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Luo X, Cui J, Long X, Chen Z. TLRs Play Crucial Roles in Regulating RA Synoviocyte. Endocr Metab Immune Disord Drug Targets 2021; 20:1156-1165. [PMID: 32338225 DOI: 10.2174/1871530320666200427115225] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/23/2020] [Accepted: 01/30/2020] [Indexed: 12/13/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes (synoviocytes) are crucial ingredients of synovium. Therein, a lot of research has focused on synoviocytes. Researches demonstrated that TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 TLR7 and TLR9 are expressed in synoviocyte. Additionally, the expression of TLR2, TLR3, TLR4 and TLR5 is increased in RA synoviocyte. In this paper, we review the exact role of TLR2, TLR3, TLR4 and TLR5 participate in regulating the production of inflammatory factors in RA synoviocyte. Furthermore, we discuss the role of vasoactive intestinal peptide (VIP), MicroRNA, Monome of Chinese herb and other cells (Monocyte and T cell) influence the function of synoviocyte by regulating TLRs. The activation of toll-like receptors (TLRs) in synoviocyte leads to the aggravation of arthritis, comparing with angiogenesis and bone destruction. Above all, TLRs are promising targets for managing RA.
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Affiliation(s)
- Xuling Luo
- Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Juncheng Cui
- Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Xin Long
- Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Zhiwei Chen
- Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang 421001, China
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Martínez C, Juarranz Y, Gutiérrez-Cañas I, Carrión M, Pérez-García S, Villanueva-Romero R, Castro D, Lamana A, Mellado M, González-Álvaro I, Gomariz RP. A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int J Mol Sci 2019; 21:E65. [PMID: 31861827 PMCID: PMC6982157 DOI: 10.3390/ijms21010065] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.
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Affiliation(s)
- Carmen Martínez
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Irene Gutiérrez-Cañas
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mar Carrión
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Selene Pérez-García
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Raúl Villanueva-Romero
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - David Castro
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Amalia Lamana
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mario Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB)/CSIC, 28049 Madrid, Spain;
| | - Isidoro González-Álvaro
- Servicio de Reumatología, Instituto de Investigación Médica, Hospital Universitario La Princesa, 28006 Madrid, Spain;
| | - Rosa P. Gomariz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
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Wu J, Gu J, Zhou S, Lu H, Lu Y, Lu L, Wang X. Anti-IL-22 Antibody Attenuates Acute Graft-versus-Host Disease via Increasing Foxp3 + T Cell through Modulation of CD11b + Cell Function. J Immunol Res 2018; 2018:1605341. [PMID: 30159338 PMCID: PMC6109487 DOI: 10.1155/2018/1605341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 06/20/2018] [Accepted: 06/28/2018] [Indexed: 12/14/2022] Open
Abstract
Transfer of splenocytes isolated from B6 mice into normal B6D2F1 mice induces acute graft-versus-host disease (aGVHD), resulting in the expansion of donor cytotoxic T lymphocytes that eliminate recipient B cells. The cytokine IL-22, secreted by Th1 cells, Th17 cells, and innate immune cells, is structurally related to IL-10. To investigate the association between IL-22 and aGVHD, an anti-mouse IL-22 antibody (IL-22Ab) was used to ablate IL-22 activity in a mouse aGVHD model. Administration of IL-22Ab significantly reduced the progression of aGVHD in B6D2F1 recipients of B6 grafts. IL-22Ab treatment also decreased the percentage of interferon-γ+ and tumor necrosis factor-α+ T cells but increased the number of forkhead box p3+ regulatory T cells (Tregs). In the presence of Tregs and donor CD11b+ cells, IL-22Ab protected against aGVHD. In vitro Treg induction was more efficient when CD4+CD25- T cells differentiated in the presence of CD11b+ cells obtained from IL-22Ab-treated GVHD mice, compared with cocultured untreated control cells. Finally, IL-22Ab modulated the expression of cytokines and costimulatory molecules in CD11b+ cells in aGVHD mice. We therefore conclude that IL-22Ab administration represents a viable approach for treating aGVHD.
