理事会企画シンポジウム 「神経—免疫のクロストーク」
JSN Symposium |
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| 2020/9/10 9:00～9:20 Zoom A
JS-01
アドレナリン作動性神経による免疫応答の制御
Adrenergic nerves control immune responses in lymph nodes
*鈴木 一博1
1. 大阪大学免疫学フロンティア研究センター
*Kazuhiro Suzuki1
1. Immunology Frontier Research Center, Osaka University
Interactions between the nervous and immune systems has long been documented, but their cellular and molecular basis have emerged only recently. Lymphoid organs receive a rich supply of adrenergic nerves, which produce the principal sympathetic neurotransmitter, noradrenaline. However, the role of adrenergic nerves in the control of lymphocyte behaviors and consequential immune responses has been incompletely understood. Here, we show in mice that adrenergic nerves control lymphocyte trafficking through lymph nodes, which is reflected in the magnitude of adaptive immune responses. Inputs from adrenergic nerves to the β2-adrenergic receptor (β2AR) expressed on lymphocytes inhibited their exit from lymph nodes. This effect was caused by β2AR-mediated augmentation of signaling through CCR7 and CXCR4, chemokine receptors that promote lymphocyte retention in lymph nodes. The night-time surge of noradrenergic inputs to lymphocyte β2AR reduced the frequency of lymph node exit, which was accompanied by an increase of lymphocyte numbers in lymph nodes. Immunization during the period of lymphocyte accumulation in lymph nodes enhanced antibody production. The diurnal variation of the immune response was dependent on β2AR-mediated neural signals and lymphocyte circulation through lymph nodes. Moreover, our recent observations suggest that adrenergic nerves control an additional aspect of the immune system other than lymphocyte trafficking. Based on these findings, I present an integrated view on immune regulation by adrenergic nerves.
| | 2020/9/10 9:20～9:40 Zoom A
JS-02
脳梗塞後の免疫細胞の動態解析
Elucidation of immune cell dynamics after ischemic stroke
*伊藤 美菜子1、吉村 昭彦2
1. 九州大学、2. 慶應義塾大学
*Minako Ito1, Akihiko Yoshimura2
1. Kyushu Univ., 2. Keio Univ.
Acute and chronic inflammation are complicatedly involved in various central nervous system diseases. It has been reported that not only multiple sclerosis and anti-NMDA receptor antibody encephalitis but also neurological diseases such as Parkinson's disease and Alzheimer are associated with inflammation. It has also been strongly suggested that autism and schizophrenia are associated with the immune system. The elucidation of the interaction between immune cells and glial cells and nerve cells in the central nervous system is also important problems in the development of therapeutic / preventive methods for various central nervous system diseases.
In the acute and subacute phases of ischemic stroke, innate immune cells including macrophages infiltrate into the brain and cause prolonged inflammation and worsening of neurological symptoms. Moreover, it has been clarified that much more T cells infiltrate into the brain during the chronic phase after stroke than in the acute phase. Mice with a cerebral infarction are resistant to EAE and recurrence of cerebral infarction, which is “ischemic tolerance”. In order to elucidate the mechanism of the resistance, we performed bulk-RNA sequencing and single cell RNA sequencing of brain cells in the acute phase, chronic phase, and contralateral side of infarct region. The population of immune cells and brain-resident cells in the brain changed dramatically after stroke. Interestingly, changes in cell population and gene expression were observed not only on the infarct side but also on the opposite side. In the parabiosis experiment, we found that the tolerance was also imparted to other individuals via blood. Furthermore, it was suggested that the serum in acute phase, and the serum and blood cells in the chronic phase are important to acquire tolerance. These data suggest that damage tolerance to recurrence of ischemic stroke may affect not only the infarct region but also the contralateral side and spinal cord via serum and immune cells after brain injury.
