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Repetitive Administration of Low-Dose Lipopolysaccharide Improves Repeated Social Defeat Stress-Induced Behavioral Abnormalities and Aberrant Immune Response 重复施用低剂量脂多糖可改善重复社交失败应激诱发的行为异常和异常免疫反应
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2024-07-27 DOI: 10.1007/s11481-024-10141-x
Vichuda Charoensaensuk, Wei-Lan Yeh, Bor-Ren Huang, Tsung-Che Hsu, Sheng-Yun Xie, Chao-Wei Chen, Yu-Wen Wang, Liang-Yo Yang, Cheng-Fang Tsai, Dah-Yuu Lu

Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.

先天性免疫细胞重复暴露于阈下剂量的内毒素成分可能会调节炎症反应。然而,中枢神经系统(CNS)与免疫系统之间相互作用的调节机制仍不清楚。本研究旨在探讨脂多糖(LPS)预处理对重复社交失败应激(RSDS)诱导的异常免疫反应和行为障碍的影响。本研究旨在利用RSDS范式阐明重复给予阈下剂量LPS对行为损伤的保护作用的机制。LPS预处理改善了RSDS失能小鼠的异常行为,同时降低了单胺氧化酶,增加了海马中糖皮质激素受体的表达。此外,LPS预处理还能显著减少外周髓系细胞(CD11b+CD45hi),主要是循环炎性单核细胞(CD11b+CD45hiLy6ChiCCR2+)在RSDS挑战下进入大脑。重要的是,我们发现 LPS 预处理是通过调节小胶质细胞中脂钙蛋白-2(LCN2)的表达来发挥其保护作用的,LCN2 随后会诱导趋化因子 CCL2 和促炎细胞因子的表达。随后,LPS-预处理减少了RSDS缺陷小鼠大脑中的常驻小胶质细胞数量(CD11b+CD45intCCL2+)。此外,LPS 预处理还减轻了骨髓、脾脏和血液中与 RSDS 相关的白细胞(CD11b+CD45+CCR2+)和中性粒细胞(CD11b+CD45+Ly6G+)的表达。特别是,LPS 预处理还促进了海马中内源性抗氧化剂和抗炎蛋白的表达。我们的研究结果表明,LPS 预处理可改善脂钙蛋白 2 相关的小胶质细胞活化和异常免疫反应,促进内源性抗氧化剂和抗炎蛋白的表达,从而维持大脑和免疫系统中促炎症/抗炎症的平衡,最终保护小鼠免受 RSDS 引起的异常免疫反应和行为变化的影响。
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引用次数: 0
JAK1/2 Regulates Synergy Between Interferon Gamma and Lipopolysaccharides in Microglia JAK1/2调控小胶质细胞中γ干扰素与脂多糖之间的协同作用
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2024-04-20 DOI: 10.1007/s11481-024-10115-z
Alexander P. Young, Eileen M. Denovan-Wright

Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.

Graphical Abstract

小胶质细胞是大脑的常驻免疫细胞,可调节神经炎症,在病理条件下可导致继发性神经元损伤和认知障碍。在能引起小胶质细胞炎症反应的众多分子中,有两种分子是脂多糖(LPS)和γ干扰素(IFNγ),前者是革兰氏阴性细菌的一种成分,后者是一种内源性促炎细胞因子。我们深入研究了培养小胶质细胞和巨噬细胞中多种细菌的 LPS 与 IFNγ 之间的浓度依赖关系。我们测量了这些免疫刺激分子对小胶质细胞促炎活性的影响,并使用一系列信号抑制剂来确定导致小胶质细胞反应的途径。我们发现,LPS 和 IFNγ 相互协同作用,诱导小胶质细胞产生促炎表型,而抑制 JAK1/2 则会完全减弱这种反应。我们确定 LPS 和 IFNγ 的这种协同作用可能依赖于 JNK 和 Akt 信号,而不是 NF-κB 等典型的促炎介质。最后,我们证明了来自大肠埃希菌、肺炎克雷伯氏菌和阿克曼粘菌的 LPS 可引起小胶质细胞和巨噬细胞的不同炎症反应,但使用 JAK1/2 抑制剂芦可替尼(ruxolitinib)可持续阻止这些反应。总之,这项研究揭示了小胶质细胞可能在 LPS 和 IFNγ 的共同作用下过度激活的机制。鉴于循环中LPS和IFNγ的升高发生在多种病理情况下,因此了解这些分子之间的药理相互作用对于开发安全有效的治疗方法来抑制这一过程至关重要。
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引用次数: 0
Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague–Dawley Rats 内皮素-1 介导的脑干胶质激活通过增强 ATP-P2X4 受体信号传导在 Sprague-Dawley 大鼠体内产生哮喘性气道迷走神经张力过高症
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2024-04-13 DOI: 10.1007/s11481-024-10116-y
Yun Lin, Tian Liu, Hong Chen, Ming Zeng, Shunwei Hu, Xiaoning Yu, Yonghua Chen, Chunmei Xia, Jin Wang, Jijiang Wang

