Symposium
New trends in neruoimmunology
シンポジウム
神経免疫学の新潮流 |
|---|
| 7月26日（金）15:15～15:35 第5会場（朱鷺メッセ 3F 302）
2S05a-1
交感神経によるリンパ球の制御
Kazuhiro Suzuki（鈴木 一博）
大阪大学免疫学フロンティア研究センター
Crosstalk between the nervous and immune systems has long been documented, but the cellular and molecular basis for neural regulation of immunity has emerged only recently. Lymphoid organs receive a rich supply of adrenergic nerve fibers, which produce the principal sympathetic neurotransmitter, noradrenaline. However, the role of adrenergic nerves in the regulation of lymphocyte behaviors and immune responses has been incompletely understood. Here, we show 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 neural 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 humoral immune response was dependent on β2AR-mediated neural signals and diminished by stopping 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 the role of adrenergic nerves in lymphocyte biology. | | 7月26日（金）15:35～15:55 第5会場（朱鷺メッセ 3F 302）
2S05a-2
Excessive T cell activation in the absence of PD-1 affects behavior
Sidonia Fagarasan（Fagarasan Sidonia）
RIKEN
We have previously shown that adaptive immune system plays a critical role in maintenance of healthy microbial communities in the gut (Kawamoto S. et al, Immunity 2014). In addition, the microbial community residing in the gut is a prominent source of metabolites, and alterations of the adaptive immune system causes microbial dysbiosis, which in turn induces excessive immune activation (Kawamoto S. et al, Science 2012). These findings strongly suggest that disregulation of the adaptive immune system may alter the pool of circulating metabolites either directly via energy demands required for immune cell metabolic reprogramming or indirectly via microbial alterations, which likely alters the absorption of nutrients and the pool of bacterial-derived compounds. Indeed, T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. We found that augmented T cell responses in Pdcd1 ko mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of most of the amino acids. The amino acid depletion in serum was due to the accumulation of amino acids in activated Pdcd1 ko T cells in the lymph nodes. The systemic decrease of two important aromatic amino acids, namely tryptophan and tyrosine, led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Thus, excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system. | | 7月26日（金）15:55～16:15 第5会場（朱鷺メッセ 3F 302）
2S05a-3
脳内モノアミンの局在と動態のイメージング
Yuki Sugiura（杉浦 悠毅）
慶應大・医化学
Due to recent technical advances in instrumentation and sample preparation protocols, current imaging mass spectrometry (IMS) allows for the visualization of small molecule tissue localization, including that of monoamine neurotransmitters like serotonin, dopamine, and norepinephrine. Although monoamine-producing neurons, as well as their projections and synapses, have been thoroughly characterized, monoamine localization within these circuits remains unclear. Moreover, it is worth studying the fluctuations in local monoamine concentration in response to physiological stimuli, drug administration, and neurodegenerative disease progression, which can be achieved by analyzing the in situ concentration maps afforded by coupling IMS with on-tissue derivatization protocols.
Recent our reports have shown that monoamines localize not only within cell bodies, but also to distant nerve terminals, indicating active transport along axons and/or local synthesis at the terminals. IMS can also reveal regionally segregated monoamine fluctuations, including, for example, rapid dopamine reduction within the nucleus accumbens (NAcc) subregion during pain sensation. Furthermore, since exogenous drug pharmacokinetics can also be visualized by IMS, it would be powerful to develop methodologies enabling the simultaneous imaging of selective serotonin reuptake inhibitors (SSRIs) and monoamines, as doing so would reveal where SSRIs administered over the long-term accumulate and how they affect local monoamine metabolism. I'll also show that how the upregulated immune metabolism alters brain monoamine signaling, by visualization of deficiency of the serotonin and dopamine in the brain, resulting in behavioral changes. | | 7月26日（金）16:15～16:35 第5会場（朱鷺メッセ 3F 302）
2S05a-4
表皮感覚神経の動的恒常性とその皮膚炎における破綻
Takaharu Okada（岡田 峰陽）1,2
1理研IMS 組織動態
2横浜市大院生命医科学
Sensory nerve endings in the epidermis detect stimuli that evoke various types of sensations including itch. Sensory nerves are thought to be protected by the epidermal barrier from chronic overexposure to environmental stimuli, and the barrier impairment leads to the development of pathogenic itch such as that of atopic dermatitis (AD). Structural homeostasis of the epidermis is dynamically maintained as it is continuously renewed by keratinocyte stem cell proliferation and differentiation to barrier-forming cells. However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. We found that epidermal nerves were contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of itching dermatitis caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we observed that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs during normal turnover of the epidermis, whereas this process was disturbed in the dermatitis model. Furthermore, aberrant Ca2+ increases in nerves were observed in association with the disorganized pruning of epidermal nerves. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to chronic activation of epidermal nerves to transmit itch during the onset of dermatitis. | | 7月26日（金）16:35～16:55 第5会場（朱鷺メッセ 3F 302）
