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      Targeting MAPK Pathways by Naringenin Modulates Microglia M1/M2 Polarization in Lipopolysaccharide-Stimulated Cultures

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          Abstract

          Neuroinflammation is considered to be an important and inevitable pathological process associated with all types of damages to, and disorders of, the central nervous system. The hallmark of neuroinflammation is the microglia activation. In response to different micro-environmental disturbances, microglia could polarize into either an M1 pro-inflammatory phenotype, exacerbating neurotoxicity, or an M2 anti-inflammatory phenotype, exerting neuroprotection. Therefore, shifting the polarization of microglia toward the M2 phenotype could possess a more viable strategy for the neuroinflammatory disorders treatment. Naringenin (NAR) is naturally a grapefruit flavonoid and possesses various kinds of pharmacological activities, such as anti-inflammatory and neuroprotective activities. In the present study, we aimed to investigate the potential effects of NAR on microglial M1/M2 polarization and further reveal the underlying mechanisms of actions. First, NAR inhibited lipopolysaccharide (LPS)-induced microglial activation. Then, NAR shifted the M1 pro-inflammatory microglia phenotype to the M2 anti-inflammatory M2 microglia state as demonstrated by the decreased expression of M1 markers (i.e., inducible TNF-α and IL-1β) and the elevated expression of M2 markers (i.e., arginase 1, IL-4, and IL-10). In addition, the effects of NAR on microglial polarization were dependent on MAPK signaling, particularly JNK inactivation, as evidenced by the fact that the selective activator of JNK abolished NAR-promoted M2 polarization and further NAR-inhibited microglial activation. Together, this study demonstrated that NAR promoted microglia M1/M2 polarization, thus conferring anti-neuroinflammatory effects via the inhibition of MAPK signaling activation. These findings might provide new alternative avenues for neuroinflammation-related disorders treatment.

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          Microglial and macrophage polarization—new prospects for brain repair.

          The traditional view of the adult brain as a static organ has changed in the past three decades, with the emergence of evidence that it remains plastic and has some regenerative capacity after injury. In the injured brain, microglia and macrophages clear cellular debris and orchestrate neuronal restorative processes. However, activation of these cells can also hinder CNS repair and expand tissue damage. Polarization of macrophage populations toward different phenotypes at different stages of injury might account for this dual role. This Perspectives article highlights the specific roles of polarized microglial and macrophage populations in CNS repair after acute injury, and argues that therapeutic approaches targeting cerebral inflammation should shift from broad suppression of microglia and macrophages towards subtle adjustment of the balance between their phenotypes. Breakthroughs in the identification of regulatory molecules that control these phenotypic shifts could ultimately accelerate research towards curing brain disorders.
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            M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma

            Background Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC). Methods Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms. Results THP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells. Conclusions We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC. Electronic supplementary material The online version of this article (10.1186/s13046-018-0815-2) contains supplementary material, which is available to authorized users.
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              Microglia/macrophage polarization dynamics in white matter after traumatic brain injury.

              Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation-induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                11 January 2019
                2018
                : 12
                : 531
                Affiliations
                Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University , Zunyi, China
                Author notes

                Edited by: Sriharsha Kantamneni, University of Bradford, United Kingdom

                Reviewed by: Sharon DeMorrow, Texas A&M Health Science Center, United States; Miriam Sciaccaluga, University of Perugia, Italy

                *Correspondence: Feng Zhang, zhangfengzmc@ 123456163.com
                Article
                10.3389/fncel.2018.00531
                6336899
                30687017
                651600a1-05e0-4de1-b1c2-f4e414b8cb4e
                Copyright © 2019 Zhang, Wei, Wang, Li, Shi and Zhang.

                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
                : 23 October 2018
                : 24 December 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 37, Pages: 11, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences
                neuroinflammation,microglia polarization,lipopolysaccharide,naringenin,mapk signaling

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