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Rabin A, Bello E, Kumar S, Zeki DA, Afshari K, Deshpande M, Francis N, Khalighinejad F, Umeton R, Radu I, Qutab F, Kwong D, Kurban M, Hemond C, Richmond JM, Ionete C. Targeted proteomics of cerebrospinal fluid in treatment naïve multiple sclerosis patients identifies immune biomarkers of clinical phenotypes. Sci Rep 2024; 14:21793. [PMID: 39294186 PMCID: PMC11411093 DOI: 10.1038/s41598-024-67769-1] [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: 04/21/2024] [Accepted: 07/12/2024] [Indexed: 09/20/2024] Open
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease with heterogeneous clinical presentations and variable long-term disability accumulation. There are currently no standard criteria to accurately predict disease outcomes. In this study we investigated the cross-sectional relationship between disease phenotype and immune-modulating cytokines and chemokines in cerebrospinal fluid (CSF). We analyzed CSF from 20 DMT-naïve MS patients using Olink Proteomics' Target 96 Inflammation panel and correlated the resulting analytes with respect to (1) disease subtype, (2) patient age and sex, (3) extent of clinical disability, and (4) MRI segmental brain volumes. We found that intrathecal IL-4 correlated with higher Expanded Disability Status Scale (EDSS) scores and longer 25-foot walk times, and CD8A correlated with decreased thalamic volumes and longer 9-hole peg test times. Male sex was associated with higher FGF-19 expression, and Tumefactive MS with elevated CCL4. Several inflammatory markers were correlated with older age at the time of LP. Finally, higher intrathecal IL-33 correlated with increased MS lesion burden and multi-compartment brain atrophy. This study confirms immune heterogeneity underlying CSF profiles in MS, but also identifies several inflammatory protein biomarkers that may be of use for predicting clinical outcomes in future algorithms.
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Affiliation(s)
- Alexandra Rabin
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Elisa Bello
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Saurabh Kumar
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Dalia Abou Zeki
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Khashayar Afshari
- Department of Dermatology, UMass Chan Medical School, Worcester, MA, USA
| | - Mugdha Deshpande
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Nimmy Francis
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | | | - Raffaella Umeton
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Irina Radu
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Fatima Qutab
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Danny Kwong
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | - Mariana Kurban
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA
| | | | - Jillian M Richmond
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
- Department of Dermatology, UMass Chan Medical School, Worcester, MA, USA.
| | - Carolina Ionete
- Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
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2
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Grunwald C, Krętowska-Grunwald A, Adamska-Patruno E, Kochanowicz J, Kułakowska A, Chorąży M. The Role of Selected Interleukins in the Development and Progression of Multiple Sclerosis-A Systematic Review. Int J Mol Sci 2024; 25:2589. [PMID: 38473835 PMCID: PMC10932438 DOI: 10.3390/ijms25052589] [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: 01/27/2024] [Revised: 02/18/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Multiple sclerosis is a disabling inflammatory disorder of the central nervous system characterized by demyelination and neurodegeneration. Given that multiple sclerosis remains an incurable disease, the management of MS predominantly focuses on reducing relapses and decelerating the progression of both physical and cognitive decline. The continuous autoimmune process modulated by cytokines seems to be a vital contributing factor to the development and relapse of multiple sclerosis. This review sought to summarize the role of selected interleukins in the pathogenesis and advancement of MS. Patients with MS in the active disease phase seem to exhibit an increased serum level of IL-2, IL-4, IL-6, IL-13, IL-17, IL-21, IL-22 and IL-33 compared to healthy controls and patients in remission, while IL-10 appears to have a beneficial impact in preventing the progression of the disease. Despite being usually associated with proinflammatory activity, several studies have additionally recognized a neuroprotective role of IL-13, IL-22 and IL-33. Moreover, selected gene polymorphisms of IL-2R, IL-4, IL-6, IL-13 and IL-22 were identified as a possible risk factor related to MS development. Treatment strategies of multiple sclerosis that either target or utilize these cytokines seem rather promising, but more comprehensive research is necessary to gain a clearer understanding of how these cytokines precisely affect MS development and progression.
