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Zhang Q, Zhao YX, Li LF, Fan QQ, Huang BB, Du HZ, Li C, Li W. Metabolism-Related Adipokines and Metabolic Diseases: Their Role in Osteoarthritis. J Inflamm Res 2025; 18:1207-1233. [PMID: 39886385 PMCID: PMC11780177 DOI: 10.2147/jir.s499835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/31/2024] [Indexed: 02/01/2025] Open
Abstract
Osteoarthritis (OA) affects several joints but tends to be more prevalent in those that are weight-bearing, such as the knees, which are the most heavily loaded joints in the body. The incidence and disability rates of OA have continued to increase and seriously jeopardise the quality of life of middle-aged and older adults. However, OA is more than just a wear and tear disease; its aetiology is complex, and its pathogenesis is poorly understood. Metabolic syndrome (MetS) has emerged as a critical driver of OA development. This condition contributes to the formation of a distinct phenotype, termed metabolic syndrome-associated osteoarthritis (MetS-OA),which differs from other metabolically related diseases by its unique pathophysiological mechanisms and clinical presentation. As key mediators of MetS, metabolic adipokines such as leptin, lipocalin, and resistin regulate inflammation and bone metabolism through distinct or synergistic signaling pathways. Their modulation of inflammatory responses and bone remodeling processes plays a critical role in the pathogenesis and progression of OA. Due to their central role in regulating inflammation and bone remodeling, metabolic adipokines not only deepen our understanding of MetS-OA pathogenesis but also represent promising targets for novel therapeutic strategies that could slow disease progression and improve clinical outcomes in affected patients.
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Affiliation(s)
- Qian Zhang
- School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, Shandong, People’s Republic of China
| | - Yi Xuan Zhao
- School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, Shandong, People’s Republic of China
| | - Long Fei Li
- Cerebrovascular Disease Ward, The First People’s Hospital of Ping Ding Shan, Pingdingshan, Henan, People’s Republic of China
| | - Qian Qian Fan
- Department of Rehabilitation Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
| | - Bin Bin Huang
- School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, Shandong, People’s Republic of China
| | - Hong Zhen Du
- School of Special Education and Rehabilitation, Binzhou Medical University, Yantai, Shandong, People’s Republic of China
| | - Chen Li
- Department of Rehabilitation Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
| | - Wei Li
- Department of Rehabilitation Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China
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Li J, Wu Z, Wu Y, Hu X, Yang J, Zhu D, Wu M, Li X, Bentum-Ennin L, Wanglai H. IL-22, a vital cytokine in autoimmune diseases. Clin Exp Immunol 2024; 218:242-263. [PMID: 38651179 PMCID: PMC11557150 DOI: 10.1093/cei/uxae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/05/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024] Open
Abstract
Interleukin-22 (IL-22) is a vital cytokine that is dysregulated in various autoimmune conditions including rheumatoid arthritis (RA), multiple sclerosis (MS), and Alzheimer's disease (AD). As the starting point for the activation of numerous signaling pathways, IL-22 plays an important role in the initiation and development of autoimmune diseases. Specifically, imbalances in IL-22 signaling can interfere with other signaling pathways, causing cross-regulation of target genes which ultimately leads to the development of immune disorders. This review delineates the various connections between the IL-22 signaling pathway and autoimmune disease, focusing on the latest understanding of the cellular sources of IL-22 and its effects on various cell types. We further explore progress with pharmacological interventions related to targeting IL-22, describing how such therapeutic strategies promise to usher in a new era in the treatment of autoimmune disease.
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Affiliation(s)
- Jiajin Li
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Zhen Wu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Yuxin Wu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - XinYu Hu
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Jun Yang
- The Second Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Dacheng Zhu
- The First Clinical School of Medicine, Anhui Medical University, Hefei, China
| | - Mingyue Wu
- The School of pharmacy, Anhui Medical University, Hefei, China
| | - Xin Li
- The School of pharmacy, Anhui Medical University, Hefei, China
| | | | - Hu Wanglai
- The School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Cimini M, Hansmann UHE, Gonzalez C, Chesney AD, Truongcao MM, Gao E, Wang T, Roy R, Forte E, Mallaredy V, Thej C, Magadum A, Joladarashi D, Benedict C, Koch WJ, Tükel Ç, Kishore R. Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.28.601297. [PMID: 39005419 PMCID: PMC11244852 DOI: 10.1101/2024.06.28.601297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Background Amyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. Methods Using wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts. Results Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSC PDPN+ communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSC PDPN+ derived exosomes (MSC PDPN+ Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSC PDPN+ exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI. Conclusion Overall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition. NOVELTY AND SIGNIFICANCE What is known? Accumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility.After myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells.Amyloid structures can accumulate in the heart after chronic inflammatory conditions. What information does this article contribute? Whether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated.The pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated.Amyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established. SUMMARY OF NOVELTY AND SIGNIFICANCE Here, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, "DRI-R5S," specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.
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Wu Q, Sheng Q, Michell D, Ramirez-Solano M, Posey O, Phothisane A, Shaik S, Vickers KC, Ormseth MJ. Anti-Inflammatory Effect of High-Density Lipoprotein Blunted by Delivery of Altered MicroRNA Cargo in Patients With Rheumatoid Arthritis. Arthritis Rheumatol 2024; 76:684-695. [PMID: 38111131 PMCID: PMC11045320 DOI: 10.1002/art.42782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 11/02/2023] [Accepted: 12/13/2023] [Indexed: 12/20/2023]
Abstract
OBJECTIVE High-density lipoprotein (HDL) has well-characterized anti-atherogenic cholesterol efflux and antioxidant functions. Another function of HDL uncharacterized in rheumatoid arthritis (RA) is its ability to transport microRNAs (miRNAs) between cells and thus alter cellular function. The study's purpose was to determine if HDL-miRNA cargo is altered and affects inflammation in RA. METHODS HDL-microRNAs were characterized in 30 RA and 30 control participants by next generation sequencing and quantitative polymerase chain reaction. The most abundant differentially expressed miRNA was evaluated further. The function of miR-1246 was assessed by miRNA mimics, antagomiRs, small interfering RNA knockdown, and luciferase assays. Monocyte-derived macrophages were treated with miR-1246-loaded HDL and unmodified HDL from RA and control participants to measure delivery of miR-1246 and its effect on interleukin-6 (IL-6). RESULTS The most abundant miRNA on HDL was miR-1246; it was significantly enriched two-fold on HDL from RA versus control participants. HDL-mediated miR-1246 delivery to macrophages significantly increased IL6 expression 43-fold. miR-1246 delivery significantly decreased DUSP3 1.5-fold and DUSP3 small interfering RNA knockdown increased macrophage IL6 expression. Luciferase assay indicated DUSP3 is a direct target of miR-1246. Unmodified HDL from RA delivered 1.6-fold more miR-1246 versus control participant HDL. Unmodified HDL from both RA and control participants attenuated activated macrophage IL6 expression, but this effect was significantly blunted in RA so that IL6 expression was 3.4-fold higher after RA versus control HDL treatment. CONCLUSION HDL-miR-1246 was increased in RA versus control participants and delivery of miR-1246 to macrophages increased IL-6 expression by targeting DUSP3. The altered HDL-miRNA cargo in RA blunted HDL's anti-inflammatory effect.
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Affiliation(s)
- Qiong Wu
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quanhu Sheng
- Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | - Olivia Posey
- Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | | | - Michelle J Ormseth
- Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN USA
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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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Almusalami EM, Lockett A, Ferro A, Posner J. Serum amyloid A—A potential therapeutic target for hyper-inflammatory syndrome associated with COVID-19. Front Med (Lausanne) 2023; 10:1135695. [PMID: 37007776 PMCID: PMC10060655 DOI: 10.3389/fmed.2023.1135695] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 02/24/2023] [Indexed: 03/18/2023] Open
Abstract
Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated with COVID-19 is a complex interaction between infection and autoimmunity and elevation of SAA is strongly correlated with severity of the inflammation. In this review we highlight the involvement of SAA in these different inflammatory conditions, consider its potential role and discuss whether it could be a potential target for treatment of the hyperinflammatory state of COVID-19 with many potential advantages and fewer adverse effects. Additional studies linking SAA to the pathophysiology of COVID-19 hyper-inflammation and autoimmunity are needed to establish the causal relationship and the therapeutic potential of inhibitors of SAA activity.
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Affiliation(s)
- Eman M. Almusalami
- Centre for Pharmaceutical Medicine Research, King’s College London, London, United Kingdom
- *Correspondence: Eman M. Almusalami,
| | - Anthony Lockett
- Centre for Pharmaceutical Medicine Research, King’s College London, London, United Kingdom
| | - Albert Ferro
- Centre for Pharmaceutical Medicine Research, King’s College London, London, United Kingdom
- School of Cardiovascular and Metabolic Medicine and Sciences, British Heart Foundation Centre for Research Excellence, King’s College London, London, United Kingdom
| | - John Posner
- Centre for Pharmaceutical Medicine Research, King’s College London, London, United Kingdom
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Affiliation(s)
- Alberto Mantovani
- From IRCCS Humanitas Research Hospital, Rozzano, and the Department of Biomedical Sciences, Humanitas University, Pieve Emanuele - both in Milan (A.M., C.G.); and William Harvey Research Institute, Queen Mary University, London (A.M.)
| | - Cecilia Garlanda
- From IRCCS Humanitas Research Hospital, Rozzano, and the Department of Biomedical Sciences, Humanitas University, Pieve Emanuele - both in Milan (A.M., C.G.); and William Harvey Research Institute, Queen Mary University, London (A.M.)
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Avdeeva AS. Inflammatory markers in rheumatic diseases. RHEUMATOLOGY SCIENCE AND PRACTICE 2022. [DOI: 10.47360/1995-4484-2022-561-569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Immune-mediated rheumatic diseases (IMRDs) are a broad group of pathological conditions based on impaired immunological tolerance to one’s own tissues leading to inflammation and irreversible organ damage. Laboratory diagnosis of IMRDs includes a wide range of biomarkers (autoantibodies, acute phase proteins, cytokines, markers of endothelial damage, components of the complement system, immunoglobulins, cryoglobulins, lymphocyte subpopulations, indicators of bone metabolism, apoptosis markers, genetic markers, etc). One of the leading aspects of laboratory diagnosis of IMRDs is the study of the level of inflammation markers in the blood (erythrocyte sedimentation rate, C-reactive protein (CRP), serum amyloid protein (CAA), ferritin, procalcitonin, apolipoprotein AI, calprotectin, etc). The analysis of inflammation markers makes it possible to assess the disease activity, the nature of the progression and the prognosis of the outcomes of a chronic inflammatory process, as well as the effectiveness of the therapy. The review presents the latest data on the role of the most frequently studied inflammatory markers such as CRP, CAA and ferritin.