2S05a-5
中枢神経系免疫細胞ミクログリアによる体性感覚情報伝達の調節
Makoto Tsuda（津田 誠）
九州大院薬ライフ
Acute nociceptive pain is a key defense system for detecting danger signals. By contrast, chronic pain (like neuropathic pain occurring after damage of the nervous system) is not simply a temporal continuum of acute nociceptive pain, but rather due to pathologically altered nervous system function. Such pathological alterations have been studied using rodent models of neuropathic pain, which are induced by peripheral nerve injury (PNI). Accumulating evidence indicates that PNI causes a variety of plastic modifications in neuronal synapses, connections, and networks at the molecular and structural levels, which may account for development and maintenance of neuropathic pain. One key question is how do these alterations occur and persist long-term? In my talk, I will highlight recent advances in our understanding of the role of microglia, immune cells in the CNS, in neuropathic pain. Spinal cord microglia respond quickly to PNI, change their morphology and cell number (due to their proliferation activity). Activated spinal microglia express a variety of genes including the purinergic receptor subtype P2X4R (non-selective cation channels activated by extracellular ATP) and that pharmacological blockade or genetic knockout of these microglial molecules suppresses neuropathic pain. In particular, the P2X4R-expressing reactive state of spinal microglia are crucial. This state requires an IRF8-IRF5 transcriptional axis. By demonstrating the role of vesicular nucleotide transporter (VNUT: a secretory vesicle protein responsible for the storage and release of ATP), we have shown that neuron-derived ATP contributes to microglia stimulation. More recent studies have also revealed active roles of brain microglia in emotion and memory-related aspects of chronic pain. These findings provide convincing evidence for the necessity and sufficiency of microglia in the pathogenesis of neuropathic pain and have important implications for the treatment of chronic pain. | | 7月26日（金）16:55～17:10 第5会場（朱鷺メッセ 3F 302）
2S05a-6
脳虚血後炎症における自然免疫の役割
Jun Tsuyama（津山 淳），Takashi Shichita（七田 崇）
都医学研脳卒中ルネサンス
Ischemic stroke causes neuronal cell death and triggers serial inflammation that exacerbates cerebral edema and brings additional cell death on the ischemic penumbra. It is known that post-ischemic inflammation is gradually resolved, followed by the recovery of neural function. However, the mechanisms for the resolution of the inflammation and repair after ischemic injury remain unknown. It is presumed that microglia and infiltrating peripheral-derived leukocytes are involved in these resolution and recovery process.
Neuronal cell death in ischemic brain injury results in the release of damage-associated molecular patterns (DAMPs) that work as endogenous ligands for pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Peroxiredoxin (PRX) family protein released from dead neurons is known as the key DAMPs for activation of infiltrating macrophages via stimulation of TLR2 and TLR4 in the post-ischemic brain. Until recently it has not been known how PRXs will be removed from the brain. We found that addition of DAMPs to cultured cells derived from ischemic brain leads to internalization by infiltrating macrophages. This data indicates that infiltrating macrophages derived from peripheral tissues change their characteristics from inflammatory to anti-inflammatory. As a result of screening the regulators of the DAMPs infiltrating ability of macrophages, we identified the transcription factor MAFB dependent expression of scavenger receptor MSR1 as necessary and sufficient factors for the efficient clearance of DAMPs to resolve inflammation. Administration of Am80 which is known to increase the expression of MAFB to MCAO mouse resulted in reduced cerebral infarct volume.
Microglia are the resident immune cells of the central nervous system (CNS) that play an important role in brain maintenance and in pathology. In the ischemic brain injury, microglia are known to contribute to recovery of nerve function. Using fluorescence-activated cell sorting (FACS), we isolated in vivo microglia from ischemic brain tissue. In the post-ischemic brain, microglia dynamically changed the epigenetic state of the genomic region around tissue repair-related genes. These data showed that infiltrating macrophages and microglia showed temporal polarization during the progression of cerebral infarction and are also involved in both exacerbation and resolution of inflammation. | |
|
|