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Affiliation(s)
- Cezary Grunwald
- Department of Neurology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Białystok, Poland; (J.K.); (A.K.)
| | - Anna Krętowska-Grunwald
- Department of Pediatric Oncology and Hematology, Medical University of Bialystok, Jerzego Waszyngtona 17, 15-274 Białystok, Poland;
| | - Edyta Adamska-Patruno
- Clinical Research Center, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Białystok, Poland;
| | - Jan Kochanowicz
- Department of Neurology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Białystok, Poland; (J.K.); (A.K.)
| | - Alina Kułakowska
- Department of Neurology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Białystok, Poland; (J.K.); (A.K.)
| | - Monika Chorąży
- Department of Neurology, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A, 15-276 Białystok, Poland; (J.K.); (A.K.)
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3
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Jia Z, Guo M, Ge X, Chen F, Lei P. IL-33/ST2 Axis: A Potential Therapeutic Target in Neurodegenerative Diseases. Biomolecules 2023; 13:1494. [PMID: 37892176 PMCID: PMC10605306 DOI: 10.3390/biom13101494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies.
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Affiliation(s)
- Zexi Jia
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mengtian Guo
- Department of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100054, China;
| | - Xintong Ge
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fanglian Chen
- Tianjin Neurological Institute, Tianjin 300052, China
| | - Ping Lei
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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4
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Gill AJ, Schorr EM, Gadani SP, Calabresi PA. Emerging imaging and liquid biomarkers in multiple sclerosis. Eur J Immunol 2023; 53:e2250228. [PMID: 37194443 PMCID: PMC10524168 DOI: 10.1002/eji.202250228] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/10/2023] [Accepted: 05/12/2023] [Indexed: 05/18/2023]
Abstract
The advent of highly effective disease modifying therapy has transformed the landscape of multiple sclerosis (MS) care over the last two decades. However, there remains a critical, unmet need for sensitive and specific biomarkers to aid in diagnosis, prognosis, treatment monitoring, and the development of new interventions, particularly for people with progressive disease. This review evaluates the current data for several emerging imaging and liquid biomarkers in people with MS. MRI findings such as the central vein sign and paramagnetic rim lesions may improve MS diagnostic accuracy and evaluation of therapy efficacy in progressive disease. Serum and cerebrospinal fluid levels of several neuroglial proteins, such as neurofilament light chain and glial fibrillary acidic protein, show potential to be sensitive biomarkers of pathologic processes such as neuro-axonal injury or glial-inflammation. Additional promising biomarkers, including optical coherence tomography, cytokines and chemokines, microRNAs, and extracellular vesicles/exosomes, are also reviewed, among others. Beyond their potential integration into MS clinical care and interventional trials, several of these biomarkers may be informative of MS pathogenesis and help elucidate novel targets for treatment strategies.
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Affiliation(s)
- Alexander J. Gill
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, US
| | - Emily M. Schorr
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, US
| | - Sachin P. Gadani
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, US
| | - Peter A. Calabresi
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, US
- Department of Neuroscience, Baltimore, MD, US
- Department of Ophthalmology, Baltimore, MD, US
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5
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Mado H, Adamczyk-Sowa M, Sowa P. Role of Microglial Cells in the Pathophysiology of MS: Synergistic or Antagonistic? Int J Mol Sci 2023; 24:ijms24031861. [PMID: 36768183 PMCID: PMC9916250 DOI: 10.3390/ijms24031861] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/05/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Many studies indicate an important role of microglia and their cytokines in the pathophysiology of multiple sclerosis (MS). Microglia are the macrophages of the central nervous system (CNS). They have many functions, such as being "controllers" of the CNS homeostasis in pathological and healthy conditions, playing a key role in the active immune defense of the CNS. Macroglia exhibit a dual role, depending on the phenotype they adopt. First, they can exhibit neurotoxic effects, which are harmful in the case of MS. However, they also show neuroprotective and regenerative effects in this disease. Many of the effects of microglia are mediated through the cytokines they secrete, which have either positive or negative properties. Neurotoxic and pro-inflammatory effects can be mediated by microglia via lipopolysaccharide and gamma interferon. On the other hand, the mediators of anti-inflammatory and protective effects secreted by microglia can be, for example, interleukin-4 and -13. Further investigation into the role of microglia in MS pathophysiology may perhaps lead to the discovery of new therapies for MS, as recent research in this area has been very promising.