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Affiliation(s)
- Jianbo Wu
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
- Department of General Surgery, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Jian Gu
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
| | - Shun Zhou
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
| | - Hao Lu
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
| | - Yunjie Lu
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
| | - Ling Lu
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
| | - Xuehao Wang
- Department of Liver Surgery, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, National Health and Family Planning Commission, Nanjing, Jiangsu Province, China
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The Anti-Inflammatory Mediator, Vasoactive Intestinal Peptide, Modulates the Differentiation and Function of Th Subsets in Rheumatoid Arthritis. J Immunol Res 2018; 2018:6043710. [PMID: 30155495 PMCID: PMC6092975 DOI: 10.1155/2018/6043710] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 07/19/2018] [Indexed: 12/15/2022] Open
Abstract
Genetic background, epigenetic modifications, and environmental factors trigger autoimmune response in rheumatoid arthritis (RA). Several pathogenic infections have been related to the onset of RA and may cause an inadequate immunological tolerance towards critical self-antigens leading to chronic joint inflammation and an imbalance between different T helper (Th) subsets. Vasoactive intestinal peptide (VIP) is a mediator that modulates all the stages comprised between the arrival of pathogens and Th cell differentiation in RA through its known anti-inflammatory and immunomodulatory actions. This “neuroimmunopeptide” modulates the pathogenic activity of diverse cell subpopulations involved in RA as lymphocytes, fibroblast-like synoviocytes (FLS), or macrophages. In addition, VIP decreases the expression of pattern recognition receptor (PRR) such as toll-like receptors (TLRs) in FLS from RA patients. These receptors act as sensors of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) connecting the innate and adaptive immune system. Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells. Finally, VIP regulates the plasticity between theses subsets. In this review, we provide an overview of VIP effects on the aforementioned features of RA pathology.
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Jiang W, Wang H, Li YS, Luo W. Role of vasoactive intestinal peptide in osteoarthritis. J Biomed Sci 2016; 23:63. [PMID: 27553659 PMCID: PMC4995623 DOI: 10.1186/s12929-016-0280-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 08/09/2016] [Indexed: 02/06/2023] Open
Abstract
Vasoactive intestinal peptide (VIP) plays important roles in many biological functions, such as, stimulation of contractility in the heart, vasodilation, promoting neuroendocrine-immune communication, lowering arterial blood pressure, and anti-inflammatory and immune-modulatory activity. Osteoarthritis (OA) is a chronic and degenerative bone disease, which is one of the most common causes of disability and most common in both sexes as people become older. Interestingly VIP can prevent chronic cartilage damage and joint remodeling. This review article provides update information on the association of VIP and OA and its treatment. Evidences suggest that VIP is down-regulated in synovial fluid of OA, and VIP down-regulation leads to increase in the production of pro-inflammatory cytokines that might contribute to the pathogenesis of OA; however contradictory reports also exist suggesting that accumulation of VIP in joints can also contribute OA. A number of studies indicated that up-regulation of VIP can counteract the action of pro-inflammatory stimuli and alleviate the pain in OA. More clinical investigations are necessary to determine the biology of VIP and its therapeutic potential in OA that might represent the future standards of care for OA.
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Affiliation(s)
- Wei Jiang
- Department of Bone and Joint, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong, 518020, China
| | - Hua Wang
- Department of Bone and Joint, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, Guangdong, 518020, China
| | - Yu-Sheng Li
- Department of Orthopaedics, Xiang-ya Hospital, Central South University, Changsha, Hunan, 410078, China.
| | - Wei Luo
- Department of Orthopaedics, Xiang-ya Hospital, Central South University, Changsha, Hunan, 410078, China.