The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5’-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5’-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5’-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

Graphical Abstract

哮喘主要症状的出现在很大程度上归因于气道迷走神经功能亢进,其中枢机制尚不清楚。本研究验证了内皮素-1 介导的脑干胶质细胞激活通过增强腺苷 5'-triphosphate 对神经元嘌呤能 P2X4 受体的作用产生哮喘气道迷走神经张力亢进的假设。使用卵清蛋白制备了大鼠哮喘模型。通过喉返神经放电和肺功能胸透测量评估了气道迷走神经张力。分别使用 ELISA、Western 印迹、荧光素-荧光素酶、定量反转录聚合酶链反应、酶活性测定和免疫荧光染色法检测了脑干的变化。结果表明,在大鼠髓质中,B型内皮素受体和P2X4受体主要分别在星形胶质细胞和神经元中表达,卵清蛋白致敏后,这两种受体和内皮素-1含量均显著增加。卵清蛋白致敏可显著增加喉部复发性放电,而急性胸腔内注射P2X4受体拮抗剂5-BDBD、敲除脑干P2X4受体和慢性腹腔内注射内皮素受体B型拮抗剂BQ788可分别阻断这种现象。卵清蛋白致敏激活了小胶质细胞和星形胶质细胞,并显著降低了髓质中外向-5'-核苷酸酶的活性,而所有这一切,连同髓质 P2X4 受体表达的增加和肺功能的降低,都被慢性 BQ788 治疗所逆转。这些结果表明,在大鼠体内,过敏性气道挑战通过增强内皮素-1/内皮素受体B型信号传导激活髓质中的小胶质细胞和星形胶质细胞,进而通过增强气道迷走神经反射中枢神经元的5'-三磷酸腺苷/P2X4受体信号传导引起气道迷走神经张力亢进。
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引用次数: 0
Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery IL8和IL18(而非IL6)的围术期水平与手术三个月后的基底核萎缩有关
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2024-03-14 DOI: 10.1007/s11481-024-10110-4