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Affiliation(s)
- Hubert Mado
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Correspondence: ; Tel.: +48-695948463; Fax: +48-323704597
| | - Monika Adamczyk-Sowa
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Paweł Sowa
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
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6
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Kaisey M, Lashgari G, Fert-Bober J, Ontaneda D, Solomon AJ, Sicotte NL. An Update on Diagnostic Laboratory Biomarkers for Multiple Sclerosis. Curr Neurol Neurosci Rep 2022; 22:675-688. [PMID: 36269540 DOI: 10.1007/s11910-022-01227-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE For many patients, the multiple sclerosis (MS) diagnostic process can be lengthy, costly, and fraught with error. Recent research aims to address the unmet need for an accurate and simple diagnostic process through discovery of novel diagnostic biomarkers. This review summarizes recent studies on MS diagnostic fluid biomarkers, with a focus on blood biomarkers, and includes discussion of technical limitations and practical applicability. RECENT FINDINGS This line of research is in its early days. Accurate and easily obtainable biomarkers for MS have not yet been identified and validated, but several approaches to uncover them are underway. Continue efforts to define laboratory diagnostic biomarkers are likely to play an increasingly important role in defining MS at the earliest stages, leading to better long-term clinical outcomes.
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Affiliation(s)
- Marwa Kaisey
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA.
| | - Ghazal Lashgari
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
| | - Justyna Fert-Bober
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
| | - Daniel Ontaneda
- Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave. U10 Mellen Center, Cleveland, OH, 44106, USA
| | - Andrew J Solomon
- Department of Neurological Sciences, Larner College of Medicine at the University of Vermont University Health Center, Arnold 2, 1 South Prospect Street, Burlington, VT, 05401, USA
| | - Nancy L Sicotte
- Cedars-Sinai Medical Center Department of Neurology, 127 S. San Vicente Blvd, A6600, Los Angeles, CA, 90048, USA
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7
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Shakerian L, Kolahdooz H, Garousi M, Keyvani V, Kamal Kheder R, Abdulsattar Faraj T, Yazdanpanah E, Esmaeili SA. IL-33/ST2 axis in autoimmune disease. Cytokine 2022; 158:156015. [PMID: 36041312 DOI: 10.1016/j.cyto.2022.156015] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/03/2022]
Abstract
Interleukin-33 (IL-33) is a member of the IL-1 family and plays an ambivalent role in autoimmune diseases. IL-33 signals via the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, NK cells, and T lymphocyte cells. The vital role of IL-33 as an active component gives rise to aberrant local and systemic damage which has been demonstrated in numerous inflammatory disorders and immune-mediated pathological conditions including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, Sjogren's syndrome, inflammatory bowel disease (IBD), etc. IL-33/ST2 axis can up-regulate pro-inflammatory cytokine release in autoimmune disease, however, in some metabolic diseases like diabetes mellitus type 1 IL-33 can be considered an anti-inflammatory cytokine. The purpose of this review is to discuss selected studies on IL-33/ST2 axis in autoimmune diseases and its potential role as a pathogenic or protective cytokine.
