D) in-vitro models have arisen as substitute platforms with the capacity to accurately depict in-vivo conditions and increasing the predictivity of clinical effects and toxicity of drug candidates. It has been found that 3D models can accurately represent complex tissue structure of human body and can be used for a wide range of disease modeling purposes. Recently, substantial progress in biomedicine, materials and engineering have been made to fabricate various 3D in-vitro models, which have been exhibited better disease progression predictivity and drug effects than convention models, suggesting a promising direction in pharmaceutics. This comprehensive review highlights the recent developments in 3D in-vitro tissue models for preclinical applications including drug screening and disease modeling targeting multiple organs and tissues, like liver, bone, gastrointestinal tract, kidney, heart, brain, and cartilage. We discuss current strategies for fabricating 3D models for specific organs with their strengths and pitfalls. We expand future considerations for establishing a physiologically-relevant microenvironment for growing 3D models and also provide readers with a perspective on intellectual property, industry, and regulatory landscape.
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Affiliation(s)
- Renjian Xie
- Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering in Jiangxi Province, Gannan Medical University, Ganzhou, JX, 341000, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, JX, China
| | - Vaibhav Pal
- Department of Chemistry, Pennsylvania State University, University Park, PA, USA; The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Yanrong Yu
- School of Pharmaceutics, Nanchang University, Nanchang, JX, 330006, China
| | - Xiaolu Lu
- Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering in Jiangxi Province, Gannan Medical University, Ganzhou, JX, 341000, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, JX, China
| | - Mengwei Gao
- School of Pharmaceutics, Nanchang University, Nanchang, JX, 330006, China
| | - Shijie Liang
- School of Pharmaceutics, Nanchang University, Nanchang, JX, 330006, China
| | - Miao Huang
- Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering in Jiangxi Province, Gannan Medical University, Ganzhou, JX, 341000, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, JX, China
| | - Weijie Peng
- Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering in Jiangxi Province, Gannan Medical University, Ganzhou, JX, 341000, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, JX, China; School of Pharmaceutics, Nanchang University, Nanchang, JX, 330006, China.
| | - Ibrahim T Ozbolat
- The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA; Engineering Science and Mechanics Department, Penn State University, University Park, PA, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, USA; Materials Research Institute, Pennsylvania State University, University Park, PA, USA; Department of Neurosurgery, Pennsylvania State College of Medicine, Hershey, PA, USA; Penn State Cancer Institute, Penn State University, Hershey, PA, 17033, USA; Department of Medical Oncology, Cukurova University, Adana, 01130, Turkey; Biotechnology Research and Application Center, Cukurova University, Adana, 01130, Turkey.
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13
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Brock J, Basu N, Schlachetzki JCM, Schett G, McInnes IB, Cavanagh J. Immune mechanisms of depression in rheumatoid arthritis. Nat Rev Rheumatol 2023; 19:790-804. [PMID: 37923863 DOI: 10.1038/s41584-023-01037-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2023] [Indexed: 11/06/2023]
Abstract
Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.
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Affiliation(s)
- James Brock
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Neil Basu
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | | | - Georg Schett
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Universitätsklinikum Erlangen, Erlangen, Germany
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Jonathan Cavanagh
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
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14
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Sur B, Kim M, Villa T, Oh S. Phytoceramide Alleviates the Carrageenan/Kaolin-Induced Arthritic Symptoms by Modulation of Inflammation. Biomol Ther (Seoul) 2023; 31:536-543. [PMID: 37381800 PMCID: PMC10468417 DOI: 10.4062/biomolther.2023.031] [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: 02/15/2023] [Revised: 04/13/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Phytoceramide (Pcer) is found mainly in plants and yeast. It can be neuroprotective and immunostimulatory on various cell types. In this study, the therapeutic effect of Pcer was explored using the carrageenan/kaolin (C/K)-induced arthritis rat model and fibroblast-like synoviocytes (FLS). Pcer treatment (1, 10, and 30 mg/kg/day) were given to the arthritic rats for 6 days after disease induction. Weight distribution ration (WDR), knee thickness, squeaking score, serum levels of proinflammatory mediators, and histological analysis were measured and performed to evaluate arthritic symptoms in the rat model. In interleukin (IL)‑1β‑stimulated FLS, proinflammatory mediators were measured after Pcer (1-30 μM) treatment. Arthritic symptoms in rats with Pcer treatment were significantly decreased at days 4 to 6 after C/K arthritis induction. Inflammation in the knee joints were also significantly decreased in rats with Pcer treatment. Furthermore, in IL-1β‑stimulated FLS, the expressions of proinflammatory mediators were also inhibited by Pcer. As shown by the results, Pcer has anti-arthritic effects in the C/K rat model and in synovial cells, suggesting that Pcer has the potential to be a useful agent in arthritis treatment.
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Affiliation(s)
- Bongjun Sur
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Mijin Kim
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Thea Villa
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Seikwan Oh
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
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15
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Chen M, Fu W, Xu H, Liu CJ. Tau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice. Arthritis Res Ther 2023; 25:146. [PMID: 37559125 PMCID: PMC10410869 DOI: 10.1186/s13075-023-03133-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/01/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Tau protein serves a pro-inflammatory function in neuroinflammation. However, the role of tau in other inflammatory disorders such as rheumatoid arthritis (RA) is less explored. This study is to investigate the role of endogenous tau and the potential mechanisms in the pathogenesis of inflammatory arthritis. METHODS We established collagen-induced arthritis (CIA) model in wild-type and Tau-/- mice to compare the clinical score and arthritis incidence. Micro-CT analysis was used to evaluate bone erosion of ankle joints. Histological analysis was performed to assess inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Serum levels of pro-inflammatory cytokines were measured by ELISA. The expression levels of macrophage markers were determined by immunohistochemistry staining and quantitative real-time PCR. RESULTS Tau expression was upregulated in joints under inflammatory condition. Tau deletion in mice exhibited milder inflammation and protected against the progression of CIA, evidenced by reduced serum levels of pro-inflammatory cytokines and attenuated bone loss, inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Furthermore, tau deficiency led to the inhibition of classically activated type 1 (M1) macrophage polarization in the synovium. CONCLUSION Tau is a previously unrecognized critical regulator in the pathogenesis of RA and may provide a potential therapeutic target for autoimmune and inflammatory joint diseases.
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Affiliation(s)
- Meng Chen
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wenyu Fu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Huiyun Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University Grossman School of Medicine, New York, NY, USA.
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.
- Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
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16
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Hedman ÅK, Winter E, Yoosuf N, Benita Y, Berg L, Brynedal B, Folkersen L, Klareskog L, Maciejewski M, Sirota-Madi A, Spector Y, Ziemek D, Padyukov L, Shen-Orr SS, Jelinsky SA. Peripheral blood cellular dynamics of rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs. Sci Rep 2023; 13:10058. [PMID: 37344505 DOI: 10.1038/s41598-023-36999-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 06/14/2023] [Indexed: 06/23/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months of treatment. We used in parallel a computational deconvolution approach based on RNA expression and flow cytometry to determine the relative cell-type frequencies. Cell-type frequencies from deconvolution of gene expression indicate that monocytes (both classical and non-classical) and CD4+ cells (Th1 and Th2) were increased in RA patients compared to controls, while NK cells and B cells (naïve and mature) were significantly decreased in RA patients. Treatment with MTX caused a decrease in B cells (memory and plasma cell), and a decrease in CD4 Th cells (Th1 and Th17), while treatment with TNFi resulted in a significant increase in the population of B cells. Characterization of the RNA expression patterns found that most of the differentially expressed genes in RA subjects after treatment can be explained by changes in cell frequencies (98% and 74% respectively for MTX and TNFi).
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Affiliation(s)
- Åsa K Hedman
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Department of Inflammation and Immunology, Pfizer, 1 Portland Street, Cambridge, MA, 02139, USA
| | | | - Niyaz Yoosuf
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - Louise Berg
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Boel Brynedal
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lasse Folkersen
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Lars Klareskog
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Mateusz Maciejewski
- Department of Inflammation and Immunology, Pfizer, 1 Portland Street, Cambridge, MA, 02139, USA
| | | | | | - Daniel Ziemek
- Department of Inflammation and Immunology, Pfizer, Berlin, Germany
| | - Leonid Padyukov
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Shai S Shen-Orr
- CytoReason, Tel-Aviv, Israel
- Technion-Israel Institute of Technology, Haifa, Israel
| | - Scott A Jelinsky
- Department of Inflammation and Immunology, Pfizer, 1 Portland Street, Cambridge, MA, 02139, USA.