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Huan C, Kim D, Ou P, Alfonso A, Stanek A. Mechanisms of interleukin-22's beneficial effects in acute pancreatitis. World J Gastrointest Pathophysiol 2016; 7:108-116. [PMID: 26909233 PMCID: PMC4753176 DOI: 10.4291/wjgp.v7.i1.108] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 11/11/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin (IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly anti-inflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the anti-autophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.
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Molligan J, Barr C, Mitchell R, Schon L, Zhang Z. Pathological role of fibroblast-like synoviocytes in charcot neuroarthropathy. J Orthop Res 2016. [PMID: 26212797 DOI: 10.1002/jor.22989] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
This study was designed to characterize the synovium in the joints of Charcot neuroarthropathy (CNA) and investigate the potential role of fibroblast-like synoviocytes (FLS) in the pathology of CNA. Synovial samples were collected from CNA patients (n = 7) and non-CNA patients (n = 7), for control, during orthopaedic procedures and used for histology and isolation of FLS. Histological characterization of synovium included innervation and FLS localization. The isolated FLS from the CNA and non-CNA synovium were cultured, with or without tumor necrosis factor-α (TNF-α), for evaluation of invasiveness, gene expression, and cartilage degradation. Vasoactive intestinal peptide (VIP), a neuropeptide, was supplemented into the co-cultures of FLS and cartilage explants. Compared with the non-CNA synovium, CNA synovium was highly inflammatory, with reduced innervation and intense expression of cadherin-11. The FLS isolated from CNA synovium, particularly when activated with TNF-α, were more invasive, increased the expression of ADAMTS4, IL-6, and RANKL, and depleted proteoglycans from cartilage explants when they were co-cultured. Addition of VIP into the culture medium neutralized the catabolic effect of the CNA FLS on cartilage explants. In conclusion, FLS plays an important role in the pathology of CNA. Therapies targeting synovium and FLS may prevent or treat the joint destruction in CNA.
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Affiliation(s)
- Jeremy Molligan
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, 201 E. University Parkway, Baltimore, Maryland, 21218
| | - Cameron Barr
- Department of Orthopaedic Surgery, MedStar Union Memorial Hospital, Baltimore, Maryland
| | - Reed Mitchell
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, 201 E. University Parkway, Baltimore, Maryland, 21218
| | - Lew Schon
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, 201 E. University Parkway, Baltimore, Maryland, 21218.,Department of Orthopaedic Surgery, MedStar Union Memorial Hospital, Baltimore, Maryland
| | - Zijun Zhang
- Orthobiologic Laboratory, MedStar Union Memorial Hospital, 201 E. University Parkway, Baltimore, Maryland, 21218
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Pérez-García S, Carrión M, Gutiérrez-Cañas I, González-Álvaro I, Gomariz RP, Juarranz Y. VIP and CRF reduce ADAMTS expression and function in osteoarthritis synovial fibroblasts. J Cell Mol Med 2016; 20:678-87. [PMID: 26818776 PMCID: PMC5126260 DOI: 10.1111/jcmm.12777] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 12/04/2015] [Indexed: 12/18/2022] Open
Abstract
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family is known to play an important role in the pathogenesis of osteoarthritis (OA), working on aggrecan degradation or altering the integrity of extracellular matrix (ECM). Thus, the main purpose of our study was to define the role of vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF), as immunoregulatory neuropeptides, on ADAMTS production in synovial fibroblasts (SF) from OA patients and healthy donors (HD). OA- and HD-SF were stimulated with pro-inflammatory mediators and treated with VIP or CRF. Both neuropeptides decreased ADAMTS-4, -5, -7 and -12 expressions, aggrecanase activity, glycosaminoglycans (GAG), and cartilage oligomeric matrix protein (COMP) degradation after stimulation with fibronectin fragments (Fn-fs) in OA-SF. After stimulation with interleukin-1β, VIP reduced ADAMTS-4 and -5, and both neuropeptides decreased ADAMTS-7 production and COMP degradation. Moreover, VIP and CRF reduced Runx2 and β-catenin activation in OA-SF. Our data suggest that the role of VIP and CRF on ADAMTS expression and cartilage degradation could be related to the OA pathology since scarce effects were produced in HD-SF. In addition, their effects might be greater when a degradation loop has been established, given that they were higher after stimulation with Fn-fs. Our results point to novel OA therapies based on the use of neuropeptides, since VIP and CRF are able to stop the first critical step, the loss of cartilage aggrecan and the ECM destabilization during joint degradation.