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Affiliation(s)
- Leila Shakerian
- Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh Kolahdooz
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mitra Garousi
- Department of Internal Medicine, Faculty of Medical Sciences, Hamedan University of Medical Sciences, Hamedan, Iran
| | - Vahideh Keyvani
- Molecular Genetics, Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Ramiar Kamal Kheder
- Medical Laboratory Science Department, College of Science, University of Raparin, Rania 46012, Sulaymaniyah, Iraq; Department of Basic Sciences, College of Medicine, Hawler Medical University, Erbil, Iraq
| | - Tola Abdulsattar Faraj
- Department of Basic Sciences, College of Medicine, Hawler Medical University, Erbil, Iraq; Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Iraq
| | - Esmaeil Yazdanpanah
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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8
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Rao X, Hua F, Zhang L, Lin Y, Fang P, Chen S, Ying J, Wang X. Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation. J Transl Med 2022; 20:369. [PMID: 35974336 PMCID: PMC9382782 DOI: 10.1186/s12967-022-03570-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 08/04/2022] [Indexed: 12/13/2022] Open
Abstract
With the advent of an aging society, the incidence of dementia is increasing, resulting in a vast burden on society. It is increasingly acknowledged that neuroinflammation is implicated in various neurological diseases with cognitive dysfunction such as Alzheimer’s disease, multiple sclerosis, ischemic stroke, traumatic brain injury, and central nervous system infections. As an important neuroinflammatory factor, interleukin-33 (IL-33) is highly expressed in various tissues and cells in the mammalian brain, where it plays a role in the pathogenesis of a number of central nervous system conditions. Reams of previous studies have shown that IL-33 has both pro- and anti-inflammatory effects, playing dual roles in the progression of diseases linked to cognitive impairment by regulating the activation and polarization of immune cells, apoptosis, and synaptic plasticity. This article will summarize the current findings on the effects IL-33 exerts on cognitive function by regulating neuroinflammation, and attempt to explore possible therapeutic strategies for cognitive disorders based on the adverse and protective mechanisms of IL-33.
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Affiliation(s)
- Xiuqin Rao
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Lieliang Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Pu Fang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Shoulin Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jun Ying
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Xifeng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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9
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IL-33 in autoimmunity; possible therapeutic target. Int Immunopharmacol 2022; 108:108887. [DOI: 10.1016/j.intimp.2022.108887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/08/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022]
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Behzadi P, Sameer AS, Nissar S, Banday MZ, Gajdács M, García-Perdomo HA, Akhtar K, Pinheiro M, Magnusson P, Sarshar M, Ambrosi C. The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs). J Immunol Res 2022; 2022:2054431. [PMID: 35378905 PMCID: PMC8976653 DOI: 10.1155/2022/2054431] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/24/2022] [Accepted: 03/08/2022] [Indexed: 12/19/2022] Open
Abstract
Interleukins (ILs)-which are important members of cytokines-consist of a vast group of molecules, including a wide range of immune mediators that contribute to the immunological responses of many cells and tissues. ILs are immune-glycoproteins, which directly contribute to the growth, activation, adhesion, differentiation, migration, proliferation, and maturation of immune cells; and subsequently, they are involved in the pro and anti-inflammatory responses of the body, by their interaction with a wide range of receptors. Due to the importance of immune system in different organisms, the genes belonging to immune elements, such as ILs, have been studied vigorously. The results of recent investigations showed that the genes pertaining to the immune system undergo progressive evolution with a constant rate. The occurrence of any mutation or polymorphism in IL genes may result in substantial changes in their biology and function and may be associated with a wide range of diseases and disorders. Among these abnormalities, single nucleotide polymorphisms (SNPs) can represent as important disruptive factors. The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.