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Yu Y, Gao Y, He L, Fang B, Ge W, Yang P, Ju Y, Xie X, Lei L. Biomaterial-based gene therapy. MedComm (Beijing) 2023; 4:e259. [PMID: 37284583 PMCID: PMC10239531 DOI: 10.1002/mco2.259] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 06/08/2023] Open
Abstract
Gene therapy, a medical approach that involves the correction or replacement of defective and abnormal genes, plays an essential role in the treatment of complex and refractory diseases, such as hereditary diseases, cancer, and rheumatic immune diseases. Nucleic acids alone do not easily enter the target cells due to their easy degradation in vivo and the structure of the target cell membranes. The introduction of genes into biological cells is often dependent on gene delivery vectors, such as adenoviral vectors, which are commonly used in gene therapy. However, traditional viral vectors have strong immunogenicity while also presenting a potential infection risk. Recently, biomaterials have attracted attention for use as efficient gene delivery vehicles, because they can avoid the drawbacks associated with viral vectors. Biomaterials can improve the biological stability of nucleic acids and the efficiency of intracellular gene delivery. This review is focused on biomaterial-based delivery systems in gene therapy and disease treatment. Herein, we review the recent developments and modalities of gene therapy. Additionally, we discuss nucleic acid delivery strategies, with a focus on biomaterial-based gene delivery systems. Furthermore, the current applications of biomaterial-based gene therapy are summarized.
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Affiliation(s)
- Yi Yu
- Department of StomatologyThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Yijun Gao
- Department of StomatologyThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Liming He
- Department of StomatologyChangsha Stomatological HospitalChangshaChina
| | - Bairong Fang
- Department of Plastic and Aesthetic (Burn) SurgeryThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Wenhui Ge
- Department of StomatologyThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Pu Yang
- Department of Plastic and Aesthetic (Burn) SurgeryThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Yikun Ju
- Department of Plastic and Aesthetic (Burn) SurgeryThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Xiaoyan Xie
- Department of StomatologyThe Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Lanjie Lei
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
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Li C, Luo X, Qian C, Huang J, Yi X, Su H, Han Y. Folate receptor-mediated targeted therapy for rheumatoid arthritis by methotrexate-phospholipid complex nano-emulsions. J Drug Target 2023; 31:402-410. [PMID: 36724823 DOI: 10.1080/1061186x.2023.2175832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease. Activated macrophages in arthritic joints play a prominent role in the initiation and persistence of RA. Despite great progress in the clinical treatment of RA, poor response and high discontinuation due to systemic toxicity remain unsolved issues, especially the well-known methotrexate (MTX). Therefore, active targeted delivery of therapeutic drugs to pathogenic cells in arthritic joints is essential to increase in situ activity and decrease systemic toxicity. Here, we developed an MTX-loaded macrophage-targeted nano-emulsion (NE) based on the overexpression of folate receptor (FR) on activated macrophages, the inherent high affinity of FR for folate (FA), as well as the property of MTX and phospholipids to form complexes (MTX@PC). Intravenous injection of DID-labelled MTX@PC-FA NEs into adjuvant-induced arthritis (AIA) mice, in vivo images and flow cytometry results revealed that the NEs were highly targeted to inflamed joints and macrophages, respectively. Therapeutic studies suggested that this strategy was conducive to achieve high efficacy and low toxicity of MTX in the treatment of RA. Our research highlights MTX@PC-FA NEs as a potential treatment option for RA targeting the FR-expressed activated macrophages.
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Affiliation(s)
- Chenglong Li
- Department of Pharmacy, People's Hospital of Deyang City, Deyang, P.R. China
| | - Xi Luo
- Department of Scientific & Education, People's Hospital of Deyang City, Deyang, P.R. China
| | - Can Qian
- Department of Pharmacy, People's Hospital of Deyang City, Deyang, P.R. China
| | - Jian Huang
- Department of Pharmacy, People's Hospital of Deyang City, Deyang, P.R. China
| | - Xingyang Yi
- Department of Neurology, People's Hospital of Deyang City, Deyang, P.R. China
| | - Huaiyu Su
- Department of Pharmacy, People's Hospital of Deyang City, Deyang, P.R. China
| | - Yangyun Han
- Department of Neurosurgery, People's Hospital of Deyang City, Deyang, P.R. China
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McBride DA, Kerr MD, Johnson WT, Nguyen A, Zoccheddu M, Yao M, Prideaux EB, Dorn NC, Wang W, Svensson MN, Bottini N, Shah NJ. Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2202720. [PMID: 36890657 PMCID: PMC10104670 DOI: 10.1002/advs.202202720] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 01/09/2023] [Indexed: 05/10/2023]
Abstract
Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (Treg ) and suppression of Treg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory Treg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of Treg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.
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Affiliation(s)
- David A. McBride
- Department of NanoengineeringUniversity of CaliforniaLa JollaSan DiegoCA92093USA
- Chemical Engineering ProgramUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Matthew D. Kerr
- Department of NanoengineeringUniversity of CaliforniaLa JollaSan DiegoCA92093USA
- Chemical Engineering ProgramUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Wade T. Johnson
- Department of NanoengineeringUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Anders Nguyen
- Department of Rheumatology and Inflammation ResearchSahlgrenska AcademyInstitute of MedicineUniversity of GothenburgGothenburg41346Sweden
| | - Martina Zoccheddu
- Department of MedicineDivision of RheumatologyAllergy and ImmunologyUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Mina Yao
- Department of Chemistry and BiochemistryUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Edward B. Prideaux
- Department of Chemistry and BiochemistryUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Nicholas C. Dorn
- Department of NanoengineeringUniversity of CaliforniaLa JollaSan DiegoCA92093USA
- Chemical Engineering ProgramUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Wei Wang
- Department of Chemistry and BiochemistryUniversity of CaliforniaLa JollaSan DiegoCA92093USA
- Department of Cellular and Molecular MedicineUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Mattias N.D. Svensson
- Department of Rheumatology and Inflammation ResearchSahlgrenska AcademyInstitute of MedicineUniversity of GothenburgGothenburg41346Sweden
| | - Nunzio Bottini
- Department of MedicineDivision of RheumatologyAllergy and ImmunologyUniversity of CaliforniaLa JollaSan DiegoCA92093USA
| | - Nisarg J. Shah
- Department of NanoengineeringUniversity of CaliforniaLa JollaSan DiegoCA92093USA
- Chemical Engineering ProgramUniversity of CaliforniaLa JollaSan DiegoCA92093USA
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20
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Adib M, Taghadosi M, Tahmasebi MN, Sharafat Vaziri A, Jamshidi A, Mahmoudi M, Farhadi E. Anti-inflammatory effects of PRIMA-1 MET (mutant p53 reactivator) induced by inhibition of nuclear factor-κB on rheumatoid arthritis fibroblast-like synoviocytes. Inflammopharmacology 2023; 31:385-394. [PMID: 36350424 DOI: 10.1007/s10787-022-01094-9] [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: 06/13/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022]
Abstract
Fibroblast-like synoviocytes (FLSs), the main pathological cells in rheumatoid arthritis (RA), display tumor-like phenotype, including hyper-proliferation, apoptosis resistance, and aggressive phenotype. Excessive proliferation and insufficient apoptosis of RA-FLSs can lead to hyperplastic synovial pannus tissue, excess production of inflammatory mediators, and destruction of joints. In this article, we investigate the effect of PRIMA-1MET on the apoptosis induction and inhibition of pro-inflammatory cytokines in RA-FLSs. Synovial tissue samples were obtained from 10 patients with RA. The FLSs were treated with different concentrations of PRIMA-1MET. The rate of apoptosis and cell survival was assessed by flow cytometry and MTT assay and Real-time quantitative PCR was performed to evaluate the transcription of p53, IL-6, IL-1β, TNF-α, Noxa, p21, PUMA, Bax, Survivin, and XIAP in treated RA-FLSs. The protein level of p53, IκBα, and phospho-IκBα were measured using Western blotting. The results showed that PRIMA-1MET induced apoptosis in RA-FLSs and increased significantly the expression of Noxa, and decreased significantly IL-6, IL-1β, p53, and phospho-IκBα expression. PRIMA-1MET can induce apoptosis in RA-FLSs through induction of Noxa expression while p53 was downregulated. Furthermore, PRIMA-1MET treatment results in the suppression of pro-inflammatory cytokine production and NF-κB inhibition. Given the role of p53 and NF-κB in RA-FLSs, PRIMA-1MET can be considered as a new therapeutic strategy for rheumatoid arthritis.
