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关键词： Microglia   Displacement   Synapse   Homeostasis   Motor learning   NEURONAL EXCITABILITY   INHIBITORY CIRCUITS   BRAIN-INJURY   INTERLEUKIN-1-BETA   IMMUNE   LIPOPOLYSACCHARIDE   ACTIVATION   MECHANISMS   PLASTICITY   IL-1-BETA  

摘要： Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1 beta negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1 beta on synaptic displacement. This study demonstrates that IL-1 beta is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.

关键词： Hepatic Tolerance   Regulatory T Cells   Immune Checkpoints   Co-inhibition   IMMUNOLOGICAL-TOLERANCE   ENDOTHELIAL-CELLS   LIVER   ANTIGEN   ADHESION   IL-10   INFLAMMATION   LYMPHOCYTES   INDUCTION   ROLES  

摘要： BACKGROUND & AIMS: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance. METHODS: Tolerance was investigated in C-reactive protein (CRP)-myelin basic protein (MBP) mice expressing the neuro-antigen MBP in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance induction was studied after transfer of MBP-specific CD4 T cells into CRP-MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies. RESULTS: Although tolerant CRP-MBP mice display increased numbers of forkhead box P3 thorn regulatory T cells, we here found them not essential for the maintenance of hepatic tolerance. Instead, upon MBP recognition in the liver, MBP-specific T cells became activated to produce interferon (IFN)gamma, which, in turn, induced local up-regulation of recruitment molecules, including Chemokine (C-X-C motif) ligand9 and its receptor C-X-C motif chemokine receptor3, facilitating endothelial translocation and redirection of MBP-specific T cells into the hepatic parenchyma. There, the translocated MBP-specific CD4 T cells partly converted into interleukin 10-producing type 1 regulatory T cells, and significantly up-regulated the expression of immune checkpoint molecules, notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Intriguingly, although liver tolerance was not affected by impairment of interleukin 10 signaling, concomitant blockade of IFN gamma and CTLA-4 abrogated hepatic tolerance induction to MBP, resulting in neuroinflammatory autoimmune disease in these mice. CONCLUSIONS: IFN gamma-mediated redirection of autoreactive CD4 T cells into the liver and up-regulation of checkpoint molecules, including CTLA-4, were essential for tolerance induction in the liver, hence r

关键词： 类风湿性关节炎   机器学习   免疫浸润   全基因组关联研究   孟德尔随机化  

摘要： 背景:类风湿性关节炎是一种慢性全身性自身免疫疾病,研究其涉及的免疫学特征改变对诊断和治疗具有重要意义。目的:通过生物信息学方法筛选类风湿性关节炎中免疫相关生物标志物,分析其免疫细胞浸润变化及与免疫细胞的潜在因果关系。方法:基于GEO与ImmPort数据库,采用差异表达分析筛选类风湿性关节炎中表达上调的免疫相关基因,采用GO与KEGG富集分析探索这些上调基因的潜在作用。采用支持向量机递归特征消除(SVM-RFE)、最小绝对收缩和选择算法(Lasso)筛选类风湿性关节炎中免疫特征基因,独立的数据集进行差异验证,绘制特征基因的受试者工作特征曲线评价诊断性能。采用免疫细胞浸润分析类风湿性关节炎中免疫细胞的差异情况及特征基因与免疫细胞的相关性。最后,进行孟德尔随机化分析,以确定免疫细胞中单核细胞与类风湿性关节炎的因果效应。结果与结论:①筛选得到了39个在类风湿性关节炎中高表达的差异基因,GO富集分析显示其主要富集在趋化性、细胞因子活性、免疫受体活性等过程,KEGG富集分析显示其在肿瘤坏死因子信号通路、白细胞外周迁移等途径显著富集;②通过Lasso与SVM-RFE两种机器学习算法确定了5个特征基因,分别为CXCL13、SDC1、IGLC1、PLXNC1和SLC29A3,独立的数据集对特征基因验证发现他们同样在类风湿性关节炎样本中高表达,5个特征基因在2个数据集中的AUC值均大于0.8;③免疫细胞浸润发现大多数免疫细胞如单核细胞、自然杀伤细胞等在类风湿性关节炎样本里表现出更高的浸润水平,相关性分析显示5个特征基因与记忆B细胞、不成熟B细胞等呈正相关性,逆方差加权法发现单核细胞与类风湿性关节炎发病风险相关。