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Li Y, Ding Q, Gao J, Li C, Hou P, Xu J, Cao K, Hu M, Cheng L, Wang X, Yang X. Novel mechanisms underlying inhibition of inflammation-induced angiogenesis by dexamethasone and gentamicin via PI3K/AKT/NF-κB/VEGF pathways in acute radiation proctitis. Sci Rep 2022; 12:14116. [PMID: 35982137 PMCID: PMC9388498 DOI: 10.1038/s41598-022-17981-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 08/03/2022] [Indexed: 11/09/2022] Open
Abstract
Acute radiation proctitis (ARP) is one of the most common complications of pelvic radiotherapy attributed to radiation exposure. The mechanisms of ARP are related to inflammation, angiogenesis, and so on. In this study we evaluated the effect of dexamethasone (DXM) combined with gentamicin (GM) enema on ARP mice, and explored its possible mechanisms by transcriptome sequencing, western blot and immunohistochemistry. C57BL/6 mice were randomly divided into 3 groups: healthy control group, ARP model group, and DXM + GM enema treatment group. ARP mice were established by using a single 6 MV X-ray dose of 27 Gy pelvic local irradiation. Transcriptome sequencing results showed that 979 genes were co-upregulated and 445 genes were co-downregulated in ARP mice compared to healthy mice. According to gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, we firstly found that PI3K/AKT/NF-κB/VEGF pathways were mostly correlated with the inflammation-induced angiogenesis in ARP mice. PI3K/AKT pathway leads to the activation of NF-κB, which promotes the transcription of VEGF and Bcl-2. Interestingly, symptoms and pathological changes of ARP mice were ameliorated by DXM + GM enema treatment. DXM + GM enema inhibited inflammation by downregulating NF-κB and upregulating AQP3, as well as inhibited angiogenesis by downregulating VEGF and AQP1 in ARP mice. Moreover, DXM + GM enema induced apoptosis by increasing Bax and suppressing Bcl-2. The novel mechanisms may be related to the downregulation of PI3K/AKT/NF-κB/VEGF pathways.
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Affiliation(s)
- Yousong Li
- Department of Traditional Chinese Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Qin Ding
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Jinsheng Gao
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China.,Ping An Healthcare and Technology Company Limited, Shanghai, 200032, China
| | - Chunxia Li
- Department of Geriatrics, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
| | - Pengxiao Hou
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Jie Xu
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Kaiqi Cao
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Min Hu
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Lin Cheng
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China
| | - Xixing Wang
- Department of Oncology, Shanxi Province Research Institute of Traditional Chinese Medicine, Taiyuan, 030012, China.
| | - Xiaoling Yang
- Department of Thoracic Oncology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
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Abstract
Rho guanosine triphosphatase (GTPases), as molecular switches, have been identified to be dysregulated and involved in the pathogenesis of various rheumatic diseases, mainly including rheumatoid arthritis, osteoarthritis, systemic sclerosis, and systemic lupus erythematosus. Downstream pathways involving multiple types of cells, such as fibroblasts, chondrocytes, synoviocytes, and immunocytes are mediated by activated Rho GTPases to promote pathogenesis. Targeted therapy via inhibitors of Rho GTPases has been implicated in the treatment of rheumatic diseases, demonstrating promising effects. In this review, the effects of Rho GTPases in the pathogenesis of rheumatic diseases are summarized, and the Rho GTPase-mediated pathways are elucidated. Therapeutic strategies using Rho GTPase inhibitors in rheumatic diseases are also discussed to provide insights for further exploration of targeted therapy in preclinical studies and clinical practice. Future directions on studies of Rho GTPases in rheumatic diseases based on current understandings are provided.
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Affiliation(s)
- Ruijie Zeng
- Department of Gastroenterology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China
- Shantou University Medical College, Shantou 515041, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Yujun Luo
- Department of Gastroenterology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- School of Medicine, South China University of Technology, Guangzhou 510006, China
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Jiang TT, Ji CF, Cheng XP, Gu SF, Wang R, Li Y, Zuo J, Han J. α-Mangostin Alleviated HIF-1α-Mediated Angiogenesis in Rats With Adjuvant-Induced Arthritis by Suppressing Aerobic Glycolysis. Front Pharmacol 2021; 12:785586. [PMID: 34987400 PMCID: PMC8721667 DOI: 10.3389/fphar.2021.785586] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
A previously validated anti-rheumatic compound α-mangostin (MAN) shows significant metabolism regulatory effects. The current study aimed to clarify whether this property contributed to its inhibition on synovial angiogenesis. Male wistar rats with adjuvant-induced arthritis (AIA) were orally treated by MAN for 32 days. Afterwards, biochemical parameters and cytokines in plasma were determined by corresponding kits, and glycometabolism-related metabolites were further accurately quantified by LC-MS method. Anti-angiogenic effects of MAN were preliminarily assessed by joints based-immunohistochemical examination and matrigel plug assay. Obtained results were then validated by experiments in vitro. AIA-caused increase in circulating transforming growth factor beta, interleukin 6, hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in blood and local HIF-1α/VEGF expression in joints was abrogated by MAN treatment, and pannus formation within matrigel plugs implanted in AIA rats was inhibited too. Scratch and transwell assays revealed the inhibitory effects of MAN on human umbilical vein endothelial cells (HUVECs) migration. Furthermore, MAN inhibited tubule formation capability of HUVECs and growth potential of rat arterial ring-derived endothelial cells in vitro. Meanwhile, MAN eased oxidative stress, and altered glucose metabolism in vivo. Glycolysis-related metabolites including glucose 6-phosphate, fructose 6-phosphate, 3-phosphoglyceric acid and phosphoenolpyruvic acid in AIA rats were decreased by MAN, while the impaired pyruvate-synthesizing capability of lactate dehydrogenase (LDH) was recovered. Consistently, MAN restored lipopolysaccharide-elicited changes on levels of glucose and LDH in HUVECs culture system, and exerted similar effects with LDH inhibitor stiripentol on glycometabolism and VEGF production as well as tubule formation capability of HUVECs. These evidences show that MAN treatment inhibited aerobic glycolysis in AIA rats, which consequently eased inflammation-related hypoxia, and hampered pathological neovascularization.
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Affiliation(s)
- Tian-Tian Jiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, China
| | - Chao-Fan Ji
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Xin’an Medicine Research Center, Wannan Medical College, Wuhu, China
| | - Xiu-Ping Cheng
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Xin’an Medicine Research Center, Wannan Medical College, Wuhu, China
| | - Shao-Fei Gu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Xin’an Medicine Research Center, Wannan Medical College, Wuhu, China
| | - Rui Wang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, China
| | - Yan Li
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Xin’an Medicine Research Center, Wannan Medical College, Wuhu, China
| | - Jian Zuo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
- Xin’an Medicine Research Center, Wannan Medical College, Wuhu, China
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China
| | - Jun Han
- Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, China
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12
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Moreira FRC, de Oliveira TA, Ramos NE, Abreu MAD, Simões E Silva AC. The role of renin angiotensin system in the pathophysiology of rheumatoid arthritis. Mol Biol Rep 2021; 48:6619-6629. [PMID: 34417705 DOI: 10.1007/s11033-021-06672-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/18/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND In rheumatoid arthritis (RA) and osteoarthritis (OA), chronic inflammatory processes lead to progresive joint destruction. The renin-angiotensin system (RAS) is involved in the pathogenesis of RA and OA. The aim of this mini-review article is to summarize evidence on the role of RAS in RA and OA. METHODS A non-systematic search in Pubmed included terms as "rheumatoid arthritis", "renin angiotensin system", "osteopenia", "RANKL", "DKK-1", "MMP", "inflammation", "angiogenesis", "local renin-angiotensin system", "angiotensin converting enzyme", "AT2 receptor", "Ang-(1-7)", "VEGF", "angiotensine receptor blocker", "angiotensin converting enzyme inhibitors", "renin inhibitors". RESULTS Both RAS axes, the classical one, formed by angiotensin converting enzyme (ACE), angiotensin (Ang) II and AT1 receptor (AT1R) and the counter-regulatory one, composed by ACE2, Ang-(1-7) and the Mas receptor, modulate inflammation and tissue damage. Ang II activates pro-inflammatory mediators and oxidative stress. Conversely, Ang-(1-7) exerts anti-inflammatory actions, decreasing cytokine release, leukocyte attraction, density of vessels, tissue damage and fibrosis. Angiogenesis facilitates inflammatory cells invasion, while osteopenia causes joint dysfunction. Up-regulated osteoclastogenisis and down-regulated osteoblastogeneses were associaed with the activation of the classical RAS axis. Three different pathways, RANKL, DKK-1 and MMPs are enhanced by classical RAS activation. The treatment of RA included methotrexate and corticosteroids, which can cause side effects. Studies with angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEi) and renin inhibitors have been conducted in experimental and clinical RA with promising results. CONCLUSION The classical RAS activation is an important mechanism in RA pathogenesis and the benefit of ARB and ACEi administration should be further investigated.
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Affiliation(s)
- Fernanda Rocha Chaves Moreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Tiago Almeida de Oliveira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Nádia Eliza Ramos
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Maria Augusta Duarte Abreu
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, room #281, Belo Horizonte, MG, 30130-100, Brazil.
- Department of Pediatrics, Faculty of Medicine, UFMG, Belo Horizonte, Brazil.
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13
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Lazari LC, Ghilardi FDR, Rosa-Fernandes L, Assis DM, Nicolau JC, Santiago VF, Dalçóquio TF, Angeli CB, Bertolin AJ, Marinho CR, Wrenger C, Durigon EL, Siciliano RF, Palmisano G. Prognostic accuracy of MALDI-TOF mass spectrometric analysis of plasma in COVID-19. Life Sci Alliance 2021; 4:e202000946. [PMID: 34168074 PMCID: PMC8321665 DOI: 10.26508/lsa.202000946] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 05/31/2021] [Accepted: 05/31/2021] [Indexed: 12/17/2022] Open
Abstract
SARS-CoV-2 infection poses a global health crisis. In parallel with the ongoing world effort to identify therapeutic solutions, there is a critical need for improvement in the prognosis of COVID-19. Here, we report plasma proteome fingerprinting that predict high (hospitalized) and low-risk (outpatients) cases of COVID-19 identified by a platform that combines machine learning with matrix-assisted laser desorption ionization mass spectrometry analysis. Sample preparation, MS, and data analysis parameters were optimized to achieve an overall accuracy of 92%, sensitivity of 93%, and specificity of 92% in dataset without feature selection. We identified two distinct regions in the MALDI-TOF profile belonging to the same proteoforms. A combination of SDS-PAGE and quantitative bottom-up proteomic analysis allowed the identification of intact and truncated forms of serum amyloid A-1 and A-2 proteins, both already described as biomarkers for viral infections in the acute phase. Unbiased discrimination of high- and low-risk COVID-19 patients using a technology that is currently in clinical use may have a prompt application in the noninvasive prognosis of COVID-19. Further validation will consolidate its clinical utility.