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Affiliation(s)
- Mehrnoosh Adib
- Immunology Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahdi Taghadosi
- Immunology Department, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Mohammad Naghi Tahmasebi
- Center of Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Sharafat Vaziri
- Center of Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Shariati Hospital, Kargar Ave, PO-BOX: 1411713137, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Shariati Hospital, Kargar Ave, PO-BOX: 1411713137, Tehran, Iran.,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Farhadi
- Rheumatology Research Center, Tehran University of Medical Sciences, Shariati Hospital, Kargar Ave, PO-BOX: 1411713137, Tehran, Iran. .,Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Werner LE, Wagner U. Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation. Front Physiol 2023; 13:1078569. [PMID: 36685206 PMCID: PMC9854345 DOI: 10.3389/fphys.2022.1078569] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 11/17/2022] [Indexed: 01/09/2023] Open
Abstract
The calcium-sensing receptor (CaSR) is expressed in many cell types - including immune cells and in particular circulating monocytes. Here, the receptor plays an important physiological role as a regulator of constitutive macropinocytosis. This review article provides an overview of the literature on the role of the calcium sensing receptor in the context of inflammatory processes. Special emphasis is laid upon the importance for monocytes in the context of rheumatoid arthritis. We have shown previously, that stimulation of the receptor by increased extracellular Ca2+ ([Ca2+]ex) triggers a pro-inflammatory response due to NLRP3 inflammasome assembly and interleukin (IL)-1β release. The underlying mechanism includes macropinocytosis of calciprotein particles (CPPs), which are taken up in a [Ca2+]ex-induced, CaSR dependent manner, and leads to strong IL-1β release. In rheumatoid arthritis (RA), this uptake and the resulting IL-1β release is significantly increased due to increased expression of the receptor. Moreover, increased [Ca2+]ex-induced CPP uptake and IL-1β release is associated with more active disease, while CaSR overexpression has been reported to be associated with cardiovascular complications of RA. Most importantly, however, in animal experiments with arthritic mice, increased local calcium concentrations are present, which in combination with release of fetuin-A from eroded bone could contribute to formation of CPPs. We propose, that increased [Ca2+]ex, CPPs and pro-inflammatory cytokines drive a vicious cycle of inflammation and bone destruction which in turn offers new potential therapeutic approaches.
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22
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Deloch L, Rückert M, Weissmann T, Lettmaier S, Titova E, Wolff T, Weinrich F, Fietkau R, Gaipl US. The various functions and phenotypes of macrophages are also reflected in their responses to irradiation: A current overview. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 376:99-120. [PMID: 36997271 DOI: 10.1016/bs.ircmb.2023.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Macrophages are a vital part of the innate immune system that are involved in healthy biological processes but also in disease modulation and response to therapy. Ionizing radiation is commonly used in the treatment of cancer and, in a lower dose range, as additive therapy for inflammatory diseases. In general, lower doses of ionizing radiation are known to induce rather anti-inflammatory responses, while higher doses are utilized in cancer treatment where they result, next to tumor control, in rather inflammatory responses. Most experiments that have been carried out in ex vivo on macrophages find this to be true, however in vivo, tumor-associated macrophages, for example, show a contradictory response to the respective dose-range. While some knowledge in radiation-induced modulations of macrophages has been collected, many of the underlying mechanisms remain unclear. Due to their pivotal role in the human body, however, they are a great target in therapy and could potentially aid in better treatment outcome. We therefore summarized the current knowledge of macrophage mediated radiation responses.
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23
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Kong JS, Jeong GH, Yoo SA. The use of animal models in rheumatoid arthritis research. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2023; 40:23-29. [PMID: 36411592 PMCID: PMC9946911 DOI: 10.12701/jyms.2022.00773] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 10/27/2022] [Accepted: 11/04/2022] [Indexed: 06/16/2023]
Abstract
The pathological hallmark of rheumatoid arthritis (RA) is a synovial pannus that comprises proliferating and invasive fibroblast-like synoviocytes, infiltrating inflammatory cells, and an associated neoangiogenic response. Animal models have been established to study these pathological features of human RA. Spontaneous and induced animal models of RA primarily reflect inflammatory aspects of the disease. Among various induced animal models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models are widely used to study the pathogenesis of RA. Improved transplantation techniques for severe combined immunodeficiency (SCID) mouse models of RA can be used to evaluate the effectiveness of potential therapeutics in human tissues and cells. This review provides basic information on various animal models of RA, including CIA and CAIA. In addition, we describe a SCID mouse coimplantation model that can measure the long-distance migration of human RA synoviocytes and cartilage destruction induced by these cells.
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Affiliation(s)
- Jin-Sun Kong
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Gi Heon Jeong
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Ah Yoo
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, College of Medicine, The Catholic University of Korea, Seoul, Korea
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24
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Talmon M, Percio M, Obeng JA, Ruffinatti FA, Sola D, Sainaghi PP, Bellis E, Cusinato S, Ianniello A, Fresu LG. Transcriptomic profile comparison of monocytes from rheumatoid arthritis patients in treatment with methotrexate, anti-TNFa, abatacept or tocilizumab. PLoS One 2023; 18:e0282564. [PMID: 36877690 PMCID: PMC9987802 DOI: 10.1371/journal.pone.0282564] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
It is well documented that patients affected by rheumatoid arthritis (RA) have distinct susceptibility to the different biologic DMARDs available on the market, probably because of the many facets of the disease. Monocytes are deeply involved in the pathogenesis of RA and we therefore evaluated and compared the transcriptomic profile of monocytes isolated from patients on treatment with methotrexate alone or in combination with tocilizumab, anti-TNFα or abatacept and from healthy donors. Whole-genome transcriptomics yielded a list of regulated genes by Rank Product statistics and DAVID was then used for functional annotation enrichment analysis. Last, data were validated by qRT-PCR. Abatacept, tocilizumab and anti-TNFa cohorts were separately compared with methotrexate, leading to the identification of 78, 6, and 436 differentially expressed genes, respectively. The upper-most ranked genes were related to inflammatory processes and immune responses. Such an approach draws the genomic profile of monocytes in treated RA patients and lays the basis for finding gene signature for tailored therapeutic choices.