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Affiliation(s)
- Payam Behzadi
- Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University, Tehran 37541-374, Iran
| | - Aga Syed Sameer
- Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India
- Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India
| | - Saniya Nissar
- Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India
- Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India
| | - Mujeeb Zafar Banday
- Molecular Disease & Diagnosis Division, Infinity Biochemistry Pvt. Ltd, Sajjad Abad, Chattabal, Srinagar, Kashmir, India
- Department of Biochemistry, Government Medical College, Karan Nagar, Srinagar, Kashmir, India
| | - Márió Gajdács
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6720 Szeged, Hungary
| | - Herney Andrés García-Perdomo
- Division of Urology, Department of Surgery, School of Medicine, UROGIV Research Group, Universidad del Valle, Cali, Colombia
| | - Kulsum Akhtar
- Department of Clinical Biochemistry, Sher I Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India
| | - Marina Pinheiro
- Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
- CHUP, Centro Hospitalar Universitário do Porto, Largo do Prof. Abel Salazar, 4099-001 Porto, Portugal
| | - Peter Magnusson
- School of Medical Sciences, Örebro University, SE, 701 82 Örebro, Sweden
- Cardiology Research Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Meysam Sarshar
- Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy
| | - Cecilia Ambrosi
- IRCCS San Raffaele Roma, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy
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11
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Role of IL-33/ST2 Axis in Chronic Inflammatory Neurological Disorderss. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2020-0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Interleukin-33 (IL-33) is a member of IL-1 family of cytokines, produced constitutively by fibroblasts, endothelial cells, and epithelial cells. IL-33 can be released passively from cells during tissue damage and cell necrosis, suggesting that it may act as an alarmin. Function of IL-33 is mediated by its interaction with ST2 molecule that is expressed on many immune cells: Th2 lymphocytes, NK, NKT and mast cells, monocytes, dendritic cells and granulocytes. IL-33/ST2 pathway plays, often dual, roles in different physiological and inflammatory processes, mediating both, pathological immune responses and tissue repair. Expression of IL-33 in the central nervous system (CNS) is significantly enhanced during various pathological processes, indicating its important role in the pathogenesis of neurological inflammatory and degenerative diseases. In this review the biological features, expression of IL-33 and its ligand ST2 in CNS, and the role of IL- 33/ST2 pathway in development of Alzheimer’s disease and multiple sclerosis are discussed.
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12
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Borovcanin MM, Vesic K. Breast cancer in schizophrenia could be interleukin-33-mediated. World J Psychiatry 2021; 11:1065-1074. [PMID: 34888174 PMCID: PMC8613763 DOI: 10.5498/wjp.v11.i11.1065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/21/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Recent epidemiological and genetic studies have revealed an interconnection between schizophrenia and breast cancer. The mutual underlying pathophysiological mechanisms may be immunologically driven. A new cluster of molecules called alarmins may be involved in sterile brain inflammation, and we have already reported the potential impact of interleukin-33 (IL-33) on positive symptoms onset and the role of its soluble trans-membranes full length receptor (sST2) on amelioration of negative symptoms in schizophrenia genesis. Furthermore, these molecules have already been shown to be involved in breast cancer etiopathogenesis. In this review article, we aim to describe the IL-33/suppressor of tumorigenicity 2 (ST2) axis as a crossroad in schizophrenia-breast cancer comorbidity. Considering that raloxifene could be tissue-specific and improve cognition and that tamoxifen resistance in breast carcinoma could be improved by strategies targeting IL-33, these selective estrogen receptor modulators could be useful in complementary treatment. These observations could guide further somatic, as well as psychiatric therapeutical protocols by incorporating what is known about immunity in schizophrenia.