| | 2020/9/10 9:40～10:00 Zoom A
JS-03
慢性ストレスによる脳内炎症の役割とメカニズム
Roles and mechanisms of chronic stress-induced neuroinflammation
*古屋敷 智之1
1. 神戸大学大学院医学研究科 薬理学分野
*Tomoyuki Furuyashiki1
1. Division of Pharmacology, Kobe University Graduate School of Medicine
Excessive and prolonged stress disturbs mental and bodily functions, and increases the risks of stress-related disorders such as depression. Rodent studies have shown that chronic stress induces microglial activation associated with the upregulation of inflammation-related molecules. Clinical studies have also suggested the presence of neuroinflammation in depressive subjects. However, the causal link between stress-induced neuroinflammation and mental disturbance remained elusive. Using repeated social defeat stress, a mouse model used to study depression, we have demonstrated that chronic stress induces microglial activation in the medial prefrontal cortex through innate immune receptors Toll-like receptor (TLR) 2/4, thereby leading to attenuated neuronal response with dendritic atrophy and depressive-like behaviors. Notably, stress-induced microglial activation occurs in selective brain regions including the medial prefrontal cortex and is enhanced with repetition of stress. To elucidate the mechanism of this microglial response, we have investigated stress-induced transcriptomic and epigenomic changes in microglia of distinct brain regions. Combined with the identification of a putative TLR2/4 ligand for the effects of chronic stress, we speculate that multiple signaling pathways from different routes contribute to microglial activation and its sensitization during chronic stress. In this symposium, I will introduce these recent findings about chronic stress-induced neuroinflammation and discuss the interaction between neurons and immune cells in this process.
| | 2020/9/10 10:00～10:20 Zoom A
JS-04
腸内環境と多発性硬化症
Gut environment and multiple sclerosis
*三宅 幸子1
1. 順天堂大学医学部 免疫学講座
*Sachiko Miyake1
1. Department of Immunology, Juntendo University Graduate School of Medicine
Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease of the central nervous system (CNS). The association of gut microbiota and various CNS diseases including neurodegenerative diseases, psychiatric diseases, and neuroinflammatory diseases such as MS have attracted attention. We have reported the presence of dysbiosis in the gut microbiota of MS patients characterized by the reduction in bacteria belonging to Clostridia clusters IV and XIVa, which produce short-chain fatty acids (SCFAs) in MS patients. Moreover, we found the reduction of the concentration of SCFAs in fecal samples obtained from MS patients. We revealed that either fiber-rich diet or administration of SCFAs ameliorated the experimental autoimmune encephalomyelitis, an animal model of MS in association with the increase of regulatory T cells. We further revealed that treatment with butyrate suppressed demyelination and enhanced remyelination in an organotypic slice culture in association with facilitating oligodendrocyte differentiation. Our findings shed light on a novel mechanism of interaction between the metabolites of gut microbiota and the CNS, and may provide a strategy to control demyelination and remyelination in MS.
| | 2020/9/10 10:20～10:40 Zoom A
JS-05
グリア−免疫連関からみた神経変性疾患
Glia-immune communication in neurodegenerative diseases
*山中 宏二1
1. 名古屋大学 環境医学研究所
*Koji Yamanaka1
1. Research Institute of Environmental Medicine, Nagoya University
Accumulating evidence indicate that glia-immune interaction plays a key role in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). However, the relationship between the innate and acquired immunity and the neuroinflammation affecting disease processes of ALS was not fully investigated.
To clarify the role of the peripheral immune environment in ALS disease course, we generated two strains of SOD1-ALS mice derived from different genetic backgrounds, C57BL/6 and Balb/c, known to have Th1- and Th2- dominant immune environments, respectively. Balb/c-ALS mice exhibited the shorter survival with a lower expression of a neurotrophic factor, IGF-I and fewer infiltrating immune cells in spinal cords. We also found defective microglia proliferation in Balb/c-ALS mice, possibly linked to deterioration of disease phenotype in ALS mice.
On the other hand, we also found that ablation of innate immune adaptor TRIF significantly shortened survival times with acceleration of disease progression of SOD1-ALS mice. Despite of dominant roles of MyD88 in Toll-like receptor signaling, MyD88 had a marginal impact on disease course of ALS. TRIF signaling also regulates the number of infiltrating immune cells into the spinal cords of ALS mice. In addition, aberrantly activated astrocytes, expressing Mac2, p62, and apoptotic markers, were accumulated in the lesions of TRIF-deficient ALS mice. These findings suggest that TRIF pathway plays an important role in protecting the brain environment by eliminating abnormal glial cells. Both studies suggest that a neuroprotective brain environment is maintained by glia-immune communications, and uncovered a novel role of TRIF in ALS.
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