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Affiliation(s)
- Maria Talmon
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Novara, Italy
| | - Marcella Percio
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Novara, Italy
| | - Joyce Afrakoma Obeng
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Novara, Italy
| | | | - Daniele Sola
- Struttura Complessa Allergologia ed Immunologia, CAAD Ipazia, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
| | - Pier Paolo Sainaghi
- Struttura Complessa Allergologia ed Immunologia, CAAD Ipazia, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
- Department of Translational Medicine, School of Medicine, University of Piemonte Orientale, Novara, Italy
| | - Emanuela Bellis
- Day Hospital Multidisciplinare—Struttura Complessa di Nefrologia e Dialisi, Ospedale di Borgomanero, Borgomanero, Italy
| | - Stefano Cusinato
- Day Hospital Multidisciplinare—Struttura Complessa di Nefrologia e Dialisi, Ospedale di Borgomanero, Borgomanero, Italy
| | - Aurora Ianniello
- Day Hospital Multidisciplinare—Struttura Complessa di Nefrologia e Dialisi, Ospedale di Borgomanero, Borgomanero, Italy
| | - Luigia G. Fresu
- Department of Health Sciences, School of Medicine, University of Piemonte Orientale, Novara, Italy
- * E-mail:
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25
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Roszkowski L, Jaszczyk B, Plebańczyk M, Ciechomska M. S100A8 and S100A12 Proteins as Biomarkers of High Disease Activity in Patients with Rheumatoid Arthritis That Can Be Regulated by Epigenetic Drugs. Int J Mol Sci 2022; 24:ijms24010710. [PMID: 36614150 PMCID: PMC9820830 DOI: 10.3390/ijms24010710] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that is still not well understood in terms of its pathogenesis and presents diagnostic and therapeutic challenges. Monocytes are key players in initiating and maintaining inflammation through the production of pro-inflammatory cytokines and S100 proteins in RA. This study aimed to test a specific DNA methylation inhibitor (RG108) and activator (budesonide) in the regulation of pro-inflammatory mediators-especially the S100 proteins. We also searched for new biomarkers of high disease activity in RA patients. RNA sequencing analysis of healthy controls (HCs) and RA monocytes was performed. Genes such as the S100 family, TNF, and IL-8 were validated by qRT-PCR following DNA-methylation-targeted drug treatment in a monocytic THP-1 cell line. The concentrations of the S100A8, S100A11, and S100A12 proteins in the sera and synovial fluids of RA patients were tested and correlated with clinical parameters. We demonstrated that RA monocytes had significantly increased levels of S100A8, S100A9, S100A11, S100A12, MYD88, JAK3, and IQGAP1 and decreased levels of IL10RA and TGIF1 transcripts. In addition, stimulation of THP-1 cells with budesonide statistically reduced the expression of the S100 family, IL-8, and TNF genes. In contrast, THP-1 cells treated with RG108 had increased levels of the S100 family and TNF genes. We also revealed a significant upregulation of S100A8, S100A11, and S100A12 in RA patients, especially in early RA compared to HC sera. In addition, protein levels of S100A8, S100A11, and S100A12 in RA synovial fluids compared to HC sera were significantly increased. Overall, our data suggest that the S100A8 and S100A12 proteins are strongly elevated during ongoing inflammation, so they could be used as a better biomarker of disease activity than CRP. Interestingly, epigenetic drugs can regulate these S100 proteins, suggesting their potential use in targeting RA inflammation.
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Affiliation(s)
- Leszek Roszkowski
- Department of Outpatient Clinics, National Institute of Geriatrics, Rheumatology and Rehabilitation (NIGRiR), 02-637 Warsaw, Poland
| | - Bożena Jaszczyk
- Department of Outpatient Clinics, National Institute of Geriatrics, Rheumatology and Rehabilitation (NIGRiR), 02-637 Warsaw, Poland
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation (NIGRiR), 02-637 Warsaw, Poland
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation (NIGRiR), 02-637 Warsaw, Poland
- Correspondence: ; Tel.: +48-22-670-95-63
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Gharavi AT, Hanjani NA, Movahed E, Doroudian M. The role of macrophage subtypes and exosomes in immunomodulation. Cell Mol Biol Lett 2022; 27:83. [PMID: 36192691 PMCID: PMC9528143 DOI: 10.1186/s11658-022-00384-y] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Macrophages are influential members of the innate immune system that can be reversibly polarized by different microenvironment signals. Cell polarization leads to a wide range of features, involving the migration, development, and organization of the cells. There is mounting evidence that macrophage polarization plays a key role in the initiation and development of a wide range of diseases. This study aims to give an overview of macrophage polarization, their different subtypes, and the importance of alternatively activated M2 macrophage and classically activated M1 macrophage in immune responses and pathological conditions. This review provides insight on the role of exosomes in M1/M2-like macrophage polarization and their potential as a promising therapeutic candidate.
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Affiliation(s)
- Abdulwahab Teflischi Gharavi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, 14911-15719, Iran
| | - Niloofar Asadi Hanjani
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, 14911-15719, Iran
| | - Elaheh Movahed
- Wadsworth Center, New York State Department of Health, Albany, New Year, USA
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, 14911-15719, Iran.
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27
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Xanthones from Securidaca inappendiculata Hassk. attenuate collagen-induced arthritis in rats by inhibiting the nicotinamide phosphoribosyltransferase/glycolysis pathway and macrophage polarization. Int Immunopharmacol 2022; 111:109137. [PMID: 36001918 DOI: 10.1016/j.intimp.2022.109137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/24/2022]
Abstract
Securidaca inappendiculata (SI) Hassk. is a traditional medicine used to treat rheumatoid arthritis. Recent studies have reported that macrophages are the primary regulators of joint homeostasis and their polarization is closely related to their metabolic mode. Here, we aimed to investigate the relationship between the joint protective effect of SI's xanthone-rich fraction (XRF) on collagen-induced arthritis (CIA) in rats and the nicotinamide phosphoribosyltransferase (NAMPT)-glycolysis-polarization axis of macrophages. CIA model rats were treated with oral XRF and therapeutic efficacy was assessed based on arthritis score, degree of paw swelling, histological examination, and immunohistochemical analysis. Serum levels of cytokines, cellular metabolite concentrations, and protein and mRNA expression were determined by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and quantitative real-time PCR (RT-qPCR), respectively. The effects of dihydroxy-3,4-dimethoxyxanthone (XAN), a representative SI-derived compound, on RAW264.7 macrophages was analyzed in vitro using confocal laser scanning and flow cytometry. We found that XRF treatment significantly alleviated disease severity in CIA model rats. Levels of pro-inflammatory cytokines in the serum and M1 markers in synovium were reduced after XRF treatment, accompanied by an increase in the levels of anti-inflammatory cytokines and M2 markers. Further, XRF significantly suppressed synovial glycolysis by regulating NAMPT. In vitro studies further showed that XAN induced repolarization of lipopolysaccharide (LPS)-induced RAW264.7 macrophages with M1-M2 phenotype. Moreover, XAN negatively regulated glycolysis in the LPS-induced RAW264.7 macrophages in correlation with changes in NAMPT expression. Overall, the findings of this study suggest that the joint protective effects of XRF are achieved by inhibiting the NAMPT/glycolysis pathway and thereby regulating macrophage polarization.
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28
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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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29
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Cutolo M, Campitiello R, Gotelli E, Soldano S. The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis. Front Immunol 2022; 13:867260. [PMID: 35663975 PMCID: PMC9161083 DOI: 10.3389/fimmu.2022.867260] [Citation(s) in RCA: 303] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/24/2022] [Indexed: 12/27/2022] Open
Abstract
Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.
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Affiliation(s)
- Maurizio Cutolo
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DIMI), University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Polyclinic Hospital, Genoa, Italy
| | - Rosanna Campitiello
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DIMI), University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Polyclinic Hospital, Genoa, Italy
| | - Emanuele Gotelli
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DIMI), University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Polyclinic Hospital, Genoa, Italy
| | - Stefano Soldano
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties (DIMI), University of Genova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Martino Polyclinic Hospital, Genoa, Italy
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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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Kim H, Back JH, Han G, Lee SJ, Park YE, Gu MB, Yang Y, Lee JE, Kim SH. Extracellular vesicle-guided in situ reprogramming of synovial macrophages for the treatment of rheumatoid arthritis. Biomaterials 2022; 286:121578. [PMID: 35594838 DOI: 10.1016/j.biomaterials.2022.121578] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/02/2022] [Accepted: 05/11/2022] [Indexed: 12/01/2022]
Abstract
Activation state of synovial macrophages is significantly correlated with disease activity and severity of rheumatoid arthritis (RA) and provides valuable clues for RA treatment. Classically activated M1 macrophages in inflamed synovial joints secrete high levels of pro-inflammatory cytokines and chemokines, resulting in bone erosion and cartilage degradation. Herein, we propose extracellular vesicle (EV)-guided in situ macrophage reprogramming toward anti-inflammatory M2 macrophages as a novel RA treatment modality based on the immunotherapeutic concept of reestablishing M1-M2 macrophage equilibrium in synovial tissue. M2 macrophage-derived EVs (M2-EVs) were able to convert activated M1 into reprogrammed M2 (RM2) macrophages with extremely high efficiency (>90%), producing a distinct protein expression pattern characteristic of anti-inflammatory M2 macrophages. In particular, M2-EVs were enriched for proteins known to be involved in the generation and migration of M2 macrophages as well as macrophage reprogramming factors, allowing for rapid and efficient driving of macrophage polarization toward M2 phenotype. After administration of M2-EVs into the joint of a collagen-induced arthritis mouse model, the synovial macrophage polarization was significantly shifted from M1 to M2 phenotype, a process that benefited greatly from the long residence time (>3 days) of M2-EVs in the joint. This superb in situ macrophage-reprogramming ability of EVs resulted in decreased joint swelling, arthritic index score and synovial inflammation, with corresponding reductions in bone erosion and articular cartilage damage and no systemic toxicity. The anti-RA effects of M2-EVs were comparable to those of the conventional disease-modifying antirheumatic drug, Methotrexate, which causes a range of toxic adverse effects, including gastrointestinal mucosal injury. Overall, our EV-guided reprogramming strategy for in situ tuning of macrophage responses holds great promise for the development of anti-inflammatory therapeutics for the treatment of various inflammatory diseases in addition to RA.