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Affiliation(s)
- Selene Pérez-García
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
| | - Mar Carrión
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
| | - Irene Gutiérrez-Cañas
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
| | - Isidoro González-Álvaro
- Reumatology Service, Medical Research Institute, La Princesa University Hospital, Madrid, Spain
| | - Rosa P Gomariz
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
| | - Yasmina Juarranz
- Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain
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Ometto F, Friso L, Astorri D, Botsios C, Raffeiner B, Punzi L, Doria A. Calprotectin in rheumatic diseases. Exp Biol Med (Maywood) 2016; 242:859-873. [PMID: 27895095 DOI: 10.1177/1535370216681551] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker. Impact statement Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.
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Affiliation(s)
- Francesca Ometto
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Lara Friso
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Davide Astorri
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Costantino Botsios
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Bernd Raffeiner
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Leonardo Punzi
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
| | - Andrea Doria
- Medicine Department - DIMED, Rheumatology Unit, University of Padova, Padova 35128, Italy
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Roeleveld DM, Koenders MI. The role of the Th17 cytokines IL-17 and IL-22 in Rheumatoid Arthritis pathogenesis and developments in cytokine immunotherapy. Cytokine 2015; 74:101-7. [PMID: 25466295 DOI: 10.1016/j.cyto.2014.10.006] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/21/2014] [Accepted: 10/24/2014] [Indexed: 01/01/2023]
Abstract
Over the past few years, the importance of Interleukin (IL)-17 and T helper (Th)17 cells in the pathology of Rheumatoid Arthritis (RA) has become apparent. RA is a systemic autoimmune disease that affects up to 1% of the population worldwide. It is characterized by an inflamed, hyperplastic synovium with pannus formation, leading to bone and cartilage destruction in the joints. By the production of effector cytokines like IL-17 and IL-22, the T helper 17 subset protects the host against bacterial and fungal infections, but it can also promote the development of various autoimmune diseases like RA. Hence, the Th17 pathway recently became a very interesting target in RA treatment. Up to now, several therapies targeting the Th17 cells or its effector cytokines have been tested, or are currently under investigation. This review clarifies the role of Th17 cells and its cytokines in the pathogenesis of RA, and provides an overview of the clinical trials using immunotherapy to target this particular T helper subset or the two main effector cytokines by which the Th17 cells exert their function, IL-17 and IL-22.
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Affiliation(s)
- Debbie M Roeleveld
- Radboud University Medical Center, Experimental Rheumatology, Department of Rheumatology, Geert Grooteplein 26-28, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
| | - Marije I Koenders
- Radboud University Medical Center, Experimental Rheumatology, Department of Rheumatology, Geert Grooteplein 26-28, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
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Nikoopour E, Bellemore SM, Singh B. IL-22, cell regeneration and autoimmunity. Cytokine 2015; 74:35-42. [PMID: 25467639 DOI: 10.1016/j.cyto.2014.09.007] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 09/18/2014] [Accepted: 09/20/2014] [Indexed: 12/16/2022]
Abstract
IL-22 as a cytokine is described with opposing pro-inflammatory and anti-inflammatory functions. Cell regeneration, tissue remodelling and balance between commensal bacteria in the gut and host immune system are considered as anti-inflammatory features of IL-22, whereas production of IL-22 from Th17 cells links this cytokine to pro-inflammatory pathways. Th17 cells and group 3 innate lymphoid cells (ILC3) are two major producers of IL-22 and both cell types express ROR-γt and Aryl hydrocarbon receptor (AhR) transcription factors. Typically, the immune system cells are the main producers of IL-22. However, targets of this cytokine are mostly non-hematopoietic cells such as hepatocytes, keratinocytes, and epithelial cells of lung and intestine. Association of IL-22 with other cytokines or transcription factors in different cell types might explain its contrasting role in health and disease. In this review we discuss the regulation of IL-22 production by AhR- and IL-23-driven pathways. A clear understanding of the biology of IL-22 will provide new opportunities for its application to improve human health involving many debilitating conditions.
