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      Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

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          Abstract

          Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain ( Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.

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          Most cited references33

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          Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

          Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.
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            Extracellular vesicles round off communication in the nervous system.

            Functional neural competence and integrity require interactive exchanges among sensory and motor neurons, interneurons and glial cells. Recent studies have attributed some of the tasks needed for these exchanges to extracellular vesicles (such as exosomes and microvesicles), which are most prominently involved in shuttling reciprocal signals between myelinating glia and neurons, thus promoting neuronal survival, the immune response mediated by microglia, and synapse assembly and plasticity. Such vesicles have also been identified as important factors in the spread of neurodegenerative disorders and brain cancer. These extracellular vesicle functions add a previously unrecognized level of complexity to transcellular interactions within the nervous system.
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              Neuroinflammation pathways: a general review.

              Activated microglial cells play an important role in immune and inflammatory responses in central nervous system and neurodegenerative diseases. Many pro-apoptotic pathways are mediated by signaling molecules that are produced during neuroinflammation. In glial cells, NF-κB, a transcription factor, initiates and regulates the expression of several inflammatory processes during inflammation which are attributed to the pathology of the several neurodegenerative diseases. In this review, we discuss the most important neuroinflammatory mediators with their pathways. Attenuating cytokines production and controlling microglial inflammatory response, which are the result of understanding neuroinflammation pathways, are considered therapeutic strategies for treating neurodegenerative diseases with an inflammatory component.
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                Author and article information

                Contributors
                herradon@ceu.es
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                20 November 2020
                20 November 2020
                2020
                : 10
                : 20259
                Affiliations
                [1 ]GRID grid.8461.b, ISNI 0000 0001 2159 0415, Departamento de Ciencias Farmacéuticas y de La Salud, Facultad de Farmacia, , Universidad San Pablo-CEU, CEU Universities, ; Urbanización Montepríncipe, 28925 Alcorcón, Madrid Spain
                [2 ]GRID grid.8461.b, ISNI 0000 0001 2159 0415, Departamento de Química y Bioquímica, Facultad de Farmacia, , Universidad San Pablo-CEU, CEU Universities, ; Urbanización Montepríncipe, 28925 Alcorcón, Madrid Spain
                [3 ]BRAINco Biopharma, S.L., Bizkaia Technology Park, Derio, Spain
                Article
                76415
                10.1038/s41598-020-76415-5
                7679445
                33219280
                755ceeac-4a28-4d1a-87de-34c0a7b08154
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 May 2020
                : 27 October 2020
                Funding
                Funded by: Ministerio de Ciencia, Innovación y Universidades
                Award ID: RTI2018-095615-B-I00
                Funded by: Ministerio de Sanidad, Servicios Sociales e Igualdad
                Award ID: PNSD2019I015
                Funded by: Fundación Universitaria San Pablo CEU – Banco Santander
                Award ID: FUSPBS-PPC06_2017
                Award Recipient :
                Funded by: Comunidad de Madrid
                Award ID: S2017/BMD-3864
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                biochemistry,neuroscience
                Uncategorized
                biochemistry, neuroscience

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