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关键词： 骨肉瘤   线粒体转移   免疫逃逸   代谢调节  

摘要： 骨肉瘤是一种具有高度侵袭性的恶性骨肿瘤，其免疫逃逸机制在肿瘤进展及治疗耐药性形成过程中起关键作用。近年来，线粒体转移作为一种新兴的细胞间通讯方式，被证实可显著影响骨肉瘤细胞的代谢重编程及免疫逃逸过程。该机制通过以下途径发挥作用：(1) 增强肿瘤细胞的能量代谢效率；(2) 减轻细胞内氧化应激水平；(3) 调控免疫检查点分子表达。这些变化共同导致宿主免疫监视功能受损，并通过代谢重塑、免疫耐受诱导及肿瘤微环境重构等机制，最终促进骨肉瘤的增殖、侵袭和远处转移。本文重点阐述线粒体转移调控骨肉瘤免疫逃逸的分子机制及其对肿瘤微环境的动态影响，同时对该靶点在精准治疗中的转化应用前景及未来研究趋势进行展望。

关键词： CSF1R   Epidermis   IL-34   Langerhans cells   Squamous cell carcinoma  

摘要： The mononuclear phagocyte system depends upon CSF1R and its 2 ligands, CSF1 and IL-34. IL-34 is expressed constitutively in the skin in mice and humans from a conserved keratinocyte-specific promoter, suggesting a specific function in epidermal homeostasis. IL-34 deficiency leads to loss of Langerhans cells, the major antigen-presenting cell of the epidermis. Decreased IL-34 expression has been reported in inflammatory and malignant epithelial skin diseases, including atopic dermatitis, psoriasis, eczema, UV-damaged skin, response to common skin sensitizers and various types of squamous cell carcinomas. We discuss the possible contribution of the loss of IL-34 to immune dysregulation in the skin.

关键词： 种植体周围炎   补体系统   骨免疫学   免疫微环境   种植体   机制   炎症调节   骨代谢  

摘要： 种植体周围疾病发病率较高,免疫炎症反应与种植体黏膜炎及种植体周围炎密切相关。补体系统是免疫系统的重要组成部分,补体系统的激活不但可调控炎症反应的发生发展,对骨重塑也起到重要调节作用。本文对补体系统核心成分C3和C5在种植体植入后骨改建各个时期以及种植体黏膜炎、种植体周围炎中发挥的作用进行综述,旨在为通过靶向调控补体蛋白水平预防和治疗种植体周围炎提供新思路。

摘要： The expanded seed cells and the supraphysiological doses of exogenous growth factors both pose huge safety risks in bone regeneration. In this study, a novel IL-8/tDM/PLGA composite scaffold was developed, where chemokine interleukin-8 (IL-8) and transferable decellularized matrix (tDM) were uniformly overlaid on exterior and interior surfaces of poly(lactic--glycolic acid) (PLGA) porous substrates. The experiments confirmed that the synergy of tDM and IL-8 achieved the obvious promotion of osteogenesis and angiogenesis enhancing chemotaxis, adhesion, spreading, osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs). IL-8 mediated the recruitment of BMSCs and macrophages binding with C-X-C motif chemokine receptor 2 (CXCR2), while maintaining cellular viability without inducing macrophage polarization. Moreover, tDM improved BMSC adhesion and spreading the recognition and binding of the affinitive ligand existing in tDM by the cell adhesion molecules (CAMs) on the BMSC cytomembrane. Furthermore, tDM promoted the osteogenic differentiation and mineralization of BMSCs, benefiting from the retained growth factors. In a rat femoral defect model, the IL-8/tDM/PLGA scaffold significantly accelerated new bone mineralization and maturation through synergistic regulations of cell recruitment, matrix adhesion, and osteogenic signaling pathways. After 8 weeks post-implantation of the IL-8/tDM/PLGA scaffolds, the bone volume fraction of the newly formed bone, trabecular number, and trabecular separation at the defect site were 47%, 1.21 mm, and 0.50 mm, respectively, which presented significantly better bone repair effects than those in other groups. These results demonstrated that the innovative bone regeneration strategy combining chemokine-driven recruitment and endogenous tDM regulation offered a potential solution for clinical repair of large-sized bone defects.