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Affiliation(s)
- Enayat Nikoopour
- Centre for Human Immunology, Department of Microbiology and Immunology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Stacey M Bellemore
- Centre for Human Immunology, Department of Microbiology and Immunology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Bhagirath Singh
- Centre for Human Immunology, Department of Microbiology and Immunology, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
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12
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Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and resultant progressive joint damage. It has become increasingly evident that cytokines play an important role in the pathogenesis of RA. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family. Recent findings suggest that not only the expression of IL-22 is abnormal both in RA patients and in arthritis mice but also the aberrant IL-22 performs significantly in disease onset of RA. In this paper, we focus on the critical role of IL-22 in RA. Hopefully, the information obtained may lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for this systemic autoimmune disease.
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Affiliation(s)
- Qiang Xie
- School of Pharmacy, Anhui Medical University , Hefei, Anhui , PR China
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Vasoactive Intestinal Peptide in Early Spondyloarthritis: Low Serum Levels as a Potential Biomarker for Disease Severity. J Mol Neurosci 2015; 56:577-84. [PMID: 25711477 PMCID: PMC4477066 DOI: 10.1007/s12031-015-0517-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/04/2015] [Indexed: 12/19/2022]
Abstract
Spondyloarthritis (SpA) is a family of inflammatory diseases sharing clinical, genetic, and radiological features. While crucial for tailoring early interventions, validated prognostic biomarkers are scarce in SpA. We analyze the correlation between serum levels of vasoactive intestinal peptide (VIP) and disease activity/severity in patients with early chronic inflammatory back pain. The study population comprised 54 patients enrolled in our early chronic inflammatory back pain register. We collected demographic information, clinical data, laboratory data, and imaging findings. VIP levels were measured by enzyme immunoassay in serum samples from 162 visits. The association between independent variables and VIP levels was analyzed using longitudinal multivariate analysis nested by patient and visit. No significant differences were observed in VIP levels between these two groups. Lower levels of VIP were significantly associated with a higher Bath Ankylosing Spondylitis Disease Activity Index (BASFI) score, presence of bone edema in magnetic resonance imaging (MRI) scan, and lower hemoglobin levels. Coexistence of cutaneous psoriasis was independently associated with lower VIP levels, and similar trend was observed for enthesitis. We conclude that SpA patients with low serum VIP levels had worse 2-year disease outcome, suggesting that serum VIP levels could be a valid prognostic biomarker.
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Sulfiredoxin-1 protects primary cultured astrocytes from ischemia-induced damage. Neurochem Int 2015; 82:19-27. [PMID: 25620665 DOI: 10.1016/j.neuint.2015.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 01/05/2015] [Accepted: 01/15/2015] [Indexed: 11/22/2022]
Abstract
Astrocytes appear to be important regulators of the inflammatory events that occur in stroke. Sulfiredoxin-1 (Srxn1), an endogenous antioxidant protein, exhibits neuroprotective effects. Although the mechanism by which Srxn1 negatively regulates oxidative and apoptotic pathways has been extensively characterized, the impact of Srxn1 on inflammation has not been well studied. In this study, we used oxygen-glucose deprivation followed by recovery (OGD/R) and hydrogen peroxide (H2O2) to mimic stress from cerebral ischemic damage on primary cultured astrocytes. We found that knockdown of Srxn1 by two shRNAs resulted in decreased cell viability of astrocytes. Decreased level of Srxn1 also correlated with excessive levels of proinflammatory cytokines and chemokines such as TNF-α, MPO, IL-1β, and IL-6. In addition, Srxn1 appeared to influence the strength of TLR4 signaling pathway; the expression of COX-2, IL-6, and NOS2 were strongly induced by OGD/R and H2O2 in astrocyte cultures with Srxn1-shRNAs. Our results suggested that loss of Srxn1 expression in astrocytes may cause excessive activation of inflammatory responses which contribute to OGD/R- and H2O2-induced cell death. Restoring Srxn1 function by gene therapy and/or pharmacology emerges as a promising strategy for the treatment of stroke and other chronic neurodegenerative diseases.
