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      The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions

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          Abstract

          Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6’s involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6’s mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6’s interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders.

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          IL-6 in inflammation, immunity, and disease.

          Toshio Tanaka, Masashi Narazaki, Tadamitsu Kishimoto (2014)
          Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.
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            Inflammation as a central mechanism in Alzheimer's disease

            Jefferson Kinney, Shane M. Bemiller, Andrew S Murtishaw … (2018)
            Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
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              Interleukin-6, a Major Cytokine in the Central Nervous System

              María Erta, Albert Quintana, Juan Hidalgo (2012)
              Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.
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                Author and article information

                Contributors
                Irina Kerkis: URI : https://loop.frontiersin.org/people/1117794Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Álvaro Prieto da Silva: Role: Role: Role: Role:
                Rodrigo Pinheiro Araldi: URI : https://loop.frontiersin.org/people/2641618Role: Role: Role:
                Journal
                Journal ID (nlm-ta): Front Immunol
                Journal ID (iso-abbrev): Front Immunol
                Journal ID (publisher-id): Front. Immunol.
                Title: Frontiers in Immunology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-3224
                Publication date (Electronic): 24 June 2024
                Publication date Collection: 2024
                Volume: 15
                Electronic Location Identifier: 1400533
                Affiliations
                [1] 1 Genetics Laboratory, Center of Development and Innovation, Butantan Institute , São Paulo, Brazil
                [2] 2 BioDecision Analytics Ltda. , São Paulo, Brazil
                [3] 3 Post-graduation Program in Structural and Functional Biology, Paulista School of Medicine Escola Paulista de Medicina (EPM), Federal University of São Paulo Universidade Federal de São Paulo (UNIFESP) , São Paulo, Brazil
                Author notes

                Edited by: Tomasz Kordula, Virginia Commonwealth University, United States

                Reviewed by: Lutz Graeve, University of Hohenheim, Germany

                Masanori A. Murayama, Kansai Medical University, Japan

                *Correspondence: Irina Kerkis, irina.kerkis@ 123456butantan.gov.br
                Article
                DOI: 10.3389/fimmu.2024.1400533
                PMC ID: 11249726
                PubMed ID: 39015561
                SO-VID: 0c9f5f12-0281-4852-acd8-bb9447f04947
                Copyright © Copyright © 2024 Kerkis, Silva and Araldi
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 13 March 2024
                Date accepted : 04 June 2024
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 167, Pages: 11, Words: 4805
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors thank the Butantan Institute and the Butantan Foundation for the financial support provided for this study. The support provided in this study by the Butantan Foundation was facilitated through the cost center BF FCDID 73012.
                Categories
                Subject: Immunology
                Subject: Review
                Custom metadata
                section-in-acceptance Cytokines and Soluble Mediators in Immunity

                ScienceOpen disciplines: Immunology
                Keywords: interleukin-6 (il-6),mesenchymal stem cells (mscs),il-6 dysregulation,neurodegenerative diseases,huntington disease (hd),stroke
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: interleukin-6 (il-6), mesenchymal stem cells (mscs), il-6 dysregulation, neurodegenerative diseases, huntington disease (hd), stroke

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