Abstract

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

Graphical Abstract

摘要 过去的研究发现,外科手术后可能会加速脑萎缩。此外,还有人描述了全身炎症与神经变性之间的关系。我们假设,术后血液循环中的白细胞介素(IL)水平以及围手术期白细胞介素水平的变化与作为大脑皮层乙酰胆碱主要来源的大细胞基底核(NBM)术后萎缩程度的增加有关。我们分析了 BioCog 队列的数据,该队列包括年龄≥ 65 岁、接受择期大手术(≥ 60 分钟)的患者。我们在手术前和术后第一天采集了血液样本。在手术前和术后三个月的随访中进行了脑部磁共振成像和神经心理学评估。我们使用线性回归分析确定了三种白细胞介素(IL6、IL8 和 IL18)与 NBM 萎缩(从术前基线到随访期间体积变化的百分比)的关系,并研究了 NBM 萎缩和体积与术后认知能力和围手术期认知变化的关系。使用接收器操作曲线来确定术前白细胞介素水平的预后价值。对于 IL8(N = 97)和 IL18(N = 217),而非 IL6(N = 240),我们观察到术后第一天较高的 IL 水平与术后三个月较高的 NBM 萎缩有显著关联。随后的分析表明,在 IL8 和 IL18 中,这种关联是由长期升高的 IL 水平和 NBM 萎缩(反映在术前 IL 浓度上)这一更普遍的关联驱动的,而不是 IL 对手术的反应(以术前和术后 IL 浓度之差衡量)。随访时,NBM体积与认知能力水平呈正相关,但NBM萎缩与围手术期的认知变化无明显关系。术前 IL 浓度对 NBM 萎缩的预后价值较低。我们的研究结果表明,术后白细胞介素水平与 NBM 萎缩的关系是由术前炎症导致的术前白细胞介素升高引起的,而不是围手术期白细胞介素水平随手术和麻醉的变化而变化。BioCog研究已于2014年10月15日在clinicaltrials.gov上注册(NCT02265263)。 图表摘要
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引用次数: 0
Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated Bmal1在脂多糖诱发的抑郁样行为及其相关行为中的潜在作用
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-02 DOI: 10.1007/s11481-024-10103-3
Dan-Dan Xu, Zhi-Qi Hou, Ya-Yun Xu, Jun Liang, Ye-Jun Gao, Chen Zhang, Fan Guo, Dan-Dan Huang, Jin-Fang Ge, Qing-Rong Xia
<p>Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an “inflammatory storm” in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic–pituitary–adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.</p><h3 data-test="abstract-sub-heading">Graphical Abstract</h3><p><b>Conclusions</b> In conclusion, our results indicated that LPS could induce depression-like behaviors and an “inflammatory storm” in vivo, activate microglia in vitro, together with a disruption of synaptic plasticity and circadian rhythm. This m
炎症在抑郁症的发病机制中起着重要作用,但其潜在机制仍不清楚。除了动物模型和抑郁症患者的昼夜节律紊乱外,有报道称时钟基因的功能障碍与炎症的进展有关。本研究旨在探讨昼夜节律时钟基因,尤其是脑和肌肉ARNT样1(Bmal1)在炎症与抑郁症之间的联系中的作用。本研究使用了受到脂多糖(LPS)挑战的大鼠和 BV2 细胞。大鼠腹腔注射四次0.5毫克/千克的LPS,每隔一天注射一次;BV2细胞在工作浓度为1毫克/升的LPS作用下接受24小时的挑战,无论是否通过小干扰RNA抑制Bmal1。结果表明,LPS能成功诱导大鼠出现抑郁样行为和 "炎症风暴",表现为强迫游泳试验中大鼠不动时间延长,糖精偏好试验中大鼠糖精偏好指数下降,下丘脑-垂体-肾上腺轴亢进,星形胶质细胞和小胶质细胞亢进,肿瘤坏死因子-α、白细胞介素6和C反应蛋白的外周和中枢含量增加。此外,海马和下丘脑中脑源性神经营养因子、髓样细胞上表达的触发受体1、Copine6和Synaptotagmin1(Syt-1)的蛋白表达水平降低,而髓样细胞上表达的触发受体2的表达水平升高。有趣的是,体温波动以及血清中褪黑激素和皮质酮的浓度在各组间存在显著差异。此外,昼夜节律运动输出周期 kaput、隐色素 2 和周期 2 的蛋白表达水平在 LPS 攻击大鼠的海马中明显降低,而 Bmal1 在海马中的表达明显增加,但在下丘脑中却有所降低,在下丘脑中,Bmal1 与神经元、小胶质细胞和星形胶质细胞共位。一致的是,除了细胞活力降低和吞噬能力增强外,LPS 挑战的 BV2 细胞与 LPS 模型大鼠海马中蛋白质表达的变化趋势相似。然而,在抑制Bmal1后,LPS诱导的BV2细胞病理变化被逆转。这些结果表明,LPS可诱导抑郁样病理变化,其潜在机制可能部分与Bmal1表达失衡及其调控的昼夜节律失调有关。这一机制可能与 Bmal1 的不平衡表达有关。我们的研究结果有助于揭示神经炎症诱导抑郁症的时钟-免疫学新机制,并为开发新的有效的抑郁症药物疗法提供启示。
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引用次数: 0
Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson’s Disease 外周 MC1R 激活可调节帕金森病小鼠模型的免疫反应并具有神经保护作用
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2023-12-19 DOI: 10.1007/s11481-023-10094-7

Abstract

Background

Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson’s disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.

Methods

C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25 + Tregs.

Results

Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP + LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1β levels in the ventral midbrain. Depletion of Tregs was associated with diminished neuroprotective effects of NDP-MSH.

Conclusions

Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.