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Affiliation(s)
- Lucas Cardoso Lazari
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Livia Rosa-Fernandes
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - José Carlos Nicolau
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
| | - Veronica Feijoli Santiago
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Claudia B Angeli
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Claudio Rf Marinho
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Carsten Wrenger
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Edison Luiz Durigon
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Giuseppe Palmisano
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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14
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Serum Amyloid A Proteins and Their Impact on Metastasis and Immune Biology in Cancer. Cancers (Basel) 2021; 13:cancers13133179. [PMID: 34202272 PMCID: PMC8267706 DOI: 10.3390/cancers13133179] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/19/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The liver responds to systemic inflammation and injury in a coordinated manner, called the acute phase response. While this normal physiological response aims to restore homeostasis, malignant transformation coopts this biology to increase the risk for metastasis, immune evasion, and therapeutic resistance. In this Review, we discuss the importance of acute phase response proteins in regulating cancer biology and treatment efficacy. We also consider potential strategies to intervene on acute phase biology as an approach to improve outcomes in cancer. Abstract Cancer triggers the systemic release of inflammatory molecules that support cancer cell metastasis and immune evasion. Notably, this biology shows striking similarity to an acute phase response that is coordinated by the liver. Consistent with this, a role for the liver in defining cancer biology is becoming increasingly appreciated. Understanding the mechanisms that link acute phase biology to metastasis and immune evasion in cancer may reveal vulnerable pathways and novel therapeutic targets. Herein, we discuss a link between acute phase biology and cancer with a focus on serum amyloid A proteins and their involvement in regulating the metastatic cascade and cancer immunobiology.
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15
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Al-Ani M, Elemam NM, Hachim IY, Raju TK, Muhammad JS, Hachim MY, Bendardaf R, Maghazachi AA. Molecular Examination of Differentially Expressed Genes in the Brains of Experimental Autoimmune Encephalomyelitis Mice Post Herceptin Treatment. J Inflamm Res 2021; 14:2601-2617. [PMID: 34168483 PMCID: PMC8216756 DOI: 10.2147/jir.s310535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/22/2021] [Indexed: 11/23/2022] Open
Abstract
Objective Herceptin (trastuzumab) is an approved drug for treating HER2+ breast cancer patients, but its use for other diseases is not established. We sought to investigate the effects of Herceptin on ameliorating experimental autoimmune encephalomyelitis (EAE) and to examine its effects on the expression of various genes. Methods We used in-silico analysis of publicly available data, qRT-PCR, and immunohistochemistry (IHC) to determine the expression of HER2+ cells in the brains of EAE mice. IHC was also utilized to determine the anti-inflammatory effects of Herceptin. The ability of Herceptin to alleviate the EAE clinical score was measured in these mice. Bioinformatics analysis of publicly available data and qRT-PCR were performed to investigate the differentially expressed genes that were either up-regulated or down-regulated during the high clinical score (HCS) of the disease. Results We observed that HER2/Erbb2, the receptor for Herceptin is upregulated in the brains of EAE mice when the brains were examined at the HCS stage. Further, we demonstrated that Herceptin ameliorates the EAE disease, increasing re-myelination, reducing brain inflammation, CD3+ T cell accumulation, and HER2+ cells in the brains of these mice. Molecular analysis demonstrated the expression of different genes that were either up-regulated or down-regulated during the HCS of the disease. Our combined bioinformatics and qRT-PCR analyses show increased mRNA expression of Atp6v0d2, C3, C3ar1, Ccl3, Ccl6, Cd74, Clec7a, Cybb, H2-Aa, Hspb1, Lilr4b, Lilrb4a, Mpeg1, Ms4a4a, Ms4a6c, Saa3, Serpina3n and Timp1, at HCS. Except for the mRNA levels of Cd74 and Clec7a which were increased at HCS when Herceptin was used in both prophylactic and therapeutic regimens, the levels of other described mRNAs were reduced. Conclusion These novel findings show that Herceptin ameliorates the clinical score in EAE mice and are the first to investigate in detail the differential gene expression post-treatment with the drug.
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Affiliation(s)
- Mena Al-Ani
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,The Immuno-Oncology Group, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Noha Mousaad Elemam
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,The Immuno-Oncology Group, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Ibrahim Y Hachim
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Tom K Raju
- The Immuno-Oncology Group, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,The Immuno-Oncology Group, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
| | - Mahmood Y Hachim
- College of Medicine, Mohammed bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Riyad Bendardaf
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,University Hospital Sharjah, Sharjah, United Arab Emirates
| | - Azzam A Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,The Immuno-Oncology Group, Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates
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16
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Abouelasrar Salama S, Gouwy M, Van Damme J, Struyf S. The turning away of serum amyloid A biological activities and receptor usage. Immunology 2021; 163:115-127. [PMID: 33315264 PMCID: PMC8114209 DOI: 10.1111/imm.13295] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/24/2020] [Accepted: 12/04/2020] [Indexed: 12/21/2022] Open
Abstract
Serum amyloid A (SAA) is an acute-phase protein (APP) to which multiple immunological functions have been attributed. Regardless, the true biological role of SAA remains poorly understood. SAA is remarkably conserved in mammalian evolution, thereby suggesting an important biological function. Since its discovery in the 1970s, the majority of researchers have investigated SAA using recombinant forms made available through bacterial expression. Nevertheless, recent studies indicate that these recombinant forms of SAA are unreliable. Indeed, commercial SAA variants have been shown to be contaminated with bacterial products including lipopolysaccharides and lipoproteins. As such, biological activities and receptor usage (TLR2, TLR4) revealed through the use of commercial SAA variants may not reflect the inherent nature of this APP. Within this review, we discuss the biological effects of SAA that have been demonstrated through more solid experimental approaches. SAA takes part in the innate immune response via the recruitment of leucocytes and executes, through pathogen recognition, antimicrobial activity. Knockout animal models implicate SAA in a range of functions, such as regulation of T-cell-mediated responses and monopoiesis. Moreover, through its structural motifs, not only does SAA function as an extracellular matrix protein, but it also binds extracellular matrix proteins. Finally, we here also provide an overview of definite SAA receptor-mediated functions and highlight those that are yet to be validated. The role of FPR2 in SAA-mediated leucocyte recruitment has been confirmed; nevertheless, SAA has been linked to a range of other receptors including CD36, SR-BI/II, RAGE and P2RX7.
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Affiliation(s)
- Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
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17
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Ji M, Ryu HJ, Hong JH. Signalling and putative therapeutic molecules on the regulation of synoviocyte signalling in rheumatoid arthritis. Bone Joint Res 2021; 10:285-297. [PMID: 33890482 PMCID: PMC8077181 DOI: 10.1302/2046-3758.104.bjr-2020-0331.r1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA. Cite this article: Bone Joint Res 2021;10(4):285–297.
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Affiliation(s)
- Minjeong Ji
- Department of Physiology, College of Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, Incheon, South Korea
| | - Hee Jung Ryu
- Department of Rheumatology, Gachon University Gil Medical Center, Incheon, South Korea
| | - Jeong Hee Hong
- Department of Physiology, College of Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, Incheon, South Korea.,Department of Health Sciences and Technology, GAIHST, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
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18
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Sorić Hosman I, Kos I, Lamot L. Serum Amyloid A in Inflammatory Rheumatic Diseases: A Compendious Review of a Renowned Biomarker. Front Immunol 2021; 11:631299. [PMID: 33679725 PMCID: PMC7933664 DOI: 10.3389/fimmu.2020.631299] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Serum amyloid A (SAA) is an acute phase protein with a significant importance for patients with inflammatory rheumatic diseases (IRD). The central role of SAA in pathogenesis of IRD has been confirmed by recent discoveries, including its involvement in the activation of the inflammasome cascade and recruitment of interleukin 17 producing T helper cells. Clinical utility of SAA in IRD was originally evaluated nearly half a century ago. From the first findings, it was clear that SAA could be used for evaluating disease severity and monitoring disease activity in patients with rheumatoid arthritis and secondary amyloidosis. However, cost-effective and more easily applicable markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), overwhelmed its use in clinical practice. In the light of emerging evidences, SAA has been discerned as a more sensitive biomarker in a wide spectrum of IRD, especially in case of subclinical inflammation. Furthermore, a growing number of studies are confirming the advantages of SAA over many other biomarkers in predicting and monitoring response to biological immunotherapy in IRD patients. Arising scientific discoveries regarding the role of SAA, as well as delineating SAA and its isoforms as the most sensitive biomarkers in various IRD by recently developing proteomic techniques are encouraging the revival of its clinical use. Finally, the most recent findings have shown that SAA is a biomarker of severe Coronavirus disease 2019 (COVID-19). The aim of this review is to discuss the SAA-involving immune system network with emphasis on mechanisms relevant for IRD, as well as usefulness of SAA as a biomarker in various IRD. Therefore, over a hundred original papers were collected through an extensive PubMed and Scopus databases search. These recently arising insights will hopefully lead to a better management of IRD patients and might even inspire the development of new therapeutic strategies with SAA as a target.
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Affiliation(s)
- Iva Sorić Hosman
- Department of Pediatrics, Zadar General Hospital, Zadar, Croatia
| | - Ivanka Kos
- Division of Nephrology, Dialysis and Transplantation, Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Lovro Lamot
- Division of Nephrology, Dialysis and Transplantation, Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia.,Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia
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19
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Yang X, Li R, Xu L, Qian F, Sun L. Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis. Immunol Cell Biol 2020; 99:34-48. [PMID: 32725692 DOI: 10.1111/imcb.12382] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/28/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023]
Abstract
Serum amyloid A (SAA) is an early and sensitive biomarker of inflammatory diseases, but its role in acute pancreatitis (AP) is still unclear. Here, we used a caerulein-induced mouse model to investigate the role of SAA in AP and other related inflammatory responses. In our study, we found that the expression of a specific SAA isoform, SAA3, was significantly elevated in a caerulein-induced AP animal model. In addition, SAA3-knockout (Saa3-/- ) mice showed lower serum levels of amylase and lipase, tissue damage and proinflammatory cytokine production in the pancreas compared with those of wild-type mice in response to caerulein administration. AP-associated acute lung injury was also significantly attenuated in Saa3-/- mice. In our in vitro experiments, treatment with cholecystokinin and recombinant SAA3 significantly induced necroptosis and cytokine production. Moreover, we found that the regulatory effect of SAA3 on acinar cell necroptosis was through a receptor-interacting protein 3 (RIP3)-dependent manner. Collectively, our findings indicate that SAA3 is required for AP by inducing an RIP3-dependent necroptosis pathway in acinar cells and is a potential drug target for AP.
