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      Vagal innervation limits brain injury by inhibiting gut-selective integrin-mediated intestinal immunocyte migration in intracerebral hemorrhage

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          Abstract

          Rationale: The vagus nerve, which connects the brain and gastrointestinal tract, helps to maintain immune balance in the intestines. Gut-specific integrins, on the other hand, help to keep immune cells in the intestines. Since immune cells from outside the intestines can significantly affect the outcome of strokes, we investigated how immune cells from the intestines affect the immune response in the brain during intracerebral hemorrhage (ICH).

          Methods: We aimed to examine the impact of vagal innervation on intestinal immunocyte trafficking and its influence on ICH outcomes using Kikume Green-Red (KikGR) and wildtype (WT) mice, with or without prior subdiaphragmatic vagotomy (SDV). Furthermore, we sought to elucidate the regulatory effects of vagal innervation on intestinal immunocyte trafficking by activating α7 nicotinic acetylcholine receptors (α7nAChR) in WT mice that underwent ICH after SDV. Additionally, we explored the potential intermediary role of gut-selective integrins in cholinergic transmitters-mediated intestinal immunocyte trafficking. Our methodology encompassed in vivo fluorescence imaging, flow cytometry, Western blotting, immunofluorescence staining, histopathology, and behavioral assessments to evaluate the outcomes.

          Results: Our findings reveal that during the acute phase of ICH, intestinal immunocytes migrated to various anatomical locations, including the circulation, hemorrhagic brain, meninges, and deep cervical lymph nodes. Pertinently, SDV resulted in diminished expression of α4β7 and αEβ7 integrins on immunocytes, leading to heightened intestinal immunocyte trafficking and exacerbated ICH outcomes. Conversely, the administration of α7nAChR agonists countered the adverse effects of vagotomy on α4β7 and αEβ7 integrin expression, thereby constraining the migration of immune cells from the intestines after ICH. The implication of α4β7 and αEβ7 integrins in this setting was supported by the ineffective influence of α7nAChR agonists on the trafficking of intestinal immunocytes enhanced by administering beta-7 integrin antagonists, such as etrolizumab. It was further supported by the exacerbated ICH outcomes by administering beta-7 integrin antagonists like etrolizumab alone.

          Conclusion: The identification of vagus nerve-mediated modulation of α4β7 and αEβ7 integrin expression in the trafficking of immune cells within the intestinal tract holds significant implications. This discovery presents new opportunities for developing therapeutic interventions for ICH and stimulates further investigation in this area.

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          Structural and functional features of central nervous system lymphatics

          One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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            Interactions between the microbiota and the immune system.

            The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.
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              Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

              Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2024
                28 October 2024
                : 14
                : 19
                : 7383-7404
                Affiliations
                [1 ]Department of Neurology, The People's Hospital of Zhengzhou University & Henan Provincial People's Hospital, 450003, Zhengzhou, P. R. China.
                [2 ]Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, P. R. China
                [3 ]The Laboratory of Cerebrovascular Diseases and Neuroimmunology, The Fifth Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, P. R. China.
                [4 ]Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, 450001, Zhengzhou, P. R. China.
                Author notes
                ✉ Corresponding authors: Chao Jiang, Department of Neurology, The People's Hospital of Zhengzhou University & Henan Provincial People's Hospital, 450003, Zhengzhou, Henan, P. R. China; Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, P. R. China; The Laboratory of Cerebrovascular Diseases and Neuroimmunology, The Fifth Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, P. R. China. (Phone: 011-86-371-66916128; E-mail: chaoj@ 123456zzu.edu.cn ; ORCID: 0000-0001-5588-4294). Or: Jian Wang, Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, 450001, Zhengzhou, P. R. China. (E-mail: jianwang2020@ 123456outlook.com ; ORCID: 0000-0003-2291-640X; Scopus ID: 36638705600; Publons Web of Science Researcher ID: I-4874-2019). Or: Jiewen Zhang, Department of Neurology, The People's Hospital of Zhengzhou University & Henan Provincial People's Hospital, 450003, Zhengzhou, Henan, P. R. China. (Phone: 011-86-371-65580851; E-mail: zhangjiewen9900@ 123456126.com ; ORCID: 0000-0001-6784-6658). Or: Junmin Wang, Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, 450001, Zhengzhou, P. R. China. (E-mail: wangjunmin@ 123456zzu.edu.cn ; ORCID: 0000-0001-9830-0164).

                # These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov14p7383
                10.7150/thno.101680
                11626938
                39659582
                945e7799-f61f-454c-9be5-e8df5273b2e3
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See https://ivyspring.com/terms for full terms and conditions.

                History
                : 30 July 2024
                : 22 October 2024
                Categories
                Research Paper

                Molecular medicine
                intracerebral hemorrhage,vagus nerve,intestinal immunocyte trafficking,α7nachrs,gut-selective integrin,immunomodulatory therapy

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