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Affiliation(s)
- Milica M Borovcanin
- Department of Psychiatry, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Serbia
| | - Katarina Vesic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Serbia
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Kozłowska E, Brzezińska-Błaszczyk E, Agier J, Wysokiński A, Żelechowska P. Alarmins (IL-33, sST2, HMGB1, and S100B) as potential biomarkers for schizophrenia. J Psychiatr Res 2021; 138:380-387. [PMID: 33957300 DOI: 10.1016/j.jpsychires.2021.04.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/03/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022]
Abstract
There is growing evidence that immune/inflammatory processes are related to the etiology of schizophrenia. Danger-/damage-associated molecular patterns (DAMPs), also called alarmins, are recognized as inflammatory mediators that play an important role in the development of many infection-induced or sterile inflammatory diseases. The importance of DAMPs particles in various mental disorders is still not clear. Therefore, this study aimed to evaluate serum levels of the most promising alarmins (IL-33, sST2, HMGB1, and S100B), as potent schizophrenia biomarkers. Sixty-eight adult patients with chronic schizophrenia and twenty-nine healthy volunteers were included in this prospective study. Enzyme-linked immunosorbent assay (ELISA) was used to assess the serum concentration of IL-33, sST2, HMGB1, and S100B. We documented that the serum levels of IL-33 (p = 0.006), sST2 (p = 0.02), HMGB1 (p = 0.01), and S100B (p = 0.04) are significantly higher in patients with schizophrenia than in healthy subjects. In male, but not in female, patients with schizophrenia, we found a significant difference in the serum IL-33, sST2, and HMGB1 concentrations as compared to the healthy men. In both male and female patients with schizophrenia, there was no significant difference in the serum concentrations of S100B in comparison to control subjects. In patients with schizophrenia, no significant correlations were noticed neither between any studied alarmins and PANSS scores nor between CDSS scores. Given that all investigated alarmins participate in the course of the neuroinflammatory process, they might be considered as biomarkers of neuroinflammatory process underlying schizophrenia. Based on our observations, it seems that the most useful biological indicator of schizophrenia would be IL-33.
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Affiliation(s)
- Elżbieta Kozłowska
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland.
| | | | - Justyna Agier
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
| | - Adam Wysokiński
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Paulina Żelechowska
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
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Mado H, Adamczyk-Sowa M, Bartman W, Wierzbicki K, Tadeusiak B, Sowa P. Plasma Interleukin-33 level in relapsing-remitting multiple sclerosis. Is it negatively correlated with central nervous system lesions in patients with mild disability? Clin Neurol Neurosurg 2021; 206:106700. [PMID: 34030079 DOI: 10.1016/j.clineuro.2021.106700] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/06/2021] [Accepted: 05/12/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND Cytokines and chemokines are undoubtedly involved in the pathogenesis of multiple sclerosis (MS). There are many reports that suggest a significant role for Interleukin-33 (IL-33) in the course of MS development, but it is not clear whether negative or positive. We therefore investigated plasma IL-33 levels in patients with relapsing-remitting MS (RRMS). METHODS The study consisted of RRMS patients (n = 73) and healthy subjects (n = 54). Blood samples were taken from all and plasma IL-33 levels were then determined using an enzyme-linked immunosorbent assay method. Patients also underwent laboratory and imaging tests and their disability status was assessed. RESULTS Plasma IL-33 levels were marginally significantly higher in patients with RRMS (p = 0.07). Higher IL-33 levels are significantly associated with higher age (p = 0.01). There was also a statistically significant negative correlation between plasma IL-33 levels and the number of high signal intensity lesions in T2-weighted MRI (p = 0.03). After dividing the number of lesions into groups < 9 and ≥ 9 T2-weighted lesions, the Student's t-test for unrelated variables showed a negative correlation, but not statistically significant (p = 0.22), while the Spearman's correlation showed a marginally significant correlation (p = 0.06) between IL-33 level and number of T2-weighted lesions. IL-33 was also shown to have a significant ability to differentiate RRMS patients from healthy subjects with a sensitivity of 99% and specificity of 70% (p = 0.00). CONCLUSIONS Patients with RRMS have elevated plasma IL-33 levels. In RRMS patients with mild disability, high plasma levels of IL-33 may have neuroprotective effects potentially by stimulating remyelination and/or suppressing autoimmune inflammation and damage. Further studies on this matter on a larger number of patients are needed.