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Affiliation(s)
- Xinyi Yang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Runsheng Li
- Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, PR China
| | - Lu Xu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Feng Qian
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China.,Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Anhui Province, Bengbu, 233003, PR China
| | - Lei Sun
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
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20
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Lin A, Liu J, Gong P, Chen Y, Zhang H, Zhang Y, Yu Y. Serum amyloid A inhibits astrocyte migration via activating p38 MAPK. J Neuroinflammation 2020; 17:254. [PMID: 32861245 PMCID: PMC7456509 DOI: 10.1186/s12974-020-01924-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 08/13/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The accumulation of astrocytes around senile plaques is one of the pathological characteristics in Alzheimer's disease (AD). Serum amyloid A (SAA), known as a major acute-phase protein, colocalizes with senile plaques in AD patients. Here, we demonstrate the role of SAA in astrocyte migration. METHODS The effects of SAA on astrocyte activation and accumulation around amyloid β (Aβ) deposits were detected in APP/PS1 transgenic mice mated with Saa3-/- mice. SAA expression, astrocyte activation, and colocalization with Aβ deposits were evaluated in mice using immunofluorescence staining and/or Western blotting. The migration of primary cultures of mouse astrocytes and human glioma U251 cells was examined using Boyden chamber assay and scratch-would assay. The actin and microtubule networks, protrusion formation, and Golgi apparatus location in astrocytes were determined using scratch-would assay and immunofluorescence staining. RESULTS Saa3 expression was significantly induced in aged APP/PS1 transgenic mouse brain. Saa3 deficiency exacerbated astrocyte activation and increased the number of astrocytes around Aβ deposits in APP/PS1 mice. In vitro studies demonstrated that SAA inhibited the migration of primary cultures of astrocytes and U251 cells. Mechanistic studies showed that SAA inhibited astrocyte polarization and protrusion formation via disrupting actin and microtubule reorganization and Golgi reorientation. Inhibition of the p38 MAPK pathway abolished the suppression of SAA on astrocyte migration and polarization. CONCLUSIONS These results suggest that increased SAA in the brain of APP/PS1 mice inhibits the migration of astrocytes to amyloid plaques by activating the p38 MAPK pathway.
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Affiliation(s)
- Aihua Lin
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jin Liu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ping Gong
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yanqing Chen
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Haibo Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yang Yu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
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21
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Tseng CC, Chen YJ, Chang WA, Tsai WC, Ou TT, Wu CC, Sung WY, Yen JH, Kuo PL. Dual Role of Chondrocytes in Rheumatoid Arthritis: The Chicken and the Egg. Int J Mol Sci 2020; 21:E1071. [PMID: 32041125 PMCID: PMC7038065 DOI: 10.3390/ijms21031071] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/04/2020] [Accepted: 02/04/2020] [Indexed: 12/22/2022] Open
Abstract
Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.
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Affiliation(s)
- Chia-Chun Tseng
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Department of Physical Medicine and Rehabilitation, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-An Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
| | - Wen-Chan Tsai
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Tsan-Teng Ou
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Cheng-Chin Wu
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Wan-Yu Sung
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Jeng-Hsien Yen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (W.-C.T.); (T.-T.O.); (C.-C.W.); (W.-Y.S.)
| | - Po-Lin Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (Y.-J.C.); (W.-A.C.)
- Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
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22
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Abstract
As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino acids in humans) and remarkably well-conserved in mammalian evolution. They are synthesized prominently, but not exclusively, in the liver. Fragments of SAA can associate into insoluble fibrils (called "amyloid") characteristic of "secondary" amyloid disease in which they can interrupt normal physiology and lead to organ failure. SAA proteins comprise a family of molecules, two members of which (SAA1 and SAA2) are (along with C-reactive protein, CRP) the most prominent members of the acute phase response (APR) during which their serum levels rise dramatically after trauma, infection and other stimuli. Biologic function (s) of SAA are unresolved but features are consistent with a prominent role in primordial host defense (including the APR ). SAA proteins are lipophilic and contribute to high density lipoproteins (HDL) and cholesterol transport. SAA proteins interact with specific receptors and have been implicated in tissue remodeling through metalloproteinases, local tissue changes in atherosclerosis, cancer metastasis, lung inflammation, maternal-fetal health and intestinal physiology. Molecular details of some of these are emerging.
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Affiliation(s)
- George H Sack
- Departments of Biological Chemistry and Medicine, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Physiology 615, Baltimore, MD, 21205, USA.
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23
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Ozaki T, Muramatsu R, Nakamura H, Kinoshita M, Kishima H, Yamashita T. Proteomic analysis of protein changes in plasma by balloon test occlusion. J Clin Neurosci 2019; 72:397-401. [PMID: 31875829 DOI: 10.1016/j.jocn.2019.12.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 12/01/2019] [Indexed: 10/25/2022]
Abstract
Transient ischemia provides the tolerance against prolonged ischemia in the brain. In mouse experimental model, transient ischemia changes the composition ratio of circulating proteins, which associate with neuroprotection; however, the human evidence is lacking. Here we mimicked balloon test occlusion (BTO) of carotid artery as a transient ischemia and investigated the change of composition ratio of the circulating protein in the human plasma. We collected blood samples from nine patients (5 men and 4 women; mean age 64.2 years; range 45 to 77 years) before and 48 h after BTO and investigated the changes of circulating molecules level in the proteome using LC-MS/MS analysis. Leucine-rich alpha-2-glycoprotein and serum amyloid A-1 increased and protein AMBP decreased in the blood samples after BTO. Transient change of blood flow in the brain alters molecular expression in the plasma. Because the alteration of plasma protein composition is involved in ischemic tolerance in animal models, the proteins whose level was changed by BTO may be also involved in neuroprotection against ischemia in human.
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Affiliation(s)
- Tomohiko Ozaki
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan; Department of Neurosurgery, Graduate School of Medicine, Osaka University, Japan; Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan
| | - Rieko Muramatsu
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan; WPI Immunology Frontier Research Center, Osaka University, Japan; Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Neurology and Psychiatry, Kodaira, Japan.
| | - Hajime Nakamura
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, Japan
| | - Manabu Kinoshita
- Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan
| | - Haruhiko Kishima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, Japan
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan; WPI Immunology Frontier Research Center, Osaka University, Japan; Department of Molecular Neuroscience, Graduate School of Frontier Biosciences, Osaka University, Japan
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24
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Huang J, Qi Z, Chen M, Xiao T, Guan J, Zhou M, Wang Q, Lin Z, Wang Z. Serum amyloid A1 as a biomarker for radiation dose estimation and lethality prediction in irradiated mouse. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:715. [PMID: 32042731 DOI: 10.21037/atm.2019.12.27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Fast and reliable biomarkers are needed to distinguish whether individuals were exposed or not to radiation and assess radiation dose, and to predict the severity of radiation damage in a large-scale radiation accident. Serum amyloid A1 (SAA1) is a protein induced by multiple factors including inflammatory. Therefore, this study aimed at exploring the role of SAA1 in the radiation dose estimation and lethality prediction after radiation. Methods C57BL/6J female mice were exposed to total body irradiation (TBI) at different doses and time points and amifostine, a drug used to reduce the side effects of radiotherapy, was injected before irradiation. Patients with nasopharyngeal carcinoma subjected to radiotherapy were used as the irradiation model in humans. Results A moderate SAA1 increase was observed at 6 hours in serum samples from irradiated mice at all doses used, with a peak at 12 hours, then decreased to day 3 after exposure. A second SAA1 increase was observed from day 5 to 7, which was associated to subsequent lethality. Treatment with amifostine before irradiation could prevent mice death and inhibit the second SAA1 increase. SAA1 increase after radiation was confirmed in human serum of nasopharyngeal carcinoma patients after radiotherapy. Conclusions Serum SAA1 levels could represent a biomarker for radiation dose estimation and its second increase might be a useful lethality indicator after radiation in a mouse model.
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Affiliation(s)
- Jinfeng Huang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China.,Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510080, China
| | - Zhenhua Qi
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Min Chen
- Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Ting Xiao
- Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Jian Guan
- Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Meijuan Zhou
- Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510080, China
| | - Qi Wang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zhongwu Lin
- Science Research Management Department of the Academy of Military Sciences, Beijing 100091, China
| | - Zhidong Wang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
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25
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Yuan ZY, Zhang XX, Wu YJ, Zeng ZP, She WM, Chen SY, Zhang YQ, Guo JS. Serum amyloid A levels in patients with liver diseases. World J Gastroenterol 2019; 25:6440-6450. [PMID: 31798280 PMCID: PMC6881510 DOI: 10.3748/wjg.v25.i43.6440] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 09/23/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum amyloid A (SAA) is an acute phase protein mainly synthesized by the liver. SAA induces inflammatory phenotype and promotes cell proliferation in activated hepatic stellate cells, the major scar forming cells in the liver. However, few studies have reported on the serum levels of SAA in human liver disease and its clinical significance in various liver diseases.
AIM To investigate the serum levels of SAA in patients with different liver diseases and analyze the factors associated with the alteration of SAA levels in chronic hepatitis B (CHB) patients.
METHODS Two hundred and seventy-eight patients with different liver diseases and 117 healthy controls were included in this study. The patients included 205 with CHB, 22 with active autoimmune liver disease (AILD), 21 with nonalcoholic steatohepatitis (NASH), 14 with drug-induced liver injury (DILI), and 16 with pyogenic liver abscess. Serum levels of SAA and other clinical parameters were collected for the analysis of the factors associated with SAA level. Mann-Whitney U test was used to compare the serum SAA levels of patients with various liver diseases with those of healthy controls. Bonferroni test was applied for post hoc comparisons to control the probability of type 1 error (alpha = 0.05/6 = 0.008). For statistical tests of other variables, P < 0.05 was considered statistically significant. Statistically significant factors determined by single factor analysis were further analyzed by binary multivariate logistic regression analysis.