关键词： 树突状细胞   未成熟树突状细胞   成熟树突状细胞   细胞因子   混合淋巴细胞反应  

摘要： 背景:树突状细胞在未成熟阶段表现出极强的抗原吞噬功能,它可以在免疫耐受、癌症的免疫治疗等方面都表现出极大的优越性。但由于未成熟树突状细胞在生物体内含量极微,这就严重限制了它在临床、科研方面的应用。目的:提取鉴别Lewis大鼠骨髓来源成熟和未成熟树突状细胞。方法:从Lewis大鼠骨髓中分离骨髓前体细胞,应用20 ng/mL粒细胞集落刺激因子、10 ng/mL白细胞介素4培养7 d诱导为未成熟树突状细胞,然后在未成熟树突状细胞中加入1μg/mL脂多糖继续培养2 d诱导为成熟树突状细胞。采用荧光倒置显微镜观察树突状细胞形态,流式细胞仪鉴定成熟和未成熟树突状细胞表面特异性分子,ELISA检测成熟和未成熟树突状细胞培养上清白细胞介素10、白细胞介素12和白细胞介素17A因子的分泌水平,混合淋巴细胞反应检测成熟和未成熟树突状细胞对T淋巴细胞的刺激反应。结果与结论:①普通荧光倒置显微镜下观察树突状细胞具有明显的突起结构;②流式细胞仪可见未成熟树突状细胞低表达CD40、CD86等共刺激分子;相反,成熟树突状细胞高表达上述共刺激分子;③未成熟树突状细胞的白细胞介素10、白细胞介素17A分泌水平要远高于成熟树突状细胞(P<0.01);未成熟树突状细胞的白细胞介素12分泌水平低于成熟树突状细胞(P<0.05);④成熟树突状细胞对T细胞的刺激明显比成熟树突状细胞强,当成熟树突状细胞与T淋巴细胞比例达到1∶10时刺激能力更强;⑤结果表明:Lewis大鼠骨髓前体细胞可以分化为树突状细胞,通过流式细胞鉴定、相关因子检测、混合淋巴细胞反应能够鉴别树突状细胞的成熟和未成熟状态。

关键词： 肌萎缩侧索硬化   免疫反应   中药   提取物   复方   间充质干细胞   运动神经元   作用机制   信号通路   炎症因子  

摘要： 背景:肌萎缩侧索硬化为一种进行性神经退行性疾病,常导致大脑和脊髓神经元死亡。肌萎缩侧索硬化发病机制极为复杂,难治率、死亡率高且目前其治疗药物仅有2种,因此开发新治疗方法以改善患者预后迫在眉睫。目的:综述中药及间充质干细胞调控免疫反应治疗肌萎缩侧索硬化的作用机制。方法:以“traditional Chinese medicine,mesenchymal stem cells,ALS,immune response”为英文检索词,以“中药,间充质干细胞,肌萎缩侧索硬化,免疫反应”为中文检索词,检索万方、中国知网、PubMed及Web of Science数据库2010-2023年的相关文献,最终纳入69篇文献进行综述分析。结果与结论:①中药调控免疫反应治疗肌萎缩侧索硬化可总结为5个机制:主要包括冰片和黄芪甲苷等中药促进闭锁小带蛋白1、闭合蛋白5表达重建血液中枢神经系统屏障完整性;复方扶芳藤合剂调节自然杀伤细胞表面受体分子抑制其自身毒性;半枝莲和广藿香等作用补体系统因子抑制其异常激活;雷公藤和钩藤等介导细胞外信号调节激酶1/2衰减诱导型一氧化氮合酶产生而抑制小胶质细胞活化;左归丸、栝蒌根等促进白细胞介素10表达调控T细胞改善免疫环境。②通过现有研究总结了间充质干细胞调控免疫反应治疗肌萎缩侧索硬化可总结为5个机制:减少水通道蛋白4表达和降低内皮型一氧化氮合酶信号传导等方面修复免疫屏障完整性;释放吲哚胺2,3-双加氧酶和前列腺素E2等因子抗自然杀伤细胞毒性;分泌因子H干扰转化酶活性抑制补体系统异常激活;调控CX3CL1/CX3CR1系统轴或分泌转化生长因子β等途径改变小胶质细胞表型抑制其活性;增加白细胞介素10表达或激活STATS磷酸化通路来恢复T细胞功能。③目前中药联合间充质干细胞治疗肌萎缩侧索硬化研究较少,已知的相关研究报道显示,肌萎灵注射液可促进干细胞增殖分化以及补阳还五汤联合骨髓间充质干细胞显著提高血脑屏障完整性,未来还需进一步探讨两者对难治性肌萎缩侧索硬化的协同治疗效果。