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Vasoactive Intestinal Peptide (VIP) Nanoparticles for Diagnostics and for Controlled and Targeted Drug Delivery. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 98:145-68. [DOI: 10.1016/bs.apcsb.2014.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Jimeno R, Gomariz RP, Garín M, Gutiérrez-Cañas I, González-Álvaro I, Carrión M, Galindo M, Leceta J, Juarranz Y. The pathogenic Th profile of human activated memory Th cells in early rheumatoid arthritis can be modulated by VIP. J Mol Med (Berl) 2014; 93:457-67. [PMID: 25430993 PMCID: PMC4366555 DOI: 10.1007/s00109-014-1232-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 09/15/2014] [Accepted: 11/12/2014] [Indexed: 12/30/2022]
Abstract
UNLABELLED Our aim is to study the behavior of memory Th cells (Th17, Th17/1, and Th1 profiles) from early rheumatoid arthritis (eRA) patients after their in vitro activation/expansion to provide information about its contribution to RA chronicity. Moreover, we analyzed the potential involvement of vasoactive intestinal peptide (VIP) as an endogenous healing mediator. CD4(+)CD45RO(+) T cells from PBMCs of HD and eRA were activated/expanded in vitro in the presence/absence of VIP. FACS, ELISA, RT-PCR, and immunocytochemistry analyses were performed. An increase in CCR6(+)/RORC(+) cells and in RORC-proliferating cells and a decrease in T-bet-proliferating cells and T-bet(+)/RORC(+) cells were shown in eRA. mRNA expression of IL-17, IL-2, RORC, RORA, STAT3, and Tbx21 and protein secretion of IL-17, IFNγ, and GM-CSF were higher in eRA. VIP decreased the mRNA expression of IL-22, IL-2, STAT3, Tbx21, IL-12Rβ2, IL-23R, and IL-21R in HD and it decreased IL-21, IL-2, and STAT3 in eRA. VIP decreased IL-22 and GM-CSF secretion and increased IL-9 secretion in HD and it decreased IL-21 secretion in eRA. VPAC2/VPAC1 ratio expression was increased in eRA. All in all, memory Th cells from eRA patients show a greater proportion of Th17 cells with a pathogenic Th17 and Th17/1 profile compared to HD. VIP is able to modulate the pathogenic profile, mostly in HD. Our results are promising for therapy in the early stages of RA because they suggest that targeting molecules involved in the pathogenic Th17, Th17/1, and Th1 phenotypes and targeting VIP receptors could have a therapeutic effect modulating these subsets. KEY MESSAGES Th17 cells are more important than Th1 in the contribution to pathogenesis in eRA patients. Pathogenic Th17 and Th17/1 profile are abundant in activated/expanded memory Th cells from eRA patients. VIP decreases the pathogenic Th17, Th1, and Th17/1 profiles, mainly in healthy donors. The expression of VIP receptors is reduced in eRA patients respect to healthy donors, whereas the ratio of VPAC2/VPAC1 expression is higher.
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Affiliation(s)
- Rebeca Jimeno
- Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, 28040, Madrid, Spain
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Affiliation(s)
- Illana Gozes
- The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Department of Humana Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, 69978, Israel,
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