RESULTS All patients with active liver diseases had higher serum SAA levels than healthy controls and the inactive CHB patients, with the highest SAA level found in patients with pyogenic liver abscess (398.4 ± 246.8 mg/L). Patients with active AILD (19.73 ± 24.81 mg/L) or DILI (8.036 ± 5.685 mg/L) showed higher SAA levels than those with active CHB (6.621 ± 6.776 mg/L) and NASH (6.624 ± 4.891 mg/L). Single (P < 0.001) and multivariate logistic regression analyses (P = 0.039) for the CHB patients suggested that patients with active CHB were associated with an SAA serum level higher than 6.4 mg/L. Serum levels of SAA and CRP (C-reactive protein) were positively correlated in patients with CHB (P < 0.001), pyogenic liver abscess (P = 0.045), and active AILD (P = 0.02). Serum levels of SAA (0.80-871.0 mg/L) had a broader fluctuation range than CRP (0.30-271.3 mg/L).
CONCLUSION Serum level of SAA is a sensitive biomarker for inflammatory activity of pyogenic liver abscess. It may also be a weak marker reflecting milder inflammatory status in the liver of patients with CHB and other active liver diseases.
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Affiliation(s)
- Zi-Ying Yuan
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
- Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
| | - Xing-Xin Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Yu-Jing Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Zhi-Ping Zeng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Wei-Min She
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Shi-Yao Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
| | - Yuan-Qing Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Jin-Sheng Guo
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai 200032, China
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26
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Abouelasrar Salama S, Lavie M, De Buck M, Van Damme J, Struyf S. Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection. Cytokine Growth Factor Rev 2019; 50:29-42. [PMID: 31718982 DOI: 10.1016/j.cytogfr.2019.10.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/17/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense.
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Affiliation(s)
- Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Muriel Lavie
- University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille, Lille, France
| | - Mieke De Buck
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, 3000, Belgium.
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27
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Nys G, Cobraiville G, Servais AC, Malaise MG, de Seny D, Fillet M. Targeted proteomics reveals serum amyloid A variants and alarmins S100A8-S100A9 as key plasma biomarkers of rheumatoid arthritis. Talanta 2019; 204:507-517. [PMID: 31357327 DOI: 10.1016/j.talanta.2019.06.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/07/2019] [Accepted: 06/10/2019] [Indexed: 01/18/2023]
Abstract
Serum amyloid A (SAA) and S100 (S100A8, S100A9 and S100A12) proteins were previously identified as biomarkers of interest for rheumatoid arthritis (RA). Among SAA family, two closely related isoforms (SAA-1 and SAA-2) are linked to the acute-phase of inflammation. They respectively exist under the form of three (α, β, and γ) and two (α and β) allelic variants. We developed a single run quantitative method for these protein variants and investigated their clinical relevance in the context of RA. The method was developed and validated according to regulations before being applied on plasma coming from RA patients (n = 46), other related inflammatory pathologies (n = 116) and controls (n = 62). Depending on the activity score of RA, SAA1 isoforms (mainly of SAA1α and SAA1β subtypes) were found to be differentially present in plasma revealing their dual role during the development of RA. In addition, the weight of SAA1α in the total SAA response varied from 32 to 80% depending on the pathology studied. A negative correlation between SAA1α and SAA1β was also highlighted for RA early-onset (r = -0.41). SAA2 and S100A8/S100A9 proteins were significantly overexpressed compared to control samples regardless of RA stage. The pathophysiological relevance of these quantitative and qualitative characteristics of the SAA response remains unknown. However, the significant negative correlation observed between SAA1α and SAA1β levels in RA early-onset suggests the existence of still unknown regulatory mechanisms in these diseases.
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Affiliation(s)
- Gwenaël Nys
- Laboratory for the Analysis of Medicines, Center for Interdisciplinary Research on Medicines (CIRM), ULiege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium
| | - Gaël Cobraiville
- Laboratory for the Analysis of Medicines, Center for Interdisciplinary Research on Medicines (CIRM), ULiege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium; Laboratory of Rheumatology, GIGA-Inflammation, Infection & Immunity, ULiege and CHU de Liege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium
| | - Anne-Catherine Servais
- Laboratory for the Analysis of Medicines, Center for Interdisciplinary Research on Medicines (CIRM), ULiege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium
| | - Michel G Malaise
- Laboratory of Rheumatology, GIGA-Inflammation, Infection & Immunity, ULiege and CHU de Liege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium
| | - Dominique de Seny
- Laboratory of Rheumatology, GIGA-Inflammation, Infection & Immunity, ULiege and CHU de Liege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium
| | - Marianne Fillet
- Laboratory for the Analysis of Medicines, Center for Interdisciplinary Research on Medicines (CIRM), ULiege, Quartier Hopital, Avenue Hippocrate 15, 4000 Liege, Belgium.
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28
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Zhang Y, Zhang J, Sheng H, Li H, Wang R. Acute phase reactant serum amyloid A in inflammation and other diseases. Adv Clin Chem 2019; 90:25-80. [PMID: 31122611 DOI: 10.1016/bs.acc.2019.01.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute-phase reactant serum amyloid A (A-SAA) plays an important role in acute and chronic inflammation and is used in clinical laboratories as an indicator of inflammation. Although both A-SAA and C-reactive protein (CRP) are acute-phase proteins, the detection of A-SAA is more conclusive than the detection of CRP in patients with viral infections, severe acute pancreatitis, and rejection reactions to kidney transplants. A-SAA has greater clinical diagnostic value in patients who are immunosuppressed, patients with cystic fibrosis who are treated with corticoids, and preterm infants with late-onset sepsis. Nevertheless, for the assessment of the inflammation status and identification of viral infection in other pathologies, such as bacterial infections, the combinatorial use of A-SAA and other acute-phase proteins (APPs), such as CRP and procalcitonin (PCT), can provide more information and sensitivity than the use of any of these proteins alone, and the information generated is important in guiding antibiotic therapy. In addition, A-SAA-associated diseases and the diagnostic value of A-SAA are discussed. However, the relationship between different A-SAA isotypes and their human diseases are mostly derived from research laboratories with limited clinical samples. Thus, further clinical evaluations are necessary to confirm the clinical significance of each A-SAA isotype. Furthermore, the currently available A-SAA assays are based on polyclonal antibodies, which lack isotype specificity and are associated with many inflammatory diseases. Therefore, these assays are usually used in combination with other biomarkers in the clinic.
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Affiliation(s)
- Yan Zhang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China
| | - Jie Zhang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China
| | - Huiming Sheng
- Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haichuan Li
- C.N. Maternity & Infant Health Hospital, Shanghai, China
| | - Rongfang Wang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, China.
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29
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Schinnerling K, Rosas C, Soto L, Thomas R, Aguillón JC. Humanized Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Cell-Based Therapies. Front Immunol 2019; 10:203. [PMID: 30837986 PMCID: PMC6389733 DOI: 10.3389/fimmu.2019.00203] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/23/2019] [Indexed: 01/12/2023] Open
Abstract
Rodent models of rheumatoid arthritis (RA) have been used over decades to study the immunopathogenesis of the disease and to explore intervention strategies. Nevertheless, mouse models of RA reach their limit when it comes to testing of new therapeutic approaches such as cell-based therapies. Differences between the human and the murine immune system make it difficult to draw reliable conclusions about the success of immunotherapies. To overcome this issue, humanized mouse models have been established that mimic components of the human immune system in mice. Two main strategies have been pursued for humanization: the introduction of human transgenes such as human leukocyte antigen molecules or specific T cell receptors, and the generation of mouse/human chimera by transferring human cells or tissues into immunodeficient mice. Recently, both approaches have been combined to achieve more sophisticated humanized models of autoimmune diseases. This review discusses limitations of conventional mouse models of RA-like disease and provides a closer look into studies in humanized mice exploring their usefulness and necessity as preclinical models for testing of cell-based therapies in autoimmune diseases such as RA.
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Affiliation(s)
- Katina Schinnerling
- Programa Disciplinario de Inmunología, Immune Regulation and Tolerance Research Group, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.,Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Carlos Rosas
- Departamento de Ciencias Morfológicas, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Lilian Soto
- Programa Disciplinario de Inmunología, Immune Regulation and Tolerance Research Group, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.,Unidad de Dolor, Departamento de Medicina, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Ranjeny Thomas
- Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia
| | - Juan Carlos Aguillón
- Programa Disciplinario de Inmunología, Immune Regulation and Tolerance Research Group, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile
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30
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Conway R, O'Neill L, McCarthy GM, Murphy CC, Fabre A, Kennedy S, Veale DJ, Wade SM, Fearon U, Molloy ES. Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis. Ann Rheum Dis 2018; 77:1815-1824. [PMID: 30097452 DOI: 10.1136/annrheumdis-2018-213488] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/18/2018] [Accepted: 07/19/2018] [Indexed: 01/30/2023]
Abstract
OBJECTIVES The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis. METHODS IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture. RESULTS Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs. CONCLUSION IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.
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Affiliation(s)
- Richard Conway
- Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital Dublin, Academic Medical Centre, Dublin 4, Ireland
- CARD Newman Research Fellow, University College Dublin, Dublin, Ireland
| | - Lorraine O'Neill
- Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital Dublin, Academic Medical Centre, Dublin 4, Ireland
| | - Geraldine M McCarthy
- Mater Misericordiae University Hospital, Dublin Academic Medical Centre, Dublin, Ireland
| | - Conor C Murphy
- RCSI Department of Ophthalmology, Royal College of Surgeons of Ireland, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
| | - Aurelie Fabre
- Department of Pathology, St Vincent's University Hospital, Dublin, Ireland
| | - Susan Kennedy
- Department of Pathology, St Vincent's University Hospital, Dublin, Ireland
| | - Douglas J Veale
- Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital Dublin, Academic Medical Centre, Dublin 4, Ireland
| | - Sarah M Wade
- Department of Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Ursula Fearon
- Department of Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Eamonn S Molloy
- Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital Dublin, Academic Medical Centre, Dublin 4, Ireland
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31
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Angeles-Han ST, Yeh S, Patel P, Duong D, Jenkins K, Rouster-Stevens KA, Altaye M, Fall N, Thornton S, Prahalad S, Holland GN. Discovery of tear biomarkers in children with chronic non-infectious anterior uveitis: a pilot study. J Ophthalmic Inflamm Infect 2018; 8:17. [PMID: 30327966 PMCID: PMC6191408 DOI: 10.1186/s12348-018-0156-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 09/06/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Biomarkers in easily obtained specimens that accurately predict uveitis in children with juvenile idiopathic arthritis (JIA) are needed. Aqueous humor has been studied for biomarkers, but is not routinely available. We evaluated tears from children with chronic anterior uveitis (CAU) for biomarkers reported in aqueous humor. In this pilot study, we used Schirmer strips to collect tears from seven children (nine eyes); three children had JIA- associated uveitis (JIA-U) and four had idiopathic disease (I-CAU). Liquid chromatography-tandem mass spectrometry was used to identify and quantify tear proteins. The Mann-Whitney U test identified differential tear protein expression between children with JIA-U and those with I-CAU. RESULTS S100A9, LAP3, TTR, MIF, sCD14, S100A8, and SAA1 were detected in tears of all children; the same cytokines have been reported in aqueous humor of children with JIA-U. Tears from children with JIA-U had higher expression of proteins associated with inflammatory arthritis (SEMA3G, TIMP1, HEXB, ERN1, and SAA1) than tears from those with I-CAU. In addition, we found higher expression of sCD14, S100A8, and SAA1, but lower expression of S100A9, LAP3, TTR, and MIF, in tears from children with JIA-U compared to tears from those with I-CAU. CONCLUSIONS Tears contain similar cytokine profiles to aqueous humor in children with CAU and may be a clinically useful source of disease biomarkers. Tears from children with JIA-U also contain cytokines associated with inflammatory arthritis; furthermore, differential expression of other tear proteins as well may provide clues to intrinsic differences between JIA-U and I-CAU, despite their similar clinical phenotypes.
