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      Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

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          Abstract

          Background

          Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP.

          Methods

          We used a skin/muscle incision and retraction (SMIR) model to establish a rat CPSP model. Microglia, CXCR7, and the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways were regulated by intrathecal injections of minocycline (a non-specific microglial inhibitor), AMD3100 (a CXCR7 agonist), and LY294002 (a specific PI3K inhibitor), respectively. Mechanical allodynia was detected with von Frey filaments. The changes in microglia, A1 astrocytes, A2 astrocytes, CXCR7, and PI3K/Akt signaling pathways were examined by enzyme-linked immunosorbent assay (ELISA), western blot, and immunofluorescence.

          Results

          Microglia were found to be activated, with an increase in interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q) in the spinal cord at an early stage after SMIR. On day 14 after SMIR, spinal cord astrocytes were also activated; these were mainly of the A1 phenotype and less of the A2 phenotype. Intrathecal injection of minocycline relieved SMIR-induced mechanical allodynia and reverted the ratio of A1/A2 reactive astrocytes. The expression of CXCR7 and PI3K/Akt signaling was decreased after SMIR, while they were increased after treatment with minocycline. Furthermore, intrathecal injection of AMD3100 also relieved SMIR-induced mechanical allodynia, reverted the ratio of A1/A2 reactive astrocytes, and activated the PI3K/Akt signaling pathway, similar to the effects produced by minocycline. However, intrathecal injection of AMD3100 did not increase the analgesic effect of minocycline. Last, LY294002 inhibited the analgesic effect and A1/A2 transformation induced by minocycline and AMD3100 after SMIR.

          Conclusion

          Our results indicated that microglia induce the transformation of astrocytes to the A1 phenotype in the spinal cord via downregulation of the CXCR7/PI3K/Akt signaling pathway during CPSP. Reverting A1 reactive astrocytes to A2 may represent a new strategy for preventing CPSP.

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          Most cited references50

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          Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration

          In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here, we show that expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to trigger death of naïve neurons directly and to propagate neuronal death through activation of naïve astrocytes to A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria to the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glia cells. The propagation of inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration – one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
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            Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy.

            Microglia, the intrinsic macrophages of the central nervous system, have previously been shown to be activated in the spinal cord in several rat mononeuropathy models. Activation of microglia and subsequent release of proinflammatory cytokines are known to play a role in inducing a behavioral hypersensitive state (hyperalgesia and allodynia) in these animals. The present study was undertaken to determine whether minocycline, an inhibitor of microglial activation, could attenuate both the development and existing mechanical allodynia and hyperalgesia in an L5 spinal nerve transection model of neuropathic pain. In a preventive paradigm (to study the effect on the development of hypersensitive behaviors), minocycline (10, 20, or 40 mg/kg intraperitoneally) was administered daily, beginning 1 h before nerve transection. This regimen produced a decrease in mechanical hyperalgesia and allodynia, with a maximum inhibitory effect observed at the dose of 20 and 40 mg/kg. The attenuation of the development of hyperalgesia and allodynia by minocycline was associated with an inhibitory action on microglial activation and suppression of proinflammatory cytokines at the L5 lumbar spinal cord of the nerveinjured animals. The effect of minocycline on existing allodynia was examined after its intraperitoneal administration initiated on day 5 post-L5 nerve transection. Although the postinjury administration of minocycline significantly inhibited microglial activation in neuropathic rats, it failed to attenuate existing hyperalgesia and allodynia. These data demonstrate that inhibition of microglial activation attenuated the development of behavioral hypersensitivity in a rat model of neuropathic pain but had no effect on the treatment of existing mechanical allodynia and hyperalgesia.
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              Essential protective roles of reactive astrocytes in traumatic brain injury.

              Astrocytes respond to traumatic brain injury (TBI) by altered gene expression, hypertrophy and proliferation that occur in a gradated fashion in relation to the severity of the injury. Both beneficial and detrimental effects have been attributed to reactive astrocytes, but their roles after brain injury are not well understood. To investigate these roles, we determined the effects on cortical tissue of ablating reactive astrocytes after contusion injury generated by controlled cortical impact (CCI) of different severities in transgenic mice that express a glial fibrillary acidic protein-herpes simplex virus-thymidine kinase transgene. Treatment of these mice with the antiviral agent, ganciclovir, conditionally ablates proliferating reactive astrocytes. Moderate or severe CCI were generated with a precisely regulated pneumatic piston, and forebrain tissue was evaluated using immunohistochemistry and quantitative morphometry. Moderate CCI in control mice triggered extensive and persisting reactive astrogliosis, with most neurons being preserved, little inflammation and an 18% loss of cortical tissue beneath the impact site. Ablation of reactive astrocytes after moderate CCI in transgenic mice caused substantial neuronal degeneration and inflammation, with a significantly greater 60% loss of cortical tissue. Severe CCI in control mice caused pronounced neuronal degeneration and loss of about 88% of cortical tissue that was not significantly altered by ablating reactive astrocytes in transgenic mice. Thus, ablation of dividing reactive astrocytes exacerbated cortical degeneration after moderate CCI, but did not alter cortical degeneration after severe CCI. These findings indicate that the reactive astrocytes play essential roles in preserving neural tissue and restricting inflammation after moderate focal brain injury.
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                Author and article information

                Contributors
                tl_2448@126.com
                D201881690@hust.edu.cn
                chenxh_2016@126.com
                lily81630@126.com
                A121500025@163.com
                y.zhang0604@hotmail.com
                wanli0604@163.com
                chzhang@tjh.tjmu.edu.cn
                wlyao82@126.com
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                14 July 2020
                14 July 2020
                2020
                : 17
                : 211
                Affiliations
                [1 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430030 Hubei Province People’s Republic of China
                [2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Ophthalmology, Tongji Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430030 Hubei Province People’s Republic of China
                [3 ]GRID grid.257143.6, ISNI 0000 0004 1772 1285, Department of Physiology, , Hubei University of Chinese Medicine, ; Wuhan, 430065 Hubei Province People’s Republic of China
                Article
                1891
                10.1186/s12974-020-01891-5
                7362409
                32665021
                6193dbf6-3767-4e20-a7c9-9bb3a7ef6df5
                © The Author(s) 2020

                Open AccessThis 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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 16 April 2020
                : 7 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81000476
                Award ID: 81171158
                Award ID: 81600965
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003819, Natural Science Foundation of Hubei Province;
                Award ID: 2019CFB444
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Neurosciences
                skin/muscle incision and retraction,a1 astrocytes,a2 astrocytes,microglia,chronic post-surgical pain

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