关键词： 基质金属蛋白酶12   破伤风毒素   癌症疫苗   肺肿瘤   趋化因子类   T淋巴细胞  

摘要： 目的 探究基于基质金属蛋白酶12（MMP12）和破伤风毒素C片段（TTC）合成的TTC-MMP12184-225疫苗对肺癌的作用及其机制。方法 通过肿瘤免疫评估资源（TIMER）数据库分析肺癌患者肿瘤组织和邻近正常组织中MMP12 mRNA的相对表达水平。于6～8周龄C57BL/6J雌性小鼠的右侧腋窝下方2～3 cm处皮下接种Lewis肺癌（LLC）细胞构建肺癌小鼠皮下肿瘤模型，待肿瘤体积约达100 mm3时分离肺组织和肿瘤组织，通过RT-qPCR实验检测组织中MMP12 mRNA的相对表达水平。使用NetCTL-1.2、SYFPEITHI以及SVMtrip网站对MMP12中CD8+T细胞表位、CD4+T细胞表位和B细胞表位进行预测。使用VaxiJen-2.0服务器分析优势肽段的免疫原性。使用DNAstar软件分析MMP12蛋白的二级结构和亲水性。通过大肠杆菌原核表达系统合成TTC-MMP12184-225蛋白，并通过考马斯亮蓝染色实验进行鉴定。于6～8周龄C57BL/6J雌性小鼠右侧腋窝下2～3 cm处皮下接种LLC细胞，并随机分为对照组和实验组，两组小鼠分别肌肉注射100μL含有20μg TTC或者TTC-MMP12184-225蛋白的PBS,每7 d注射1次，共注射3次；在末次注射后的第3天分离肿瘤组织并测量肿瘤体积，通过流式细胞术检测两组小鼠肿瘤组织内CD4+T细胞和CD8+T细胞比例，通过RT-qPCR实验检测肿瘤组织中的C-C基序趋化因子配体5（CCL5）、C-X-C基序趋化因子配体9（CXCL9）、白细胞介素-2（IL-2）、γ干扰素（IFN-γ）、颗粒酶B（GRZB）和穿孔素（PFP）mRNA相对表达水平。结果 TIMER数据库分析和RT-qPCR实验结果显示，MMP12在肺癌患者和肺癌小鼠皮下肿瘤模型肿瘤组织中的表达分别显著高于相应邻近正常组织和肺组织（P<0.001、0.05）。表位预测结果显示，MMP12184-225包含12个CD8+T细胞表位、9个CD4+T细胞表位以及3个B细胞表位。VaxiJen-2.0服务器分析结果显示，MMP12184-225免疫原性评分为0.61。DNAstar软件的分析结果显示，MMP12184-225是以β-转角为主的亲水肽段。考马斯亮蓝染色结果显示，TTC-MMP12184-225蛋白在相对分子质量60 000下方出现明显的条带。与对照组相比较，实验组小鼠肿瘤体积明显减小，肿瘤组织内CD4+T细胞和CD8+T细胞比例显著升高，肿瘤组织内CCL5、CXCL9、IL-2、IFN-γ、GRZB和PFP mRNA的相对表达水平均显著上调（t=2.57～4.60,P<0.05）。结论 TTC-MMP12184-225疫苗能够促进肺癌小鼠肿瘤组织中CD4+和CD8+T细胞的募集以及抗肿瘤相关细胞因子的表达，从而发挥对肺癌的抗肿瘤效果。

摘要： E3 ligases and RNA-binding protein-mediated dysregulation of proinflammatory cytokines leads to autoimmune and inflammatory diseases. However, whether RNA-binding E3 ligases can regulate specific proinflammatory cytokine expression remains unclear. Here we found that the RNA-binding E3 ligase MKRN2 selectively inhibits the expression of interleukin-6 (IL-6) in lipopolysaccharide-activated macrophages. LysM-CreMkrn2 mice showed increased amounts of IL-6 in the serum after lipopolysaccharide treatment and exhibited increased severity of experimental colitis, which was associated with increased IL-6. Expression of MKRN2 negatively correlated with expression of IL-6 in clinical samples from individuals with ulcerative colitis and rheumatoid arthritis. Mechanistically, after binding to Il6 messenger RNA, MKRN2 linked K29 polyubiquitin chains to the Lys 179 residue of PAIP1, a translation initiation coactivator, which blocked PAIP1-eIF4A interaction and thus inhibited the translational efficiency of Il6 mRNA. Our findings provide mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation of specific proinflammatory cytokines.