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Affiliation(s)
- Sheila T Angeles-Han
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
| | - Steven Yeh
- Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd B, Atlanta, GA, 30322, USA
| | - Purnima Patel
- Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, 1365 Clifton Rd B, Atlanta, GA, 30322, USA
| | - Duc Duong
- Emory Integrated Proteomics Core, Emory University, 1510 Clifton Rd, Atlanta, GA, 30322, USA
| | - Kirsten Jenkins
- Childrens Healthcare of Atlanta, Emory Children's Center, 2015 Uppergate Drive, Atlanta, GA, 30322, USA
| | - Kelly A Rouster-Stevens
- Childrens Healthcare of Atlanta, Emory Children's Center, 2015 Uppergate Drive, Atlanta, GA, 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Mekibib Altaye
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 5041, Cincinnati, OH, 45229, USA
| | - Ndate Fall
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
| | - Sherry Thornton
- Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA
| | - Sampath Prahalad
- Childrens Healthcare of Atlanta, Emory Children's Center, 2015 Uppergate Drive, Atlanta, GA, 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Gary N Holland
- UCLA Stein Eye Institute and David Geffen School of Medicine at University of California, 100 Stein Plaza, Los Angeles, CA, 90095-7000, USA
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Suzuki H, Sugaya M, Nakajima R, Oka T, Takahashi N, Nakao M, Miyagaki T, Asano Y, Sato S. Serum amyloid A levels in the blood of patients with atopic dermatitis and cutaneous T-cell lymphoma. J Dermatol 2018; 45:1440-1443. [PMID: 30289574 DOI: 10.1111/1346-8138.14665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 08/27/2018] [Indexed: 01/04/2023]
Abstract
Serum amyloid A (SAA) is an acute phase protein, which activates immune cells and induces cytokines and chemokine. SAA levels in blood have been reported to be elevated in case of inflammation, infections, neoplasia and tissue injury. In this study, we examined SAA levels in the blood of patients with atopic dermatitis (AD) and cutaneous T-cell lymphoma (CTCL). SAA levels in sera of AD patients, those of CTCL patients and those of healthy controls were not significantly different. When AD or CTCL patients were classified by disease severity, there was still no difference in SAA levels. In AD patients, however, SAA levels positively correlated with the number of eosinophils in peripheral blood and serum soluble interleukin-2 receptor (sIL-2R) levels. There were significant correlations between SAA levels in blood and the number of white blood cells in peripheral blood and serum sIL-2R levels in CTCL patients. AD patients without topical steroid treatment and CTCL patients without narrowband ultraviolet B therapy showed increased levels of SAA, which suggested that SAA levels may easily fluctuate with treatment. These results imply a possible contribution of SAA in development of AD and CTCL.
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Affiliation(s)
- Hideko Suzuki
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Makoto Sugaya
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Department of Dermatology, International University of Health and Welfare, Chiba, Japan
| | - Rina Nakajima
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tomonori Oka
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Naomi Takahashi
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Momoko Nakao
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yoshihide Asano
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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MacDonald IJ, Liu SC, Su CM, Wang YH, Tsai CH, Tang CH. Implications of Angiogenesis Involvement in Arthritis. Int J Mol Sci 2018; 19:ijms19072012. [PMID: 29996499 PMCID: PMC6073145 DOI: 10.3390/ijms19072012] [Citation(s) in RCA: 154] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 06/25/2018] [Accepted: 07/08/2018] [Indexed: 12/28/2022] Open
Abstract
Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases.
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Affiliation(s)
- Iona J MacDonald
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
| | - Shan-Chi Liu
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung 40447, Taiwan.
| | - Chen-Ming Su
- Department of Biomedical Sciences Laboratory, Wenzhou Medical University, Dongyang 325035, Zhejiang, China.
| | - Yu-Han Wang
- Graduate Institute of Biomedical Science, China Medical University, Taichung 40402, Taiwan.
| | - Chun-Hao Tsai
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung 40447, Taiwan.
- School of Medicine, China Medical University, Taichung 40402, Taiwan.
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan.
- School of Medicine, China Medical University, Taichung 40402, Taiwan.
- Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan.
- Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan.
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Shridas P, De Beer MC, Webb NR. High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species generation and NLRP3 inflammasome activation. J Biol Chem 2018; 293:13257-13269. [PMID: 29976759 DOI: 10.1074/jbc.ra118.002428] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/18/2018] [Indexed: 12/11/2022] Open
Abstract
Serum amyloid A (SAA) is a high-density apolipoprotein whose plasma levels can increase more than 1000-fold during a severe acute-phase inflammatory response and are more modestly elevated in chronic inflammation. SAA is thought to play important roles in innate immunity, but its biological activities have not been completely delineated. We previously reported that SAA deficiency protects mice from developing abdominal aortic aneurysms (AAAs) induced by chronic angiotensin II (AngII) infusion. Here, we report that SAA is required for AngII-induced increases in interleukin-1β (IL-1β), a potent proinflammatory cytokine that is tightly controlled by the Nod-like receptor protein 3 (NLRP3) inflammasome and caspase-1 and has been implicated in both human and mouse AAAs. We determined that purified SAA stimulates IL-1β secretion in murine J774 and bone marrow-derived macrophages through a mechanism that depends on NLRP3 expression and caspase-1 activity, but is independent of P2X7 nucleotide receptor (P2X7R) activation. Inhibiting reactive oxygen species (ROS) by N-acetyl-l-cysteine or mito-TEMPO and inhibiting activation of cathepsin B by CA-074 blocked SAA-mediated inflammasome activation and IL-1β secretion. Moreover, inhibiting cellular potassium efflux with glyburide or increasing extracellular potassium also significantly reduced SAA-mediated IL-1β secretion. Of note, incorporating SAA into high-density lipoprotein (HDL) prior to its use in cell treatments completely abolished its ability to stimulate ROS generation and inflammasome activation. These results provide detailed insights into SAA-mediated IL-1β production and highlight HDL's role in regulating SAA's proinflammatory effects.
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Affiliation(s)
- Preetha Shridas
- From the Departments of Internal Medicine, .,Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky 40536
| | - Maria C De Beer
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky 40536.,Physiology, and.,Pharmacology and Nutritional Sciences
| | - Nancy R Webb
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky 40536.,Pharmacology and Nutritional Sciences.,Saha Cardiovascular Research Center, and
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Gouwy M, De Buck M, Abouelasrar Salama S, Vandooren J, Knoops S, Pörtner N, Vanbrabant L, Berghmans N, Opdenakker G, Proost P, Van Damme J, Struyf S. Matrix Metalloproteinase-9-Generated COOH-, but Not NH 2-Terminal Fragments of Serum Amyloid A1 Retain Potentiating Activity in Neutrophil Migration to CXCL8, With Loss of Direct Chemotactic and Cytokine-Inducing Capacity. Front Immunol 2018; 9:1081. [PMID: 29915572 PMCID: PMC5994419 DOI: 10.3389/fimmu.2018.01081] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 04/30/2018] [Indexed: 12/21/2022] Open
Abstract
Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH2-terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes via the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation, SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes in vitro and in vivo. Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52–104), SAA1(57–104), and SAA1(58–104), with a relative molecular mass of 5,884.4, 5,327.3, and 5,256.3, respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1, we chemically synthesized the COOH-terminal SAA fragments SAA1(52–104) and SAA1(58–104) and the complementary NH2-terminal peptide SAA1(1–51). In contrast to intact SAA1, the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover, these fragments possessed no direct chemotactic activity for neutrophils, as observed for intact SAA1. However, comparable to intact SAA1, SAA1(58–104) cooperated with CXCL8 in neutrophil activation and migration, whereas SAA1(1–51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence, proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation.
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Affiliation(s)
- Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Mieke De Buck
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Jennifer Vandooren
- Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Sofie Knoops
- Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Noëmie Pörtner
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Lotte Vanbrabant
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Nele Berghmans
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
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36
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The ectoenzyme-side of matrix metalloproteinases (MMPs) makes inflammation by serum amyloid A (SAA) and chemokines go round. Immunol Lett 2018; 205:1-8. [PMID: 29870759 DOI: 10.1016/j.imlet.2018.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/16/2018] [Accepted: 06/01/2018] [Indexed: 12/18/2022]
Abstract
During an inflammatory response, a large number of distinct mediators appears in the affected tissues or in the blood circulation. These include acute phase proteins such as serum amyloid A (SAA), cytokines and chemokines and proteolytic enzymes. Although these molecules are generated within a cascade sequence in specific body compartments allowing for independent action, their co-appearance in space and time during acute or chronic inflammation points toward important mutual interactions. Pathogen-associated molecular patterns lead to fast induction of the pro-inflammatory endogenous pyrogens, which are evoking the acute phase response. Interleukin-1, tumor necrosis factor-α and interferons simultaneously trigger different cell types, including leukocytes, endothelial cells and fibroblasts for tissue-specific or systemic production of chemokines and matrix metalloproteinases (MMPs). In addition, SAA induces chemokines and both stimulate secretion of MMPs from multiple cell types. As a consequence, these mediators may cooperate to enhance the inflammatory response. Indeed, SAA synergizes with chemokines to increase chemoattraction of monocytes and granulocytes. On the other hand, MMPs post-translationally modify chemokines and SAA to reduce their activity. Indeed, MMPs internally cleave SAA with loss of its cytokine-inducing and direct chemotactic potential whilst retaining its capacity to synergize with chemokines in leukocyte migration. Finally, MMPs truncate chemokines at their NH2- or COOH-terminal end, resulting in reduced or enhanced chemotactic activity. Therefore, the complex interactions between chemokines, SAA and MMPs either maintain or dampen the inflammatory response.