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Affiliation(s)
- Hyosuk Kim
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Ji Hyun Back
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea; Chemical & Biological integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Geonhee Han
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Su Jin Lee
- Chemical & Biological integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Yae Eun Park
- Chemical & Biological integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Man Bock Gu
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Yoosoo Yang
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Ji Eun Lee
- Chemical & Biological integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
| | - Sun Hwa Kim
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
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Chen Y, Liu K, Qin Y, Chen S, Guan G, Huang Y, Chen Y, Mo Z. Effects of Pereskia aculeate Miller Petroleum Ether Extract on Complete Freund’s Adjuvant-Induced Rheumatoid Arthritis in Rats and its Potential Molecular Mechanisms. Front Pharmacol 2022; 13:869810. [PMID: 35614946 PMCID: PMC9124934 DOI: 10.3389/fphar.2022.869810] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: To investigate the therapeutic effect of petroleum ether extract of P. aculeate Miller (PEEP) on rheumatoid arthritis (RA).Methods:In vitro: The Cell Counting Kit-8 (CCK-8) was used to detect cell activity and select the optimal concentration of the extract; the effective site was screened by nitric oxide (NO) colorimetric method and Q-PCR method; the expression of p38, p-p38, p-MK2, and Tristetraprolin (TTP) in RAW 264.7 cells were detected by Western blot. In vivo: The rat model was established by complete Freund’s adjuvant (CFA). The different doses of PEEP on CFA rats were observed with life status, paw swelling, spleen index, X-ray, Hematoxylin eosin (HE) staining; the secretion of Tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and Prostaglandin E2 (PGE2) were detected by Enzyme linked immunosorbent assay (ELISA); the expressions of p38, p-p38, p-MK2, and TTP in the ankle joints of CFA rats were detected by Western blot.Result:In vitro: PEEP, Ethyl Acetate Extract of P. aculeate Miller (EEEP), N-butanol Extract of P. aculeate Miller (BEEP) have no toxic effects on RAW264.7 macrophages. PEEP, EEEP, and BEEP reduce the secretion of NO in RAW264.7 cells induced by lipopolysaccharide (LPS), only PEEP significantly inhibited the mRNA expression levels of inflammatory factors TNF-α and IL-6; PEEP-dependently reduce the secretion of TNF-α and IL-6, decrease the expression of p-p38 and p-MK2, and the level of TTP phosphorylation in LPS-induced RAW264.7 cells. In vivo: PEEP improve the living conditions of CFA rats, reduce foot swelling, spleen index, bone surface erosion and joint space narrowing; reduce the formation of synovial cells, inflammatory cells and pannus in the foot and ankle joints. PEEP reduce the secretion of TNF-α, IL-6, PGE2 in rat serum, downregulate the expression of p-p38 and p-MK2 in the ankle joint, and reduce the phosphorylation of TTP.Conclusion: PEEP improve the living conditions of CFA rats, reduce the degree of foot swelling, protect immune organs, reduce inflammatory cell infiltration, cartilage damage, pannus formation, reduce inflammation and RA damage. The mechanism through regulating the signal pathway of p38 mitogen-activated protein kinase (p38/MAPK), which reduces the release of TNF-α, IL-6, and PGE2 in the serum.
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Affiliation(s)
- Yifei Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- School of Pharmacy, Guilin Medical University, Guilin, China
| | - Kaifei Liu
- School of Pharmacy, Guilin Medical University, Guilin, China
| | - Yingyuan Qin
- Nephrology, Guilin TCM Hospital of China, Guilin, China
| | - Suyi Chen
- School of Pharmacy, Guilin Medical University, Guilin, China
| | - Guokai Guan
- School of Pharmacy, Guilin Medical University, Guilin, China
| | - Yao Huang
- School of Pharmacy, Guilin Medical University, Guilin, China
| | - Yu Chen
- School of Pharmacy, Guilin Medical University, Guilin, China
- *Correspondence: Yu Chen, ; Zhixian Mo,
| | - Zhixian Mo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Yu Chen, ; Zhixian Mo,
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Wang J, Xue Y, Zhou L. Comparison of immune cells and diagnostic markers between spondyloarthritis and rheumatoid arthritis by bioinformatics analysis. J Transl Med 2022; 20:196. [PMID: 35509008 PMCID: PMC9066892 DOI: 10.1186/s12967-022-03390-y] [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: 02/24/2022] [Accepted: 04/09/2022] [Indexed: 12/19/2022] Open
Abstract
Background Spondyloarthritis (SpA) and rheumatoid arthritis (RA) are chronic autoimmune diseases, but they are usually difficult to distinguish in the early stage of the diseases. The purpose of this study is to explore the differences of immune mechanism and diagnostic markers through bioinformatics analysis. Methods First, microarray datasets from patients with SpA, RA and normal controls were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between groups were identified in R software. Functional and pathway enrichment of DEGs were analyzed by David database. Then, we screened the hub genes using Cytoscape plugin, and constructed the protein–protein interaction (PPI) network and heatmap of hub genes. After that, CIBERSORT was used to evaluate the differences and connections of immune cells in SpA and RA, and screened out diagnostic markers. Correlation analysis was used to analyze the relationship between immune cells and diagnostic markers. Finally, quantitative real-time polymerase chain reaction (qRT‐PCR) was used to verify the effectiveness of immunodiagnostic markers. Results We obtained three datasets, from which we can see that the functional enrichment of DEGs is mainly in cell chemotaxis, lymphocyte activation, primary immunodeficiency and other immune responses. The difference of immune cells between SpA, RA and normal control was concentrated in B, T lymphocytes cells, macrophages and dendritic cells. C19orf12 + S1PR3 is most associated with these immune cells and S1PR3 can be used as a diagnostic marker of this kind of immune diseases. In addition, MZB1 + XIST is closely related to T cells, NK cells and dendritic cells, and is expected to be used as a marker to distinguish the two diseases. Conclusion Although the clinical manifestations of SpA and RA are similar, the pathogenesis is different. The screening of immune cells and diagnostic markers provides a more accurate target for the treatment of this kind of diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03390-y.
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Affiliation(s)
- Jiaqian Wang
- Department of Orthopaedic, Wuxi No.5 People's Hospital, Wuxi, 214000, China.
| | - Yuan Xue
- Department of Orthopaedic, Wuxi Ninth People's Hospital of Soochow University, Wuxi, 214000, China
| | - Liang Zhou
- Department of Orthopaedic, Lianshui County Hospital, Huai'an, 223001, 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 T 1-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] [Key Words] [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 r 2/r 1 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
| | - 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
| | - Quan Zhou
- Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - 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
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Sun P, Su J, Wang X, Zhou M, Zhao Y, Gu H. Nucleic Acids for Potential Treatment of Rheumatoid Arthritis. ACS APPLIED BIO MATERIALS 2022; 5:1990-2008. [PMID: 35118863 DOI: 10.1021/acsabm.1c01205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Rheumatoid arthritis (RA) is a common systemic inflammatory autoimmune disease that severely affects the life quality of patients. Current therapeutics in clinic mainly focus on alleviating the development of RA or relieving the pain of patients. The emerging biological disease-modifying antirheumatic drugs (DMARDs) require long-term treatment to achieve the expected efficacy. With the development of bionanotechnology, nucleic acids fulfill characters as therapeutics or nanocarriers and can therefore be alternatives to combat RA. This review summarizes the therapeutic RNAs developed through RNA interference (RNAi), nucleic acid aptamers, DNA nanostructures-based drug delivery systems, and nucleic acid vaccines for the applications in RA therapy and diagnosis. Furthermore, prospects of nucleic acids for RA therapy are intensively discussed as well.
