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关键词： Pathogenic Th17 (pTh17) cells   Interleukin-18 (IL-18)   Autoimmunity  

摘要： Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 receptor alpha chain (IL-18R alpha) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted Stat3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sj & ouml;gren's syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sj & ouml;gren's syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.

关键词： Glioblastoma microenvironment   IL-1 beta(+) macrophages   PGE2   TNF alpha   C/EBP beta  

摘要： Glioblastoma (GBM) harbors a highly inflammatory microenvironment driven predominantly by activated innate immune cells, despite being classified as an immunologically cold tumor due to limited T cell infiltration. Tumor-associated macrophages (TAMs) are key contributors to disease progression, in part through their production of interleukin-1 beta (IL-1 beta), a pro-inflammatory cytokine with tumor-promoting functions. However, the precise role of IL-1 beta(+) TAMs in GBM remains incompletely understood. This study aimed to elucidate the functional contributions of IL-1 beta(+) TAMs to GBM malignancy and to explore their therapeutic relevance. Single-cell RNA sequencing (scRNA-seq) analysis revealed that IL-1 beta(+) TAMs were enriched in GBM tissues compared to normal brain tissue, with their elevated infiltration correlating with aggressive tumor phenotypes and poor prognosis. Functionally, IL-1 beta stimulated GBM cells to secrete inflammatory mediators such as PGE2 and TNF alpha. These mediators, in turn, upregulated C/EBP beta expression in macrophages, thereby enhancing IL-1 beta transcription. Mechanistically, tumor-derived PGE2 and TNF alpha synergistically activated C/EBP beta via EP4 receptor signaling, initiating a self-sustaining IL-1 beta-PGE2/TNF alpha-EP4-C/EBP beta-IL-1 beta feedback loop that amplified pro-inflammatory crosstalk between GBM cells and TAMs. Disruption of PGE2/EP4 signaling effectively suppressed IL-1 beta(+) TAM generation and attenuated tumor growth in preclinical models. Our finding highlights how GBM cells induce macrophages to secrete IL-1 beta through the synergistic action of PGE2 and TNF alpha via the EP4 receptor and C/EBP beta activation. This feedback loop between tumor cells and macrophages fosters a pro-inflammatory TME that drives GBM progression. Targeting the PGE2/EP4-C/EBP beta signaling axis may therefore present a promising immunotherapeutic strategy to disrupt tumor-TAM crosstalk and suppress GBM progression.

关键词： 肠道B细胞   自动化解离   免疫调节功能   流式细胞术  

摘要： 目的：优化小肠固有层B淋巴细胞的提取方法以提高得率，并联合应用流式细胞内因子检测及细胞共培养实验探究其功能特性。方法：预处理小鼠小肠组织后，采用美天旎肠道解离试剂盒和八通道全自动组织解离器进行消化，通过EasySep?磁极结合EasySep?小鼠B细胞分离试剂盒筛选B细胞。利用流式细胞数检测肠道B细胞分泌IgA及IL-10水平，并将其与CD4+T细胞共培养实验以评估免疫调节功能。结果：与手动提取相比，gentle MACS组织处理器自动提取的肠道固有层淋巴细胞数量显著增加（P<0.001），且稳定性更高，更适于下游实验。流式检测显示，LPS刺激后肠道B细胞分泌IgA的水平随时间延长显著升高（P<0.001），而IL-10表达则降低（P<0.01）。共培养实验表明，肠道B细胞对CD4+T细胞增殖的抑制能力显著强于脾脏B细胞（P<0.01）。结论：本研究建立的自动化解离方法可高效获取肠道固有层B细胞，并揭示其具有分泌IgA及IL-10的功能，同时其体外免疫抑制能力显著优于脾脏B细胞。

关键词： inflammation   innate immunity   myeloid cells   Lymphoid cells   Immunopathology  

摘要： Interleukin-1 (IL-1) was the first interleukin identified as a potent proinflammatory and multifunctional molecule involved in innate immune responses against microbes, as well as in conditions of tissue injury associated with infections and sterile conditions. IL-1 is part of a large system, the IL-1 system, comprising a family of ligands that act as agonists, receptor antagonists, and anti-inflammatory cytokines, as well as a family of receptors that includes signaling receptor complexes, decoy receptors and negative regulators. All the members of the IL-1 system are involved in inflammatory diseases, innate and adaptive immune responses, conditions associated with dysmetabolism, and cancer by affecting both the tumor microenvironment and cancer cells. The deregulated or excessive activation of several pathways associated with the IL-1 system may lead to detrimental inflammatory or immune reactions, including autoinflammatory, autoimmune, infectious and degenerative diseases. The negative regulation of the IL-1 system mediated by antagonists, decoy receptors, scavengers, and dominant-negative molecules plays nonredundant roles in controlling these conditions. Owing to the central role of IL-1 in the pathogenesis of inflammation-driven diseases, IL-1 blocking agents are approved for clinical use in several inflammatory conditions, and inhibitory agents for other members of the family are under development. Here, the complexity of the IL-1 system, the involvement of its different members in inflammation-driven diseases, and the therapeutic approaches to target members of pathways associated with these conditions are presented and discussed.