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Serum Amyloid A1 Is an Epithelial Prorestitutive Factor. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:937-949. [PMID: 29366677 DOI: 10.1016/j.ajpath.2017.12.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 11/10/2017] [Accepted: 12/05/2017] [Indexed: 12/12/2022]
Abstract
Several proteins endogenously produced during the process of intestinal wound healing have demonstrated prorestitutive properties. The presence of serum amyloid A1 (SAA1), an acute-phase reactant, within inflamed tissues, where it exerts chemotaxis of phagocytes, is well recognized; however, a putative role in intestinal wound repair has not been described. Herein, we show that SAA1 induces intestinal epithelial cell migration, spreading, and attachment through a formyl peptide receptor 2-dependent mechanism. Induction of the prorestitutive phenotype is concentration and time dependent and is associated with epithelial reactive oxygen species production and alterations in p130 Crk-associated substrate staining. In addition, using a murine model of wound recovery, we provide evidence that SAA1 is dynamically and temporally regulated, and that the elaboration of SAA1 within the wound microenvironment correlates with the influx of SAA1/CD11b coexpressing immune cells and increases in cytokines known to induce SAA expression. Overall, the present work demonstrates an important role for SAA in epithelial wound recovery and provides evidence for a physiological role in the wound environment.
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38
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Yang M, Liu F, Higuchi K, Sawashita J, Fu X, Zhang L, Zhang L, Fu L, Tong Z, Higuchi K. Serum amyloid A expression in the breast cancer tissue is associated with poor prognosis. Oncotarget 2017; 7:35843-35852. [PMID: 27058895 PMCID: PMC5094967 DOI: 10.18632/oncotarget.8561] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 02/28/2016] [Indexed: 12/14/2022] Open
Abstract
Background Serum amyloid A (SAA), an acute-phase protein, is expressed primarily in the liver, and recently found also expressed in cancer tissues. However, its expression and prognostic value in breast cancer have not been described. Results SAA protein was found expressed in tumor cells in 44.2% cases and in TAM in 62.5% cases. FISH showed more frequent SAA mRNA expression in TAM than in tumor cells (76% versus 12%, p < 0.001), and a significant association between the frequencies of SAA mRNA expression in TAM and tumor cells (rs = 0.603, p < 0.001). The immunoreactivities of SAA protein in TAM and tumor cells were both associated with lymphovascular invasion and lymph node metastasis. Moreover, SAA-positivity in TAMs was associated with larger tumor-size, higher histological-grade, negative estrogen-receptor and progesterone-receptor statuses, and HER-2 overexpression. It was also linked to worse recurrence-free survival in a multivariable regression model. Methods Immunohistochemistry was applied on the tumor tissues from 208 breast cancer patients to evaluate the local SAA-protein expression with additional CD68 stain to identify the tumor-associated macrophage (TAM) on the serial tissue sections. Fluorescent in situ hybridization (FISH) was conducted on serial tissue sections from 25 of the 208 tumors to examine the expression and location of SAA mRNA. Conclusions Our results suggested that the TAMs may be a pivotal and main source of SAA production in tumor microenvironment of breast cancer. SAA immunoreactivity in TAM is associated with worse recurrence-free survival, and is therefore a biomarker candidate for postoperative surveillance and perhaps a therapeutic target for breast cancer.
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Affiliation(s)
- Mu Yang
- Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Fangfang Liu
- Department of Breast Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Kayoko Higuchi
- Department of Pathology, Aizawa Hospital, Matsumoto, Japan
| | - Jinko Sawashita
- Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.,Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
| | - Xiaoying Fu
- Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Li Zhang
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Lanjing Zhang
- Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA.,Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Department of Pathology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
| | - Li Fu
- Department of Breast Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhongsheng Tong
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Keiichi Higuchi
- Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.,Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan
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Serum amyloid A inhibits dendritic cell differentiation by suppressing GM-CSF receptor expression and signaling. Exp Mol Med 2017; 49:e369. [PMID: 28857084 PMCID: PMC5579511 DOI: 10.1038/emm.2017.120] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 03/07/2017] [Accepted: 03/09/2017] [Indexed: 12/18/2022] Open
Abstract
In this study, we report that an acute phase reactant, serum amyloid A (SAA), strongly inhibits dendritic cell differentiation induced by GM-CSF plus IL-4. SAA markedly decreased the expression of MHCII and CD11c. Moreover, SAA decreased cell surface GM-CSF receptor expression. SAA also decreased the expression of PU.1 and C/EBPα, which play roles in the expression of GM-CSF receptor. This inhibitory response by SAA is partly mediated by the well-known SAA receptors, Toll-like receptor 2 and formyl peptide receptor 2. Taken together, we suggest a novel insight into the inhibitory role of SAA in dendritic cell differentiation.
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40
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Watanabe R, Hosgur E, Zhang H, Wen Z, Berry G, Goronzy JJ, Weyand CM. Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis. Joint Bone Spine 2017; 84:421-426. [PMID: 27663755 PMCID: PMC5639893 DOI: 10.1016/j.jbspin.2016.07.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Accepted: 07/06/2016] [Indexed: 01/09/2023]
Abstract
Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8+NOX2+ regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4T cell compartment, resulting in widespread CD4T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations.
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Affiliation(s)
- Ryu Watanabe
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Ebru Hosgur
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Hui Zhang
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Zhenke Wen
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Gerald Berry
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Seidl SE, Pessolano LG, Bishop CA, Best M, Rich CB, Stone PJ, Schreiber BM. Toll-like receptor 2 activation and serum amyloid A regulate smooth muscle cell extracellular matrix. PLoS One 2017; 12:e0171711. [PMID: 28257481 PMCID: PMC5336220 DOI: 10.1371/journal.pone.0171711] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 01/24/2017] [Indexed: 11/19/2022] Open
Abstract
Smooth muscle cells contribute to extracellular matrix remodeling during atherogenesis. De-differentiated, synthetic smooth muscle cells are involved in processes of migration, proliferation and changes in expression of extracellular matrix components, all of which contribute to loss of homeostasis accompanying atherogenesis. Elevated levels of acute phase proteins, including serum amyloid A (SAA), are associated with an increased risk for atherosclerosis. Although infection with periodontal and respiratory pathogens via activation of inflammatory cell Toll-like receptor (TLR)2 has been linked to vascular disease, little is known about smooth muscle cell TLR2 in atherosclerosis. This study addresses the role of SAA and TLR2 activation on smooth muscle cell matrix gene expression and insoluble elastin accumulation. Cultured rat aortic smooth muscle cells were treated with SAA or TLR2 agonists and the effect on expression of matrix metallopeptidase 9 (MMP9) and tropoelastin studied. SAA up-regulated MMP9 expression. Tropoelastin is an MMP9 substrate and decreased tropoelastin levels in SAA-treated cells supported the concept of extracellular matrix remodeling. Interestingly, SAA-induced down-regulation of tropoelastin was not only evident at the protein level but at the level of gene transcription as well. Contributions of proteasomes, nuclear factor κ B and CCAAT/enhancer binding protein β on regulation of MMP9 vs. tropoleastin expression were revealed. Effects on Mmp9 and Eln mRNA expression persisted with long-term SAA treatment, resulting in decreased insoluble elastin accumulation. Interestingly, the SAA effects were TLR2-dependent and TLR2 activation by bacterial ligands also induced MMP9 expression and decreased tropoelastin expression. These data reveal a novel mechanism whereby SAA and/or infection induce changes in vascular elastin consistent with atherosclerosis.
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Affiliation(s)
- Stephanie E. Seidl
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Lawrence G. Pessolano
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Christopher A. Bishop
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Michael Best
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Celeste B. Rich
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Phillip J. Stone
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Barbara M. Schreiber
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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Lymphocytes T pro-inflammatoires et anti-inflammatoires dans l’artérite à cellules géantes. ACTA ACUST UNITED AC 2017. [DOI: 10.1016/j.rhum.2016.12.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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De Buck M, Gouwy M, Wang JM, Van Snick J, Opdenakker G, Struyf S, Van Damme J. Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults. Curr Med Chem 2017; 23:1725-55. [PMID: 27087246 PMCID: PMC5405626 DOI: 10.2174/0929867323666160418114600] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 03/31/2016] [Accepted: 04/15/2016] [Indexed: 12/23/2022]
Abstract
Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100-fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (> 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.
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Affiliation(s)
| | | | | | | | | | | | - Jo Van Damme
- University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
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Yu N, Zhang S, Lu J, Li Y, Yi X, Tang L, Su L, Ding Y. Serum amyloid A, an acute phase protein, stimulates proliferative and proinflammatory responses of keratinocytes. Cell Prolif 2016; 50. [PMID: 27910163 DOI: 10.1111/cpr.12320] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/27/2016] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Serum amyloid A (SAA), an acute phase protein, is highly expressed in psoriatic lesions but its function is not fully understood. The aim of this study was to explore its role in activation of keratinocytes. MATERIALS AND METHODS Real-time PCR and immunofluorescence were performed to examine SAA expression in imiquimod (IMQ)-induced psoriasis-like mice. In vivo function of SAA was examined by treating psoriasis-like mice with SAA neutralising antibody. Cell viability was monitored using the CCK-8 assay. Real-time PCR was performed to determine expression of genes associated with differentiation and inflammation. Ki67+ percentage and immunological markers were analysed by flow cytometry. Involvement of formyl peptide receptor-like 1 (FPRL1) in SAA signal transduction was determined by RNA interference. Binding of SAA and FPRL1 was examined by co-immunoprecipitaion. Western blotting was conducted to assess phosphorylation of downstream signalling molecules. RESULTS SAA was highly expressed in skin lesions of IMQ-treated psoriasis-like mice and neutralising SAA attenuated epidermal hyperplasia and inflammation. SAA in vitro promoted keratinocyte proliferation and expression of immunological mediators, while inhibiting differentiation. Effects of SAA on keratinocyte proliferation and inflammation were mediated by FPRL1, as well as activation of the PI3K/Akt pathway. CONCLUSIONS These observations indicate that SAA/FPRL1 contributed to pathogenesis of psoriasis by promoting keratinocyte proliferation and inflammation, thus providing a potential therapeutic target for disease therapy.