关键词： NSCLC cell migration and invasion   IL-17   p300   STAT3   MMP19   Acetylation and phosphorylation  

摘要： The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.

关键词： Macrophage   Inflammatory cytokine   Lipopolysaccharides   NF   kappa B signaling pathway   Wnt/ beta-catenin signaling pathway   CYTOKINE EXPRESSION   INTERLEUKIN-6   ACTIVATION  

摘要： Proinflammatory cytokine plays a central role in host defense and acute inflammatory responses. Both positive and negative correlations of NF-kappa B and Wnt/beta-catenin pathways have been reported depending on cell types in response to inflammatory stimuli for IL -6 cytokine production. Macrophages are vital to the regulation of immune responses and the development of inflammation, but the crosstalk between two pathways has not been elucidated so far in macrophages. We observed a positive cross-regulation between the NF-kappa B and Wnt/beta-catenin pathways for IL -6 production in human macrophages. To verify the functional validity of this interaction, LY294002 or PNU74654, representative blockers of each pathway, were treated. IL -6 secretion was reduced to the basal level by both inhibitor treatments, even when stimulated by LPS. We also found that NF-kappa B p65 migrated to the nucleus and interacted with the transcription factor TCF-4 in macrophages upon LPS stimulation.

关键词： Particulate matter   TGF- beta 1   Oxidative stress   Epithelial-mesenchymal transition   Pulmonary fibrosis   Cells   PULMONARY-FIBROSIS   AHVAZ   DUST   PM10   CHILDREN   IMPACTS   SMAD3   PM2.5   OXIDE   IRAN  

摘要： Epidemiological evidence presents that dust storms are related to respiratory diseases, such as pulmonary fibrosis (PF). However, the precise underlying mechanisms of SPM-elicited adverse effects still need to be investigated. Epithelial-mesenchymal transition (EMT) process is a characteristic of PF. We discussed whether suspended particulate matter (SPM) is involved in EMT induction via transforming growth factor-beta 1 (TGF-beta 1). In this study, a detailed elemental analysis (55 elements), particle size, and morphology were determined. To investigate the toxicity of SPM, an MTT test was performed to detect cell viability. Next, A549 cells were exposed to selected concentrations of SPM (20 and 40 mu g/mL) for single and repeated exposures. The DCFH-DA assay showed that exposure to SPM could produce reactive oxygen species (ROS). The ELISA assay demonstrated increased levels of interleukin-8 (IL -8) and TGF-beta 1 in the supernatant. Western blot was used to detect the expression of proteins associated with EMT and the SMAD3-dependent pathway. Results of western blot demonstrated that E-cadherin was reduced, whereas p-SMAD3, vimentin, and alpha-smooth muscle actin were elevated. Our findings indicated that SPM triggered EMT by induction of oxidative stress, inflammation, and the TGF-beta 1/SMAD3 pathway activation. (c) 2024 The Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences. Published by Elsevier B.V.

摘要： Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low "ILC9" phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.

关键词： Epigallocatechin gallate(EGCG)   Inflammasome   Nuclear factor erythroid 2-related factor 2(Nrf2)   Receptor for advanced glycation end products(RAGE)   Soluble RAGE(sRAGE)  

摘要： Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.