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Affiliation(s)
- Hubert Mado
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland.
| | - Monika Adamczyk-Sowa
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
| | - Wojciech Bartman
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
| | - Krzysztof Wierzbicki
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
| | - Bartosz Tadeusiak
- Department of Neurology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
| | - Paweł Sowa
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
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15
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Shajarian M, Alsahebfosoul F, Etemadifar M. The Effect of IFN-β Treatment on Plasma Levels of BDNF and IL-6 in Relapsing-Remitting Multiple Sclerosis Patients. Neuroimmunomodulation 2021; 28:150-157. [PMID: 34182566 DOI: 10.1159/000515595] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/26/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND In recent investigations addressing neurodegenerative diseases, especially multiple sclerosis (MS), the roles of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) have been examined. METHODS Forty-five relapsing-remitting MS (RRMS) patients, including 32 IFN-β-treated and 13 newly identified untreated cases as well as 45 sex- and age-matched healthy controls, were recruited in the study. Plasma levels of BDNF and IL-6 were assessed using the ELISA method. Data were analyzed by SPSS (ver.21). RESULTS There were significant differences between the case and healthy control groups in terms of the plasma levels of BDNF (p value = 0.044) and IL-6 (p value <0.001). Besides, the treatment with IFN-β had no significant impact on the level of BDNF or IL-6 in RRMS patients as compared to healthy controls (p value = 0.716 and 0.623 for BDNF and IL-6, respectively). Furthermore, the increase in the plasma levels of BDNF and IL-6 indicated a direct correlation in the case group (r = 0.508, p value = 0.008). In detail, following the classification of the case group into 2 subgroups of IFN-β-treated and untreated patients, a direct positive correlation was observed between the plasma levels of BDNF and IL-6 in IFN-β-treated patients (r = 0.495, p value = 0.026). CONCLUSION The IFN-β treatment seems not to be effective for upregulating BDNF and IL-6 in RRMS patients.
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Affiliation(s)
- Mansour Shajarian
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fereshteh Alsahebfosoul
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masoud Etemadifar
- Department of Neurosurgery, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Ahmadi M, Fathi F, Fouladi S, Alsahebfosul F, Manian M, Eskandari N. Serum IL-33 Level and IL-33, IL1RL1 Gene Polymorphisms in Asthma and Multiple Sclerosis Patients. Curr Mol Med 2020; 19:357-363. [PMID: 30950351 DOI: 10.2174/1566524019666190405120137] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/23/2019] [Accepted: 03/27/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Asthma is a chronic and complex inflammatory disease of the respiratory tract. Also, multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Against this background, IL-33 and IL1RL1 play a critical role in autoimmune and inflammatory disorders. Here, we explored the IL-33 serum level and two potential genetic variants in the IL33 gene and its receptor in Iranian asthma and MS patients. METHODS This study consisted of asthma (n=140) and MS patients (n=140), and healthy subjects (n=72). Genotyping was carried out in two genetic polymorphisms, rs1342326 variant of IL-33 and rs10204137SNP variant of IL-33 receptor genes, using High- Resolution Melt Real- Time PCR based method. The level of serum IL-33 was also measured using enzyme-linked immunosorbent assay method. RESULTS The level of IL33 was significantly higher in asthma and MS patients compared to the control group (P< 0.001- P<0.001).The frequency distribution of the genotype in rs1342326 variant of IL-33 gene in patients with asthma, MS and healthy subjects was not significantly different (P>0.05). The frequency distribution of the genotype in rs10204137 variant of IL-33 gene in MS patients and healthy subjects was significantly different (p = 0.013). CONCLUSION Our findings demonstrated that asthma and MS patients had a higher level of IL-33, and IL-33 receptor genetic polymorphism was associated with MS. Further studies in a larger multicenter setting are needed to explore the value of this marker as a risk stratification biomarker.