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Affiliation(s)
- Ning Yu
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Shujie Zhang
- Experimental Research Center, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Jiajing Lu
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Ying Li
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Xuemei Yi
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Li Tang
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Lina Su
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
| | - Yangfeng Ding
- Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, China
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Jacobsen S, Ladefoged S, Berg LC. Production of serum amyloid A in equine articular chondrocytes and fibroblast-like synoviocytes treated with proinflammatory cytokines and its effects on the two cell types in culture. Am J Vet Res 2016; 77:50-8. [PMID: 26709936 DOI: 10.2460/ajvr.77.1.50] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the role of the major equine acute phase protein serum amyloid A (SAA) in inflammation of equine intraarticular tissues. SAMPLE Articular chondrocytes and fibroblast-like synoviocytes (FLSs) from 8 horses (4 horses/cell type). PROCEDURES Chondrocytes and FLSs were stimulated in vitro for various periods up to 48 hours with cytokines (recombinant interleukin [IL]-1β, IL-6, tumor necrosis factor-α, or a combination of all 3 [IIT]) or with recombinant SAA. Gene expression of SAA, IL-6, matrix metalloproteinases (MMP)-1 and -3, and cartilage-derived retinoic acid-sensitive protein were assessed by quantitative real-time PCR assay; SAA protein was evaluated by immunoturbidimetry and denaturing isoelectric focusing and western blotting. RESULTS All cytokine stimulation protocols increased expression of SAA mRNA and resulted in detectable SAA protein production in chondrocytes and FLSs. Isoforms of SAA in lysed chondrocytes and their culture medium corresponded to those previously detected in synovial fluid from horses with joint disease. When exposed to SAA, chondrocytes and FLSs had increased expression of IL-6, SAA, and MMP3, and chondrocytes had increased expression of MMP-1. Chondrocytes had decreased expression of cartilage-derived retinoic acid-sensitive protein. CONCLUSIONS AND CLINICAL RELEVANCE Upregulation of SAA in chondrocytes and FLSs stimulated with proinflammatory cytokines and the proinflammatory effects of SAA suggested that SAA may be involved in key aspects of pathogenesis of the joint inflammation in horses.
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Connolly M, Rooney PR, McGarry T, Maratha AX, McCormick J, Miggin SM, Veale DJ, Fearon U. Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms. Ann Rheum Dis 2016; 75:1392-8. [PMID: 26290589 DOI: 10.1136/annrheumdis-2015-207655] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 08/01/2015] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Acute-phase serum amyloid A (A-SAA) has cytokine-like properties and is expressed at sites of inflammation. We examined whether A-SAA-induced pro-inflammatory mechanisms are mediated through Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA). METHODS The effect of A-SAA on human embryonic kidney (HEK), TLR2 or TLR4 cells was quantified by nuclear factor (NF)-κB luciferase reporter assays. A-SAA-induced RASFC and dHMVEC function were performed in the presence of a specific neutralising anti-TLR2 mAb (OPN301) (1 μg/mL) and matched IgG isotype control Ab (1 μg/mL). Cell surface expression of intracellular adhesion molecule (ICAM)-1, chemokine expression, cell migration, invasion and angiogenesis were assessed by flow cytometry, ELISA, Matrigel invasion chambers and tube formation assays. MyD88 expression was assessed by real-time PCR and western blot. RESULTS A-SAA induced TLR2 activation through induction of NF-κB (p<0.05), but failed to induce NF-κB in HEK-TLR4 cells, confirming specificity for TLR2. A-SAA-induced proliferation, invasion and migration were significantly inhibited in the presence of anti-TLR2 (all p<0.05), with no significant effect observed for tumour necrosis factor-α-induced events. Additionally, A-SAA-induced ICAM-1, interleukin-8, monocyte chemoattractant protein-1, RANTES and GRO-α expression were significantly reduced in the presence of anti-TLR2 (all p<0.05), as was A-SAA induced angiogenesis (p<0.05). Finally, A-SAA induced MyD88 signalling in RASFC and dHMVEC (p<0.05). CONCLUSIONS A-SAA is an endogenous ligand for TLR2, inducing pro-inflammatory effects in RA. Blocking the A-SAA/TLR2 interaction may be a potential therapeutic intervention in RA.
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Affiliation(s)
- Mary Connolly
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
| | - Peter R Rooney
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
| | - Trudy McGarry
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
| | - Ashwini X Maratha
- Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland
| | - Jennifer McCormick
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
| | - Sinead M Miggin
- Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, County Kildare, Ireland
| | - Douglas J Veale
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
| | - Ursula Fearon
- Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre and Conway Institute of Biomolecular and Biomedical Research, Dublin 4, Ireland
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Hwang YG, Balasubramani GK, Metes ID, Levesque MC, Bridges SL, Moreland LW. Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker. Arthritis Res Ther 2016; 18:108. [PMID: 27188329 PMCID: PMC4869396 DOI: 10.1186/s13075-016-1009-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022] Open
Abstract
Background The aim was to compare the effect of etanercept (ETN) and conventional synthetic disease-modifying anti-rheumatic drug (DMARD) therapy on serum amyloid A (SAA) levels and to determine whether SAA reflects rheumatoid arthritis (RA) disease activity better than C-reactive protein (CRP). Methods We measured SAA and CRP at baseline, 24, 48, and 102 week follow-up visits in 594 patients participating in the Treatment of early RA (TEAR) study. We used Spearman correlation coefficients (rho) to evaluate the relationship between SAA and CRP and mixed effects models to determine whether ETN and methotrexate (MTX) treatment compared to triple DMARD therapy differentially lowered SAA. Akaike information criteria (AIC) were used to determine model fits. Results SAA levels were only moderately correlated with CRP levels (rho = 0.58, p < 0.0001). There were significant differences in SAA by both visit (p = 0.0197) and treatment arm (p = 0.0130). RA patients treated with ETN plus MTX had a larger reduction in SAA than patients treated with traditional DMARD therapy. Similar results were found for serum CRP by visit (p = 0.0254) and by treatment (p < 0.0001), with a more pronounced difference than for SAA. Across all patients and time points, models of the disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) using SAA levels were better than models using CRP; the ΔAIC between the SAA and CRP models was 305. Conclusions SAA may be a better biomarker of RA disease activity than CRP, especially during treatment with tumor necrosis factor (TNF) antagonists. This warrants additional studies in other cohorts of patients on treatment for RA. Trial registration (ClinicalTrials.gov identifier: NCT00259610, Date of registration: 28 November 2005)
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Affiliation(s)
- Yong Gil Hwang
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 3500 Terrace Street, Pittsburgh, PA, 15261, USA.
| | - Goundappa K Balasubramani
- Department of Epidemiology, School of Public Health, University of Pittsburgh, 130 DeSoto Street, 127 Parran Hall, Pittsburgh, PA, 15261, USA
| | - Ilinca D Metes
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 3500 Terrace Street, Pittsburgh, PA, 15261, USA
| | - Marc C Levesque
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 3500 Terrace Street, Pittsburgh, PA, 15261, USA.,AbbVie Inc, 100 Research Dr, Worcester, MA, 01605, USA
| | - S Louis Bridges
- Department of Medicine, Division of Clinical Immunology and Rheumatology Birmingham, University of Alabama at Birmingham, Shelby Building, Room 178B, 1825 University Blvd., Birmingham, AL, 35294-2182, USA
| | - Larry W Moreland
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, 3500 Terrace Street, Pittsburgh, PA, 15261, USA
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De Buck M, Gouwy M, Wang JM, Van Snick J, Proost P, Struyf S, Van Damme J. The cytokine-serum amyloid A-chemokine network. Cytokine Growth Factor Rev 2015; 30:55-69. [PMID: 26794452 DOI: 10.1016/j.cytogfr.2015.12.010] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 12/22/2015] [Accepted: 12/22/2015] [Indexed: 12/14/2022]
Abstract
Levels of serum amyloid A (SAA), a major acute phase protein in humans, are increased up to 1000-fold upon infection, trauma, cancer or other inflammatory events. However, the exact role of SAA in host defense is yet not fully understood. Several pro- and anti-inflammatory properties have been ascribed to SAA. Here, the regulated production of SAA by cytokines and glucocorticoids is discussed first. Secondly, the cytokine and chemokine inducing capacity of SAA and its receptor usage are reviewed. Thirdly, the direct (via FPR2) and indirect (via TLR2) chemotactic effects of SAA and its synergy with chemokines are unraveled. Altogether, a complex cytokine-SAA-chemokine network is established, in which SAA plays a key role in regulating the inflammatory response.
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Affiliation(s)
- Mieke De Buck
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Mieke Gouwy
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Ji Ming Wang
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
| | - Jacques Van Snick
- Ludwig Cancer Research, Brussels Branch, Brussels, Belgium; e Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
| | - Paul Proost
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Sofie Struyf
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Jo Van Damme
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
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Kim J, Yang J, Park OJ, Kang SS, Yun CH, Han SH. Serum amyloid A inhibits osteoclast differentiation to maintain macrophage function. J Leukoc Biol 2015; 99:595-603. [DOI: 10.1189/jlb.3a0415-173r] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 10/19/2015] [Indexed: 01/07/2023] Open
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Timur H, Kokanali MK, Inal HA, Tuzluoglu D, Yilmaz N. A study on the association between serum amyloid A and sperm concentration. Andrologia 2015; 48:626-30. [PMID: 26437740 DOI: 10.1111/and.12491] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/26/2015] [Indexed: 01/29/2023] Open
Abstract
Our aim was to compare peripheral blood and seminal fluid serum amyloid A (SAA) protein levels in men classified on the basis of sperm concentration and investigate whether SAA protein is an important marker of male infertility. A total of 74 first-attempt IVF male partners of infertile couples classified as azoospermic (n = 25), oligozoospermic (n = 25) and normozoospermic group (n = 24) were recruited for this cross-sectional study. There was no difference with respect to age, BMI, infertility period and smoking ratio. No difference in haematologic parameters including white blood cell count, neutrophil ratio, lymphocyte ratio, neutrophil-to-lymphocyte ratio and blood SAA level was found between the groups. Seminal fluid SAA level was 17.85 ± 2.21 ng ml(-1) in azoospermics, 16.13 ± 3.58 ng ml(-1) in oligozoospermics and 15.67 ± 4.77 ng ml(-1) in normozoospermics, showing no significant difference. Seminal SAA level was found to be not correlated with blood SAA levels. Therefore, we could not find any associations between these parameters at all. However, further studies with more participants are needed to address the exact action of SAA on spermatogenesis.
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Affiliation(s)
- H Timur
- Department of Reproductive Endocrinology, Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey
| | - M K Kokanali
- Department of Reproductive Endocrinology, Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey
| | - H A Inal
- Department of Gynecology and Obstetrics, Konya Education and Research Hospital, Konya, Turkey
| | - D Tuzluoglu
- Department of Urology, Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey
| | - N Yilmaz
- Department of Reproductive Endocrinology, Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey
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