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Affiliation(s)
- Pengchao Sun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Jingjing Su
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Xiaonan Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Mo Zhou
- Fudan University Shanghai Cancer Center, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Stomatological Hospital, Fudan University, Shanghai 200433, China
| | - Yongxing Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Hongzhou Gu
- Fudan University Shanghai Cancer Center, and the Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Stomatological Hospital, Fudan University, Shanghai 200433, China
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Crum RJ, Hall K, Molina CP, Hussey GS, Graham E, Li H, Badylak SF. Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis. NPJ Regen Med 2022; 7:13. [PMID: 35110573 PMCID: PMC8810774 DOI: 10.1038/s41536-022-00208-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.
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Affiliation(s)
- Raphael J Crum
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA
| | - Kelsey Hall
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA
| | - Catalina Pineda Molina
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA.,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - George S Hussey
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA.,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.,ECM Therapeutics, Inc., 118 Marshall Dr., Warrendale, PA, 15086, USA
| | - Emma Graham
- Musculoskeletal Growth and Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, 450 Technology Drive, Suite 206, Pittsburgh, PA, 15219, USA
| | - Hongshuai Li
- Department of Orthopedics and Rehabilitation, University of Iowa, 25 Grand Ave, Iowa City, IA, 52246, USA
| | - Stephen F Badylak
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA, 15219, USA. .,Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA, 15213, USA. .,ECM Therapeutics, Inc., 118 Marshall Dr., Warrendale, PA, 15086, USA. .,Department of Bioengineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15261, USA.
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Qin L, Wang H, Zhao C, Chen C, Chen H, Li X, Wang J, Hu N, Huang W. Serum and Synovial Biomarkers for Distinguishing Between Chronic Periprosthetic Joint Infections and Rheumatoid Arthritis: A Prospective Cohort Study. J Arthroplasty 2022; 37:342-346. [PMID: 34555458 DOI: 10.1016/j.arth.2021.09.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 09/01/2021] [Accepted: 09/13/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Inflammatory responses in patients with active rheumatoid arthritis (RA) may lead to the current serum and synovial fluid biomarkers that misidentify chronic periprosthetic joint infection (PJI). We sought to investigate the expression of serum and synovial biomarkers in patients with active RA and to calculate thresholds for valuable biomarkers that distinguish between chronic PJI and active RA. METHODS This prospective study was initiated to enroll 70 patients undergoing revision arthroplasty from January 2019 to January 2021, and 30 patients with active RA cumulative knee from August 2020 to March 2021. The Musculoskeletal Infection Society definition of PJI was utilized for the classification of cases as aseptic or infected. Serum d-dimer, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6 (IL-6), as well as synovial IL-6, percentage of polymorphonuclear neutrophils, and CD64 index level were measured preoperatively. RESULTS An increase in biomarker concentrations were observed in group C (active RA). Synovial fluid CD64 index exhibited good discriminatory power between group B (chronic PJI) and group C with an area under curve of 0.930. For the diagnosis of chronic PJI in the presence of active RA, the optimal threshold value of synovial CD64 index was 0.87, with a sensitivity of 82.86% and a specificity of 93.33%. CONCLUSION Current serum biomarkers (erythrocyte sedimentation rate, C-reactive protein, IL-6, and d-dimer) did not apply to the diagnosis of suspected PJI with active RA. Fortunately, satisfactory results can be achieved by adjusting the threshold of synovial fluid biomarkers.
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Affiliation(s)
- Leilei Qin
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hai Wang
- Department of Orthopaedics, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Chen Zhao
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Chen
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Chen
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xinyu Li
- Department of pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiawei Wang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Hu
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Huang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Jang S, Kwon EJ, Lee JJ. Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells. Int J Mol Sci 2022; 23:ijms23020905. [PMID: 35055087 PMCID: PMC8780115 DOI: 10.3390/ijms23020905] [Citation(s) in RCA: 242] [Impact Index Per Article: 80.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated with synovial tissue proliferation, pannus formation, cartilage destruction, and systemic complications. Currently, advanced understandings of the pathologic mechanisms of autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies that cause RA have been achieved, despite the fact that much remains to be elucidated. This review provides an updated pathogenesis of RA which will unveil novel therapeutic targets.
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Affiliation(s)
- Sunhee Jang
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.J.); (E.-J.K.)
- Yonsei Hangang Hospital, 25 Mapodaero, Mapogu, Seoul 04167, Korea
| | - Eui-Jong Kwon
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.J.); (E.-J.K.)
- Chemical, Biological, Radiological, and Nuclear (CBRN) Defense Research Institute, Armed Forces CBRN Defense Command, Seoul 06591, Korea
| | - Jennifer Jooha Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.J.); (E.-J.K.)
- Correspondence: ; Tel.: +82-2-2258-6010; Fax: +82-2-2258-2022
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Gouveia VM, Rizzello L, Vidal B, Nunes C, Poma A, Lopez‐Vasquez C, Scarpa E, Brandner S, Oliveira A, Fonseca JE, Reis S, Battaglia G. Targeting Macrophages and Synoviocytes Intracellular Milieu to Augment Anti‐Inflammatory Drug Potency. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202100167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Virgínia M. Gouveia
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
- SomaServe Ltd Babraham Research Campus Cambridge CB22 3AT UK
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
- Abel Salazar Biomedical Sciences Institute University of Porto Porto 4050‐313 Portugal
| | - Loris Rizzello
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute for Bioengineering of Catalonia (IBEC) The Barcelona Institute of Science and Technology Barcelona 08028 Spain
- Department of Pharmaceutical Sciences University of Milan Milan 20133 Italy
- National Institute of Molecular Genetics (INGM) Milan 20122 Italy
| | - Bruno Vidal
- Rheumatology Research Unit Institute of Molecular Medicine – IMM João Lobo Antunes Faculty of Medicine University of Lisbon Lisbon 1649‐028 Portugal
| | - Claudia Nunes
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
| | - Alessandro Poma
- Department of Chemistry University College London London WC1H 0AJ UK
- Division of Biomaterials and Tissue Engineering Eastman Dental Institute Royal Free Hospital UCL Medical School London NW3 2PF UK
| | - Ciro Lopez‐Vasquez
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
| | - Edoardo Scarpa
- Department of Chemistry University College London London WC1H 0AJ UK
- Department of Pharmaceutical Sciences University of Milan Milan 20133 Italy
- National Institute of Molecular Genetics (INGM) Milan 20122 Italy
| | - Sebastian Brandner
- Department of Neurodegenerative Disease Queen Square Institute of Neurology University College London London WC1N 3BG UK
| | - António Oliveira
- Abel Salazar Biomedical Sciences Institute University of Porto Porto 4050‐313 Portugal
| | - João E. Fonseca
- Rheumatology Research Unit Institute of Molecular Medicine – IMM João Lobo Antunes Faculty of Medicine University of Lisbon Lisbon 1649‐028 Portugal
- Serviço de Reumatologia Centro Hospitalar Universitário Lisboa Norte Centro Academico de Medicina de Lisboa Lisbon 1649‐028 Portugal
| | - Salette Reis
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
| | - Giuseppe Battaglia
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
- Institute for Bioengineering of Catalonia (IBEC) The Barcelona Institute of Science and Technology Barcelona 08028 Spain
- Catalan Institution for Research and Advanced Studies (ICREA) Barcelona 08010 Spain
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Cao Y, Liu J, Huang C, Tao Y, Wang Y, Chen X, Huang D. Wilforlide A ameliorates the progression of rheumatoid arthritis by inhibiting M1 macrophage polarization. J Pharmacol Sci 2022; 148:116-124. [PMID: 34924115 DOI: 10.1016/j.jphs.2021.10.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/27/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease with increased M1 macrophages. The classical activated M1 macrophages produce various cytokines to control inflammation. Wilforlide A is a natural product that displays anti-inflammatory activities. However, the effect of Wilforlide A on RA progression and the potential mechanisms are unclear. Herein, the collagen-induced arthritis (CIA) mouse was used as an experimental model of RA. The administration of Wilforlide A reduced clinical scores, joint swelling and histological damage in ankle joints of RA mice. The secreted pro-inflammatory factors (MCP1, GM-CSF and M-CSF) and M1 biomarker iNOS in synovium were inhibited by Wilforlide A. In vitro, macrophages deriving from THP-1 cells were stimulated with LPS/IFN-γ to mimic M1 polarization. Similarly, Wilforlide A blocked macrophages polarizing towards M1 subsets. The in vitro results demonstrated that Wilforlide A suppressed LPS/IFN-γ-induced TLR4 upregulation, IκBα degradation and NF-κB p65 activation. In addition, TAK242 (a TLR4 inhibitor) treatment caused a similar inhibitory effect on M1 polarization with Wilforlide A, whereas it was less than the combination of TAK242 and Wilforlide A. Therefore, this work supports that Wilforlide A ameliorates M1 macrophage polarization in RA, which is partially mediated by TLR4/NF-κB signaling pathway inactivation.