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Affiliation(s)
- Maryam Ahmadi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farshid Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saloomeh Fouladi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fereshteh Alsahebfosul
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mostafa Manian
- Department of Immunology, school of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Migliorini P, Italiani P, Pratesi F, Puxeddu I, Boraschi D. The IL-1 family cytokines and receptors in autoimmune diseases. Autoimmun Rev 2020; 19:102617. [PMID: 32663626 DOI: 10.1016/j.autrev.2020.102617] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 03/13/2020] [Indexed: 12/12/2022]
Abstract
The role of the cytokines and receptors of the IL-1 family in inflammation is well known. Several cytokines of the family have a powerful inflammatory activity, with IL-1β being the best-characterized factor. The inflammatory activity of IL-1 cytokines is regulated by other factors of the family, including receptor antagonists, soluble receptors and anti-inflammatory cytokines. The causative role of IL-1β is well-established in autoinflammatory diseases, mainly due to gain-of-function mutations in genes encoding the IL-1β-maturing inflammasome. Exaggerated production of IL-1β and IL-18 correlates with disease and disease severity also in several autoimmune and chronic inflammatory and degenerative pathologies, although it is not clear whether they have a causative role or are only involved in the downstream disease symptoms. A better understanding of the pathological role of IL-1 family cytokines in autoimmunity involves a deeper evaluation, in the pathological situations, of the possible anomalies in the feed-back anti-inflammatory mechanisms that in physiological reactions control and dump IL-1-mediated inflammation. Thus, we expect that IL-1 cytokines may be pathogenic only when, in addition to enhanced production, there is a concomitant failure of their control mechanisms. In this review we will examine the current knowledge on the role of IL-1 family cytokines in autoimmune and chronic inflammatory and degenerative diseases, with a particular focus on their endogenous control mechanisms, mainly based on soluble receptors/inhibitors and receptor antagonists. This will allow us to formulate a knowledge-based hypothesis on the involvement of IL-1 cytokines in the pathogenesis vs. the clinical features of these diseases.
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Affiliation(s)
- Paola Migliorini
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Paola Italiani
- Institute of Biochemistry and Cell Biology, National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
| | - Federico Pratesi
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Ilaria Puxeddu
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Diana Boraschi
- Institute of Biochemistry and Cell Biology, National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
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Saçmacı H, Sabah Özcan S. A critical role for expression of atypical chemokine receptor 2 in multiple sclerosis: A preliminary project. Mult Scler Relat Disord 2020; 38:101524. [DOI: 10.1016/j.msard.2019.101524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 11/02/2019] [Accepted: 11/11/2019] [Indexed: 02/06/2023]
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The role of the IL-33/ST2 axis in autoimmune disorders: Friend or foe? Cytokine Growth Factor Rev 2019; 50:60-74. [DOI: 10.1016/j.cytogfr.2019.04.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/01/2019] [Indexed: 12/12/2022]
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20
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Du LX, Wang YQ, Hua GQ, Mi WL. IL-33/ST2 Pathway as a Rational Therapeutic Target for CNS Diseases. Neuroscience 2017; 369:222-230. [PMID: 29175156 DOI: 10.1016/j.neuroscience.2017.11.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 11/13/2017] [Accepted: 11/16/2017] [Indexed: 12/22/2022]
Abstract
Interleukin (IL)-33 is a member of the interleukin-1 cytokine family that is produced by many different types of tissues including the central nervous system (CNS). IL-33 mediates its effects via its heterodimeric receptor complex, comprised of ST2 and the IL-1 receptor accessory protein (IL-1RAcp). As a pleiotropic nuclear cytokine, IL-33 is a crucial factor in the development of cardiovascular diseases, allergic diseases, infectious diseases, and autoimmune diseases. Recently, accumulated evidence shows that the IL-33/ST2 axis plays a crucial and diverse role in the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infectious diseases, traumatic CNS injury, chronic pain, etc. In this review, we discuss the recent findings in the cellular signaling of IL-33 and advancement of the role of IL-33 in several CNS diseases, as well as its therapeutic potential for the treatment of those diseases.
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Affiliation(s)
- Li-Xia Du
- Department of Integrative Medicine and Neurobiology, Academy of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, People's Republic of China
| | - Yan-Qing Wang
- Department of Integrative Medicine and Neurobiology, Academy of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, People's Republic of China
| | - Guo-Qiang Hua
- Institute of Radiation Medicine, Fudan University, Shanghai 200032, People's Republic of China
| | - Wen-Li Mi
- Department of Integrative Medicine and Neurobiology, Academy of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, People's Republic of China.
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