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    Home > Active Ingredient News > Study of Nervous System > Protein & Cell | Yang Jing's team reveals a new immunomodulatory effect on degenerative diseases of the enteric nervous system

    Protein & Cell | Yang Jing's team reveals a new immunomodulatory effect on degenerative diseases of the enteric nervous system

    • Last Update: 2021-05-09
    • Source: Internet
    • Author: User
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    EditorNeurodegeneration (neurodegeneration) is one of the important neurological diseases.

    Among them, axonal degeneration is widespread in various neurodegenerative diseases such as traumatic nerve damage, chemotherapy nerve damage, diabetic nerve damage, multiple sclerosis, glaucoma, etc.
    , which leads to nerve damage by directly destroying nerve circuits.
    disfunction.

    Because of this, the past decades of research have been trying to explain the molecular signaling mechanism of axon degeneration.

    Researcher Yang Jing of Peking University participated in the identification of the core signal protein SARM1 that controls axon degeneration during his postdoctoral period (Osterloh et al.
    , Science 2012).

    The subsequent work of Prof.
    Yang Jing revealed that SARM1 protein is intrinsically closely related to axon energy metabolism (see BioArt report for details: Nature | Zhang Zhe/Yang Jing group jointly revealed the NAD+-mediated regulation mechanism of nerve cell "killer" Sarm1 protein activity ) (Yang et al.
    , Cell 2015; Jiang et al.
    , Nature 2020).

    At present, a large number of studies have shown that the signal pathway mediated by SARM1 protein controls axon degeneration under various nerve injury conditions, making SARM1 protein a new drug target for the treatment of neurodegeneration.

    It is worth noting that the traditional concept believes that axon degeneration will inevitably lead to negative and harmful neuropathological consequences, so why the SARM1 signaling pathway that can trigger this pathological process is preserved in evolution is an unsolved question in the field.

    In fact, it has never been reported whether axonal degeneration may play a beneficial role under certain disease conditions.

    The answer to this question is essential for a comprehensive understanding of neurodegenerative diseases, and for early warning of possible side effects in the development of related therapeutic drugs.

    The enteric nervous system (enteric nervous system) can operate independently of the central nervous system and peripheral nervous system (also often referred to as the "second brain"), and plays an important control function for various physiological functions of the intestine.

    However, few studies have reported on pathological changes of the enteric nervous system, especially degenerative diseases.

    In response to the above-mentioned research gaps, on April 19, 2021, Jing Yang’s research group published an article (research long article) Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon in Protein & Cell, revealing acute The phenomenon of catecholaminergic neurodegeneration in the intestine under inflammatory conditions, and explained that this neuropathological phenomenon is controlled by the SARM1 signaling pathway and unexpectedly exerts a protective function against the disease.

    As a starting point for this research, Yang Jing's group used advanced whole-tissue immunostaining and three-dimensional fluorescence imaging technology to systematically analyze the three-dimensional distribution of the enteric nervous system of adult mice, macaques, and humans for the first time in the field.

    Subsequently, studies found that there is large-scale catecholaminergic nerve damage in human colon tissues with ulcerative colitis.

    Similarly, in a mouse model of acute colitis induced by dextran sodium sulfate (DSS), there are also catecholaminergic nerve degeneration; on the contrary, the acetylcholinergic nerve in the enteric nervous system can induce colitis in DSS.
    There is no significant change in it.

    Furthermore, Jing Yang's group proved that this degenerative disease of the enteric nervous system is induced by TNF-alpha and is dependent on SARM1, which shows that Sarm1 gene knockout can significantly block the damage of catecholaminergic nerves in DSS-induced colitis.

    Surprisingly, however, Sarm1 gene knockout (Sarm1-/-) or catecholaminergic neurospecific Sarm1 gene knockout (Th-Cre; Sarm1fl/fl) both resulted in a significant deterioration of colitis symptoms.

    On the contrary, pharmacological methods remove catecholaminergic nerves in the enteric nervous system or chemical genetics inhibit the activity of these nerves, which can significantly improve the disease degree of colitis.

    In order to explore the specific mechanism of this new discovery, Yang Jing's group discovered that the catecholaminergic neurotransmitter norepinephrin (norepinephrin) can promote the expression of IL-17 proinflammatory factor cells in Th17 lymphocytes and ILC3s natural lymphoid cells.

    The pro-inflammatory function of norepinephrine is achieved by increasing the expression level of the important transcription factor RORgt in the above two types of immune cells.

    These research results suggest that TNF-alpha produced under colitis triggers the SARM1 signaling pathway to cause catecholaminergic neurodegenerative diseases, so as to reduce the production of IL-17 pro-inflammatory cytokines.

    In this nerve-immune circuit in the intestine, the catecholaminergic nerve functions as a "fuse", that is, through the fusing mechanism to avoid possible damage to the tissues caused by excessive inflammation.

    In summary, the latest research of Jing Yang's group has revealed a new and previously unknown beneficial effect of neurodegenerative diseases in maintaining the nerve-immune homeostasis in the intestinal tract.

    It is worth mentioning that Professor David Simon of Cornell University School of Medicine will comment on this work in the form of Commentary.

    Jing Yang's group is committed to the cutting-edge direction of neuroimmune regulation by integrating whole-tissue three-dimensional fluorescence imaging technology, disease animal models, non-human primate and human clinical samples, neurobiology, immunology, physiology, etc.
    A multidisciplinary approach, dedicated to systematically elucidating the new mechanisms and important roles of neuro-immune regulation.

    The work of the research group in recent years has revealed the key mechanisms of neuromodulation in classical immune organs and barrier tissues, and at the same time proved the innovative concept of local neurodegenerative diseases participating in immune regulation.

    These research results have opened up a new perspective on neuro-immune regulation under physiological or pathological conditions, and at the same time provided a key entry point for the treatment of various immune-related diseases.

    Original link: https://link.
    springer.
    com/article/10.
    1007/s13238-021-00835-w Platemaker: Instructions for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article.
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