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Affiliation(s)
- Yunxiang Cao
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
| | - Jian Liu
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China.
| | - Chuanbing Huang
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
| | - Yanhong Tao
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
| | - Yuan Wang
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
| | - Xi Chen
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
| | - Dan Huang
- Department of Rheumatology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (TCM), Hefei, Anhui, 230031, China
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Yu Y, Wang Z, Yang Q, Ding Q, Wang R, Li Z, Fang Y, Liao J, Qi W, Chen K, Li M, Zhu YZ. A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats. Drug Deliv 2021; 28:1031-1042. [PMID: 34060389 PMCID: PMC8172227 DOI: 10.1080/10717544.2021.1921075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 12/29/2022] Open
Abstract
PURPOSE S-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H2S) donor, could elevate H2S levels via the cystathionine γ-lyase (CSE)/H2S pathway both in vitro and in vivo. However, the immediate release of H2S in vivo and daily administration of SPRC potentially limited its clinical use. METHODS To solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H2S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied. RESULTS The spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H2S in a sustained manner through CSE/H2S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed. CONCLUSIONS A sustained H2S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H2S releasing donor might be of good use for the treatment of AIA.
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Affiliation(s)
- Yue Yu
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Zhou Wang
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Qinyan Yang
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Qian Ding
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Ran Wang
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Zhaoyi Li
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Yudong Fang
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Junyi Liao
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Wei Qi
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Keyuan Chen
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Meng Li
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
| | - Yi Zhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, Macau University of Science and Technology, Taipa, China
- Shanghai Key Laboratory of Bioactive Small Molecules & School of Pharmacy, Fudan University, Shanghai, China
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Jian L, Li C, Wang X, Sun L, Ma Z, Zhao J. IL-21 impairs pro-inflammatory activity of M1-like macrophages exerting anti-inflammatory effects on rheumatoid arthritis. Autoimmunity 2021; 55:75-85. [PMID: 34842006 DOI: 10.1080/08916934.2021.2007374] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Objective：Macrophages are the main source of inflammatory mediators and play important roles in the pathogenesis of rheumatoid arthritis (RA). Interleukin-21 (IL-21) regulates both innate and adaptive immune responses and exerts major effects on inflammatory responses that promote the development of RA. However, its effect on macrophage polarisation remains unclear.Methods：CD14+ monocytes of the peripheral blood of Human healthy donors (HD) and RA, and macrophages of RA synovial fluid (RA-SF MΦs) were isolated. IL-21 receptor (IL-21R) was detected by flow cytometry. Cytokine production by MΦs from different sources pre-treated with IL-21 and/or LPS was measured by real-time polymerase chain reaction (RT-PCR) and ELISA. CD14+ monocytes were differentiated into M1-like and M2-like macrophages via stimulation with GM-CSF, interferon-γ (IFN-γ), and LPS or M-CSF, IL-4, and IL-13, respectively. To determine the effect of IL-21 on macrophage polarisation, macrophage phenotypes, gene expression, and cytokine secretion were detected by flow cytometry, RT-PCR, and ELISA. TLR4 and ERK1/2 were determined by western blotting.Results：IL-21 exerted different effects on LPS-mediated inflammatory responses in various derived MΦs, and inhibited macrophages polarisation to M1-like macrophages and promote their polarisation to M2-like macrophages in HD and RA. Moreover, IL-21 inhibited LPS-mediated secretion of inflammatory cytokines, probably by downregulating the ERK1/2, in RA-SF MΦs.Conclusion：For the first time, we indicated that IL-21 inhibits LPS-mediated cytokine production in RA-SF MΦs, and impairs pro-inflammatory activity of M1-like macrophages, hereby exerting anti-inflammatory effects on RA. Thus, IL-21 might not be an appropriate therapeutic target for RA.
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Affiliation(s)
- Leilei Jian
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China.,Department of Rheumatology and Immunology, Huadong Hospital affiliated to Fudan University, Shanghai, China
| | - Changhong Li
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Xinyu Wang
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Lin Sun
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Zhenzhen Ma
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Jinxia Zhao
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
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Zhao G, Ren R, Wei X, Jia Z, Chen N, Sun Y, Zhao Z, Lele SM, Zhong HA, Goldring MB, Goldring SR, Wang D. Thermoresponsive polymeric dexamethasone prodrug for arthritis pain. J Control Release 2021; 339:484-497. [PMID: 34653564 PMCID: PMC8599655 DOI: 10.1016/j.jconrel.2021.10.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022]
Abstract
Intra-articular (IA) glucocorticoids (GC) are commonly used for clinical management of both osteoarthritis and rheumatoid arthritis, but their efficacy is limited by the relatively short duration of action and associated side effects. To provide sustained efficacy and to improve the safety of GCs, we previously developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug. Serendipitously, we discovered that, by increasing the Dex content of the prodrug to unusually high levels, the aqueous solution of the polymeric prodrug becomes thermoresponsive, transitioning from a free-flowing liquid at 4 °C to a hydrogel at 30 °C or greater. Upon IA injection, the prodrug solution forms a hydrogel (ProGel-Dex) that is retained in the joint for more than 1 month, where it undergoes gradual dissolution, releasing the water-soluble polymeric prodrug. The released prodrug is swiftly internalized and intracellularly processed by phagocytic synoviocytes to release free Dex, resulting in sustained amelioration of joint inflammation and pain in rodent models of inflammatory arthritis and osteoarthritis. The low molecular weight (6.8 kDa) of the ProGel-Dex ensures rapid renal clearance once it escapes the joint, limiting systemic GC exposure and risk of potential off-target side effects. The present study illustrates the translational potential of ProGel-Dex as a potent opioid-sparing, locally delivered adjuvant analgesic for sustained clinical management of arthritis pain and inflammation. Importantly, the observed thermoresponsive properties of the prodrug establishes ProGel as a platform technology for the local delivery of a broad spectrum of therapeutic agents to treat a diverse array of pathological conditions.