摘要 背景 黑色素皮质素1受体(MC1R)是一种关键的色素沉着基因,产生红毛的MC1R变体功能缺失可能与帕金森病(PD)有关。我们以前曾报道过 Mc1r 突变小鼠的多巴胺能神经元存活率下降,以及向大脑局部注射 MC1R 激动剂或全身注射具有明显中枢神经系统(CNS)渗透性的 MC1R 激动剂对多巴胺能神经元的保护作用。除黑色素细胞和多巴胺能神经元外,MC1R 还表达于其他外周组织和细胞类型,包括免疫细胞。本研究探讨了不通过 BBB 的合成黑皮质素受体(MCR)激动剂 NDP-MSH 对免疫系统和黑质多巴胺能系统的影响。 方法 从第 1 天到第 4 天,用盐酸 MPTP(20 毫克/千克)和 LPS(1 毫克/千克)对 C57BL/6 小鼠进行全身治疗;从第 1 天到第 12 天,用 NDP-MSH(400 微克/千克)或药物对小鼠进行全身治疗,然后将小鼠处死。对外周和中枢神经系统免疫细胞进行表型,并测量炎症标记物。对黑质多巴胺能系统进行了行为学、化学、免疫学和病理学评估。为了解调节性 T 细胞(Tregs)在该模型中的作用,使用了 CD25 单克隆抗体来清除 CD25 + Tregs。 结果 全身注射 NDP-MSH 能显著减轻 MPTP + LPS 引起的纹状体多巴胺耗竭和黑质多巴胺能神经元丢失。NDP-MSH还能改善极点试验的行为结果。在 MPTP 和 LPS 范例中注射 NDP-MSH 的 Mc1r 突变小鼠的纹状体多巴胺水平没有变化,这表明 NDP-MSH 是通过 MC1R 途径发挥作用的。虽然在大脑中未检测到 NDP-MSH,但外周 NDP-MSH 可减轻神经炎症,这表现在黑质区域的小胶质细胞活化减少,腹侧中脑的 TNF-α 和 IL1β 水平降低。Tregs 的耗竭与 NDP-MSH 神经保护作用的减弱有关。 结论 我们的研究表明,外周作用的 NDP-MSH 可保护多巴胺能黑质神经元,并减少过度激活的小胶质细胞。NDP-MSH 可调节外周免疫反应,而 Tregs 可能参与了 NDP-MSH 的神经保护作用。
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引用次数: 0
Host-Immune Interactions in JC Virus Reactivation and Development of Progressive Multifocal Leukoencephalopathy (PML). JC病毒活化和进行性多灶性白质脑病(PML)发展过程中的宿主免疫相互作用
IF 5.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2019-12-01 Epub Date: 2019-08-27 DOI: 10.1007/s11481-019-09877-8
Amir Khalili, Michael Craigie, Martina Donadoni, Ilker Kudret Sariyer

With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.

随着免疫调节疗法的出现和艾滋病病毒(HIV)的流行,由于进行性多灶性白质脑病(Progressive Multifocal Leukoencephalopathy,PML)发病率的增加,JC 病毒(JCV)对公共卫生系统的影响也大大增加。目前,还没有针对 JCV 感染的药物来治疗和预防导致 PML 发生的病毒再活化。由于 JCV 主要在免疫力低下的患者中再活化,因此有人认为免疫系统(主要是细胞免疫成分)在调节 JCV 以防止产生性感染和 PML 的发展中起着关键作用。然而,JCV 免疫调节和再激活的确切机制尚不十分清楚。同样,宿主因素对 JCV 调节和再激活的影响也是另一个研究不足的领域。在此,我们讨论了目前有关宿主因子介导和免疫因子介导的 JCV 基因表达调控的文献,目的是建立一个模型,说明在 JCV 再激活过程中哪些因子被绕过,从而成为开发抑制 PML 启动的治疗干预措施的潜在靶点。图解摘要。
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引用次数: 0
Protease Inhibitors, Saquinavir and Darunavir, Inhibit Oligodendrocyte Maturation: Implications for Lysosomal Stress 蛋白酶抑制剂沙奎那韦和达那韦抑制少突胶质细胞成熟:对溶酶体应激的影响
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2019-11-28 DOI: 10.1007/s11481-019-09893-8
L. Festa, Lindsay M. Roth, Brigid K. Jensen, J. Geiger, K. Jordan-Sciutto, J. Grinspan
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引用次数: 13
A Broad Application of CRISPR Cas9 in Infectious, Inflammatory and Neurodegenerative Diseases CRISPR Cas9在感染性、炎症性和神经退行性疾病中的广泛应用
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2019-11-28 DOI: 10.1007/s11481-019-09889-4
K. Pahan
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引用次数: 4
Hemorrhage Associated Mechanisms of Neuroinflammation in Experimental Traumatic Brain Injury 实验性创伤性脑损伤出血相关的神经炎症机制
IF 6.2 3区 医学 Q1 NEUROSCIENCES Pub Date : 2019-11-26 DOI: 10.1007/s11481-019-09882-x
Xiaotang Ma, Yiming Cheng, Ricardo Garcia, J. Haorah
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引用次数: 11
期刊
Journal of Neuroimmune Pharmacology
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