关键词： GPCR-cAMP pathway   IL-12 signaling   protein kinase A (PKA)   Th1 differentiation  

摘要： Naïve CD4+ T cells differentiate into Th1 cells upon T-cell Receptor (TCR) stimulation in the presence of Interferon gamma (IFN-γ) and Interleukin 12 (IL-12). However, the intracellular signaling networks that temporally coordinate these inputs to reinforce Th1 lineage commitment remain incompletely defined. Here, we identify protein kinase A (PKA) as a time-gated regulator of IL-12 responsiveness and Th1 differentiation. Using a conditional knockout mouse model that deletes both catalytic PKA subunits in CD4+ T cells, we show that PKA is dispensable for early T cell activation but is essential for the late-phase induction of IL-12 receptor β2 (Il12rb2) and signal transducer and activator of transcription (STAT4). PKA-deficient CD4+ T cells fail to differentiate into Th1 cells in vitro and cannot induce Th1-mediated colitis in vivo. Instead, they adopt a Th2-skewed phenotype and drive eosinophilic lung inflammation and fibrosis. Mechanistically, prolonged TCR stimulation induces the expression of the peptide hormone Adrenomedullin and its receptor component Ramp3, which activate PKA and its downstream effector cAMP response element binding protein (CREB). Activated CREB drives Il12rb2 and Stat4 transcription, establishing a feedforward circuit that integrates signal duration with cytokine responsiveness. In the absence of PKA, this transcriptional program fails to initiate, leading to impaired IL-12 signaling and a loss of Th1 identity. These findings define a PKA–CREB signaling module that links sustained antigen stimulation to transcriptional and epigenetic commitment in CD4+ T cells, offering a mechanistic explanation for the temporal gating of Th1 differentiation and the prevention of Th2-driven tissue pathology. Copyright © 2025 the Author(s).

关键词： Glioblastoma   Extracellular vesicles   Hippo pathway inhibitors   Inflammation   Vasculogenic mimicry  

摘要： BackgroundGlioblastoma (GBM) secrete extracellular vesicles (EVs) which play a pivotal role in brain tumor progression by mediating intercellular communication within the inflamed tumor microenvironment (TME). EVs' cargo transports biomolecules that promote tumor progression, immune evasion, and resistance to therapies. While Hippo inhibitors play a significant role in mitigating cancer inflammation, their specific impact on EVs cargo remains *** grade IV U87 GBM-derived cells were cultured and EVs isolated from the conditioned media of tumor necrosis factor (TNF)alpha-primed cells. Total RNA was extracted using TRIzol (TM), and differential gene expression assessed through gene arrays and validated by RT-qPCR. Protein cell and EVs lysates were used for immunoblotting. 3D mesenchymal stem/stromal cells (MSC) in vitro vasculogenic mimicry (VM) was assessed using Cultrex *** study shows that U87 cells are responsive to pro-inflammatory stimulation by TNF alpha as the phosphorylation status of ERK, I kappa B, and NF kappa B increased. Among the Hippo pathway inhibitors tested, VT107 inhibited both the TNF alpha-induced phosphorylation, induction of the downstream Hippo pathway CYR61, and cargo of secreted EVs as assessed upon gene array screens. Pro-inflammatory genes that were reduced by VT107 in EVs included, among others, COX2, IL6, IL1B, and several members of the CCL, CXCL, and Interleukin/Interleukin receptors family. EVs isolated from VT107-treated TNF alpha-primed U87 cells had decreased paracrine regulation of MSC in vitro *** inhibiting the Hippo pathway and TNF alpha-induced pro-inflammatory cargo of GBM-derived EVs, our data support VT107 as a potential candidate to inhibit tumor-promoting processes involved in therapy resistance such as paracrine induction of MSC-mediated VM.