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Affiliation(s)
- Gang Zhao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Ensign Pharmaceutical, Inc., Omaha, NE 68106, USA
| | - Rongguo Ren
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xin Wei
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Zhenshan Jia
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ningrong Chen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Yuanyuan Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Zhifeng Zhao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Subodh M Lele
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5900, USA
| | - Haizhen A Zhong
- Department of Chemistry, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | | | - Steven R Goldring
- Ensign Pharmaceutical, Inc., Omaha, NE 68106, USA; Hospital for Special Surgery, New York, NY 10021, USA
| | - Dong Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Ensign Pharmaceutical, Inc., Omaha, NE 68106, USA; Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Dissecting the Molecular Mechanism of Wang-Bi Capsule in the Treatment of Experimental Rheumatoid Arthritis Based on Synovial Tissue Proteomic Analysis. J Immunol Res 2021; 2021:5539008. [PMID: 34708132 PMCID: PMC8545597 DOI: 10.1155/2021/5539008] [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: 01/20/2021] [Accepted: 09/24/2021] [Indexed: 11/30/2022] Open
Abstract
Wang-Bi capsule (WB) is a traditional Chinese medicine formula and has been applied for rheumatoid arthritis (RA) treatment for many years. However, its underlying molecular mechanisms still remain unclear. In this study, collagen-induced arthritis (CIA) rats were used to observe the therapeutic effect of WB used at different time points, and the proteomic analysis of synovial tissue was applied to reveal its basic molecular mechanisms. The results demonstrated that WB not only effectively ameliorated the symptoms and synovitis, but also downregulated the serum levels of inflammatory cytokines/chemokines in CIA rats. Furthermore, the proteomic analysis of synovial tissue showed that WB could regulate several signaling pathways associated with inflammation or cell migration, such as “IL-1 signaling,” “IL-8 signaling,” and “CXCR4 signaling.” The expression levels of proteins including matrix metalloproteinase 3 (MMP3), MMP19, lipopolysaccharide-binding protein (LBP), serine/threonine kinase interleukin-1 receptor-associated kinase 4 (IRAK4), and actin-related protein 2/3 complex subunit 5 (ARPC5) in these pathways were downregulated significantly by WB when compared with the model group. In sum, this study indicated that WB had obvious inhibitory effects on synovitis of CIA rats, and the mechanisms of which may be involved in downregulating the expression levels of several key proteins including MMP3, MMP19, LBP, IRAK4, and ARPC5.
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Rothbauer M, Byrne RA, Schobesberger S, Olmos Calvo I, Fischer A, Reihs EI, Spitz S, Bachmann B, Sevelda F, Holinka J, Holnthoner W, Redl H, Toegel S, Windhager R, Kiener HP, Ertl P. Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research. LAB ON A CHIP 2021; 21:4128-4143. [PMID: 34505620 DOI: 10.1039/d1lc00130b] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Rheumatoid arthritis is characterised by a progressive, intermittent inflammation at the synovial membrane, which ultimately leads to the destruction of the synovial joint. The synovial membrane as the joint capsule's inner layer is lined with fibroblast-like synoviocytes that are the key player supporting persistent arthritis leading to bone erosion and cartilage destruction. While microfluidic models that model molecular aspects of bone erosion between bone-derived cells and synoviocytes have been established, RA's synovial-chondral axis has not yet been realised using a microfluidic 3D model based on human patient in vitro cultures. Consequently, we established a chip-based three-dimensional tissue coculture model that simulates the reciprocal cross talk between individual synovial and chondral organoids. When co-cultivated with synovial organoids, we could demonstrate that chondral organoids induce a higher degree of cartilage physiology and architecture and show differential cytokine response compared to their respective monocultures highlighting the importance of reciprocal tissue-level cross talk in the modelling of arthritic diseases.
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Affiliation(s)
- Mario Rothbauer
- Karl Chiari Lab for Orthopaedic Biology (KCLOB), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Ruth A Byrne
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
- Division of Rheumatology, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Silvia Schobesberger
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Isabel Olmos Calvo
- Division of Rheumatology, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Anita Fischer
- Karl Chiari Lab for Orthopaedic Biology (KCLOB), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
- Division of Rheumatology, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
- Ludwig Boltzmann Institute of Arthritis and Rehabilitation, Vienna, Austria
| | - Eva I Reihs
- Karl Chiari Lab for Orthopaedic Biology (KCLOB), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Sarah Spitz
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
| | - Barbara Bachmann
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
- AUVA Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Florian Sevelda
- Division of Orthopedics, Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Johannes Holinka
- Division of Orthopedics, Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Wolfgang Holnthoner
- AUVA Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Heinz Redl
- AUVA Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Stefan Toegel
- Karl Chiari Lab for Orthopaedic Biology (KCLOB), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
- Ludwig Boltzmann Institute of Arthritis and Rehabilitation, Vienna, Austria
| | - Reinhard Windhager
- Karl Chiari Lab for Orthopaedic Biology (KCLOB), Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
- Division of Orthopedics, Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Hans P Kiener
- Division of Rheumatology, Department of Medicine III, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
| | - Peter Ertl
- Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
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Yu R, Zhang J, Zhuo Y, Hong X, Ye J, Tang S, Zhang Y. Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies. Front Immunol 2021; 12:724934. [PMID: 34691030 PMCID: PMC8526926 DOI: 10.3389/fimmu.2021.724934] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/17/2021] [Indexed: 01/07/2023] Open
Abstract
Background Rheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society. Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. In the present study, the aim was at examining RA's diagnostic signatures and the effect of immune cell infiltration in this pathology. Methods Gene Expression Omnibus (GEO) database provided three datasets of gene expressions. Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses. Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA's diagnostic signatures and further verify by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells. Results On the whole, 54 robust DEGs received the recognition. Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA's diagnostic markers and showed their statistically significant difference by qRT-PCR. As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA. Additionally, all diagnostic signatures might be different degrees of correlation with immune cells. Conclusions In conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.
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Affiliation(s)
- Rongguo Yu
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Jiayu Zhang
- School of Clinical Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Youguang Zhuo
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Xu Hong
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Jie Ye
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Susu Tang
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Yiyuan Zhang
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Xiamen University, Xiamen, China
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Ross EA, Devitt A, Johnson JR. Macrophages: The Good, the Bad, and the Gluttony. Front Immunol 2021; 12:708186. [PMID: 34456917 PMCID: PMC8397413 DOI: 10.3389/fimmu.2021.708186] [Citation(s) in RCA: 246] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/27/2021] [Indexed: 12/16/2022] Open
Abstract
Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.
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Affiliation(s)
- Ewan A Ross
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, United Kingdom
| | - Andrew Devitt
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, United Kingdom
| | - Jill R Johnson
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, United Kingdom
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Fu W, Hu W, Yi YS, Hettinghouse A, Sun G, Bi Y, He W, Zhang L, Gao G, Liu J, Toyo-Oka K, Xiao G, Solit DB, Loke P, Liu CJ. TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity. J Clin Invest 2021; 131:e144016. [PMID: 34185706 DOI: 10.1172/jci144016] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 06/25/2021] [Indexed: 12/13/2022] Open
Abstract
TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.
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Affiliation(s)
- Wenyu Fu
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Wenhuo Hu
- Human Oncology and Pathogenesis Program and Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Young-Su Yi
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Aubryanna Hettinghouse
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Guodong Sun
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Yufei Bi
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Wenjun He
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Lei Zhang
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Guanmin Gao
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Jody Liu
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA
| | - Kazuhito Toyo-Oka
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Guozhi Xiao
- Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China
| | - David B Solit
- Human Oncology and Pathogenesis Program and Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Png Loke
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USA
| | - Chuan-Ju Liu
- Department of Orthopedic Surgery, New York University Grossman School of Medicine, New York, New York, USA.,Department of Cell Biology, New York University Grossman School of Medicine, New York, New York, USA
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49
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Targeted delivery of mPGES-1 inhibitors to macrophages via the folate receptor-β for inflammatory pain. Bioorg Med Chem Lett 2021; 50:128313. [PMID: 34390827 DOI: 10.1016/j.bmcl.2021.128313] [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: 03/26/2021] [Revised: 07/27/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E2 (PGE2). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation despite their well-known toxicity. New NSAIDs target an enzyme downstream of COXs, microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of mPGES-1 in inflammatory macrophages promises to retain NSAID efficacy while limiting toxicity. We conjugated a potent mPGES-1 inhibitor, MK-7285, to folate, but the construct released the drug inefficiently. Folate conjugation to the primary alcohol of MK-7285 improved the construct's stability and the release of free drug. Surprisingly, the drug-folate conjugate potentiated PGE2 in FR-positive KB cells, and reduced PGE2 in macrophages independently of the FR. Folate conjugation of NSAIDs is not an optimal strategy for targeting of macrophages.
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Folate receptor-targeting semiconducting polymer dots hybrid mesoporous silica nanoparticles against rheumatoid arthritis through synergistic photothermal therapy, photodynamic therapy, and chemotherapy. Int J Pharm 2021; 607:120947. [PMID: 34358541 DOI: 10.1016/j.ijpharm.2021.120947] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/09/2021] [Accepted: 07/22/2021] [Indexed: 12/31/2022]
Abstract
With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity.
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