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      Electro‐nape‐acupuncture regulates the differentiation of microglia through PD‐1/PD‐L1 reducing secondary brain injury in acute phase intracerebral hemorrhage rats

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          Abstract

          Introduction

          This study aimed to investigate the effect of electro‐nape‐acupuncture (ENA) on the differentiation of microglia and the secondary brain injury in rats with acute‐phase intracerebral hemorrhage (ICH) through the programmed cell death protein‐1/ligand‐1 (PD‐1/PD‐L1) pathway.

          Methods

          A total of 27 male Sprague‐Dawley rats were randomly divided into three groups: sham group, ICH group, and ENA group. The autologous blood infusion intracerebral hemorrhage model was used to study the effects of ENA by administering electroacupuncture at GB20 (Fengchi) and Jiaji (EX‐B2) acupoints on 24 h after the modeling, once per day for 3 days. The neurological function damage, hematoma lesion, and inflammatory cell infiltration were measured by the beam walking test and hematoxylin‐eosin staining. The expression of PD‐1, PD‐L1, CD86, CD206, and related cytokines around the hematoma was measured by western blot, quantitative reverse transcription polymerase chain reaction, and immunofluorescence.

          Results

          The ICH group had significant neurological deficits ( p < .001), hematoma lesions, and inflammatory cell infiltration. The levels of CD86 protein, inflammatory factors tumor necrosis factors (TNF)‐α, interleukin (IL)‐1β, and IL‐6 were increased ( p < .001), while CD206 protein was reduced ( p < .01), and the number of CD86 +/CD11b + cells was also increased ( p < .001) compared to the sham group. However, after ENA intervention, there was a significant reduction in neurological function damage ( p < .05), infiltration of inflammatory cells, and the expression levels of CD86 +/CD11b + cells ( p < .05), resulting in the increased expression of PD‐1 protein and differentiation of M2 phenotype significantly ( p < .001).

          Conclusion

          The study concludes that ENA could reduce neurological function damage, inhibit the expression of pro‐inflammatory cytokines, and improve the infiltration of inflammatory cells to improve secondary brain injury in acute‐phase intracerebral hemorrhage rats. These effects could be related to the increased expression of PD‐1 around the lesion, promoting the differentiation of microglia from M1 to M2 phenotype.

          Abstract

          Electro‐nape‐acupuncture can reduce neurological function damage, inhibited the expression of pro‐inflammatory cytokines, and reduced the infiltration of inflammatory cells, thus improving the secondary brain injury.

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          Most cited references44

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          Restoring function in exhausted CD8 T cells during chronic viral infection.

          Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.
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            Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke.

            Microglia/macrophages are the major immune cells involved in the defence against brain damage. Their morphology and functional changes are correlated with the release of danger signals induced by stroke. These cells are normally responsible for clearing away dead neural cells and restoring neuronal functions. However, when excessively activated by the damage-associated molecular patterns following stroke, they can produce a large number of proinflammatory cytokines that can disrupt neural cells and the blood-brain barrier and influence neurogenesis. These effects indicate the important roles of microglia/macrophages in the pathophysiological processes of stroke. However, the modifiable and adaptable nature of microglia/macrophages may also be beneficial for brain repair and not just result in damage. These distinct roles may be attributed to the different microglia/macrophage phenotypes because the M1 population is mainly destructive, while the M2 population is neuroprotective. Additionally, different gene expression signature changes in microglia/macrophages have been found in diverse inflammatory milieus. These biofunctional features enable dual roles for microglia/macrophages in brain damage and repair. Currently, it is thought that the proper inflammatory milieu may provide a suitable microenvironment for neurogenesis; however, detailed mechanisms underlying the inflammatory responses that initiate or inhibit neurogenesis remain unknown. This review summarizes recent progress concerning the mechanisms involved in brain damage, repair and regeneration related to microglia/macrophage activation and phenotype transition after stroke. We also argue that future translational studies should be targeting multiple key regulating molecules to improve brain repair, which should be accompanied by the concept of a "therapeutic time window" for sequential therapies.
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              Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

              Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients.
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                Author and article information

                Contributors
                drcuihai@163.com
                Journal
                Brain Behav
                Brain Behav
                10.1002/(ISSN)2157-9032
                BRB3
                Brain and Behavior
                John Wiley and Sons Inc. (Hoboken )
                2162-3279
                23 August 2023
                November 2023
                : 13
                : 11 ( doiID: 10.1002/brb3.v13.11 )
                : e3229
                Affiliations
                [ 1 ] School of Traditional Chinese Medicine, Capital Medical University Beijing China
                Author notes
                [*] [* ] Correspondence

                Cui Hai, School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China.

                Email: drcuihai@ 123456163.com .

                Article
                BRB33229
                10.1002/brb3.3229
                10636396
                37614117
                431c3260-3b57-4892-b8e9-f4b3c8e0e3bb
                © 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 July 2023
                : 22 March 2023
                : 09 August 2023
                Page count
                Figures: 5, Tables: 1, Pages: 11, Words: 6757
                Funding
                Funded by: Science and Technology Development Plan of Education Committee of Beijing
                Award ID: KM201810025018
                Funded by: Beijing Municipal Government
                Categories
                Original Article
                Original Article
                Custom metadata
                2.0
                November 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.4 mode:remove_FC converted:10.11.2023

                Neurosciences
                electro‐nape‐acupuncture,intracerebral hemorrhage,microglia differentiation,programmed cell death protein‐1

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