关键词： 应激   心身障碍   细胞因子   回肠   胰腺  

摘要： 目的：考察慢性不可预期性温和应激对小鼠回肠末端和胰腺炎性细胞因子和NF-κB表达的影响。方法：20只7～8周龄雄性C57BL/6J小鼠随机分为对照组和应激组，应激组采用21天慢性不可预期性温和应激进行处理。应激结束后采用旷场实验评价动物行为学改变，采用免疫组化、酶联免疫吸附试验和实时定量PCR检测回肠末端和胰腺炎性细胞因子IL-1β,IL-6,TNF-α和NF-κB表达水平。结果：21天慢性不可预期性温和应激导致动物出现抑郁样行为。在回肠末端，应激导致IL-1β,IL-6蛋白水平显著升高，TNF-α mRNA水平显著升高；NF-κB蛋白水平、mRNA水平和免疫组化阳性细胞百分比显著升高。提示慢性应激激活TLR4-NF-κB炎症通路，导致回肠末端的高炎症状态。在胰腺，应激组和对照组炎性细胞因子在蛋白水平和mRNA水平均无显著性差异，但应激组NF-κB蛋白水平、mRNA水平和免疫组化阳性细胞百分比均显著高于对照组。提示慢性应激在胰腺导致TLR4-NF-κB炎症通路激活。结论：慢性应激导致抑郁样行为的同时，引起外周器官炎性因子水平升高和TLR4/NF-κB信号通路的激活，这可能构成应激致心身症状的机制。应激导致不同器官炎性细胞因子水平存在差异，提示不同器官对应激刺激的脆弱易感程度不同。

摘要： The escalating industrial activities in metal processing, textile manufacturing, petroleum refining, leather production, and pulp industries have generated substantial amounts of industrial wastewater, presenting critical environmental challenges that require immediate attention. In this study, we developed a novel polyacrylonitrile grafted ionic liquid (PAN-g-IL) membrane through gamma-ray irradiation-induced grafting of 1-vinyl-3-ethylimidazolium bromide onto polyacrylonitrile, followed by non-solvent induced phase separation (NIPS) membrane fabrication[1] . The developed membrane exhibited exceptional separation performance for both dye-laden and oil-contaminated wastewater systems. The PAN-g-IL membrane demonstrated a pure water flux of 358.1 L m-2 h-1 with remarkable rejection rates exceeding 98% for cationic dyes, and for oil-water emulsions has a very good retention performance[2] , indicating superior antifouling properties and long-term operational stability.

关键词： 拉曼光谱   在线监测   人工神经网络   小波散射变换   单克隆抗体   抗体聚集体  

摘要： 在生物制药过程中，实时监测产品质量属性至关重要，拉曼光谱作为一种在线监测技术，面临复杂信号带来的建模挑战。本文提出了一种结合小波散射变换和人工神经网络（ST-ANN）的建模方法，用于在线监测流穿模式层析过程中的抗体单体与聚集体浓度变化。结果表明，相较于传统的偏最小二乘回归、K-最近邻、人工神经网络和卷积神经网络模型，ST-ANN对验证集的预测误差显著降低，单体和聚集体的测试集决定系数R2均达到0.982。ST-ANN展现出更强的泛化能力，为拉曼光谱应用于生物制药下游分离过程在线监测提供了新的建模方法。

关键词： Intracerebral hemorrhage   Endothelial inflammation   Targeted nanoparticles   Brain drug delivery   Hemorrhagic stroke  

摘要： Intracerebral hemorrhage (ICH) is a lethal and highly morbid form of stroke for which there is no disease-specific therapy. Inflammation after ICH is an important mechanism of secondary damage, and the inflamed endothelium in ICH is a promising therapeutic target as it is the gateway for recruitment of peripheral inflammatory cells to the brain. Systemic therapies that target inflammation have been unsuccessful in stroke, in part due to side effects or poor brain delivery. We hypothesized that targeting mRNA encoding IL-10, a potent anti-inflammatory cytokine, to the brain vasculature would improve outcomes in an experimental mouse model of ICH. We manufactured lipid nanoparticles (LNPs) using microfluidics, packaged them with IL-10 mRNA, and conjugated them with antibodies against vascular cellular adhesion molecule (VCAM), which can bind the inflamed brain endothelium after ICH. VCAM LNPs distributed to the brain similar to 4x more than nonspecific LNPs and expressed their cargo in the brain at 10x higher levels. Treatment with VCAM-LNPs containing IL-10 mRNA led to similar to 69% reduction in hematoma size at 72 h by histology and decreased lesion size in MRI, and similar to 65% improvement in motor behavior in our model. Finally, we propose that VCAM-IL10-LNPs enact their therapeutic benefit via modulation of brain macrophage phenotype. Our data bring forth a promising therapeutic and delivery strategy for ICH, and shed light on the effects of acute targeting of inflammation in ICH lesion size and behavior. Future experiments will seek to understand how serial dosing affects LNP expression in our model and whether treatment at later time points after ICH can still confer therapeutic effects.