关键词： 胶质瘤   IL-18   生物信息学   生物标志物  

摘要： 目的 利用生物信息学技术分析白细胞介素-18(interleukin-18,IL-18)与脑胶质瘤患者临床病理特征的关系。方法 利用UALCAN分析IL-18在低、高级别脑胶质瘤中的表达与患者临床病理特征相关性;通过c Bio Portal分析IL-18基因突变情况;选取手术切除且经病理证实的109例标本(24例脑膜瘤,85例各级别恶性脑胶质瘤)为研究对象,应用免疫组织化学染色法检测IL-18表达。结果 生物信息学研究结果发现,IL-18低表达组的低级别脑胶质瘤(LGG)患者生存期更长(P<0.01),IL-18水平对胶质母细胞瘤(GBM)患者生存期无明显影响(P>0.05)。在LGG中,星形细胞瘤组织中IL-18表达水平明显高于少突星形细胞瘤和少突胶质细胞瘤(P<0.01);与TP53突变组比较,TP53非突变组IL-18表达水平显著降低(P<0.01)。与正常脑组织样本比较,GBM组织样本IL-18表达水平显著升高(P<0.01),GBM组织中无论TP53是否突变,IL-18表达水平均明显升高(P<0.01);根据IL-18启动子甲基化状态,TP53非突变组与TP53突变组比较,IL-18表达水平显著增加(P<0.01)。免疫组织化学染色结果发现,IL-18表达与患者年龄、肿瘤大小及肿瘤分级之间关联密切,≥50岁脑胶质瘤患者IL-18表达水平明显增强;肿瘤体积越大,IL-18表达越强,低级别脑胶质瘤组织(Ⅰ+Ⅱ期)IL-18表达明显低于高级别脑胶质瘤组织(Ⅲ+Ⅳ期)(P<0.01)。结论 低级别脑胶质瘤患者中,IL-18可能具有抑制肿瘤发生、发展作用,而在高级别脑胶质瘤患者中,IL-18可能是促进胶质瘤进展的因素之一。

关键词： 原发性高血压   左室几何构型   超声心动描记术   二维应变   白细胞介素-10   白细胞介素-18  

摘要： 目的 探讨原发性高血压（PHT）患者IL-10和IL-18与左室几何构型（LVG）及左室功能的相关性。方法 选取2023年7月至2024年5月就诊于山西医科大学第一医院确诊为PHT患者224例，分为4组：正常构型（NG）组127例、向心性重构（CR）组51例、离心性肥厚（EH）组27例和向心性肥厚（CH）组19例。另选取同期本院健康体检中心招募的年龄、性别匹配，且无高血压、心血管疾病及代谢性疾病的健康者25例作为对照组。比较5组间一般资料、血清IL-10、IL-18水平及左室参数[左室舒张末期内径（LVEDD）、室间隔厚度（IVST）、左室后壁厚度（LVPWT）、左房收缩末期前后径（LAD）、左室质量指数（LVMI）、相对室壁厚度（RWT）；二尖瓣口舒张早期血流峰值速度（E）、二尖瓣口舒张晚期血流峰值速度（A）、E/A、二尖瓣环舒张早期心肌运动速度（e′）、E/e′、左室射血分数（LVEF）、左室整体纵向应变（GLS）]。采用Pearson相关及多因素Logistic回归分析IL-10、IL-18与LVG和左室功能的关系。结果 与对照组相比，PHT组患者血清IL-10水平降低（P<0.05）,IL-18水平升高（P<0.05），其中EH组和CH组变化显著（均P<0.05）。Pearson相关分析显示，IL-10与LVEDD、IVST、LVPWT、A、E/e′呈负相关（P<0.05），与e′、E/A、LVEF、GLS呈正相关（P<0.05）;IL-18与LVEDD、IVST、LVPWT、A、E/e′呈正相关（P<0.05），与e′、E/A、LVEF、GLS呈负相关（P<0.05）。多因素Logistic回归显示，IL-10是CR、EH及CH的独立保护因素（P<0.05）;IL-18是CR、EH及CH的独立风险因素（P<0.05）。结论 IL-10和IL-18与PHT患者左室结构及功能密切相关，可能参与PHT患者左室结构和功能异常的过程。

摘要： Protein kinase R (PKR) expression is induced by interferons. This protein is activated by double-stranded (ds) RNAs or RNAs containing duplex regions, produced after different stimuli, such as after viral infections, leading to the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α), and subsequently inhibiting cellular and viral protein translation. This function may lead to different effects such as to impairing the replication of RNA viruses by inhibiting viral protein translation, and to modulating the innate immune responses after viral infections by affecting the translation of effector proteins. In this work, we identify, for the first time, an interaction of IFN alpha inducible protein 27 (IFI27) with PKR-activating protein (PACT or PRKRA) and with PKR, showing that the interaction of IFI27 with PACT is likely mediated by dsRNAs or RNAs containing duplex regions, and that the interaction of IFI27 with PKR is PACT-dependent. Interestingly, using IFI27 knocked-down, knocked-out and overexpressing tumour-derived, established cells, we show that these interactions trigger a potentiation of the activity of PKR and, therefore, a decrease in protein translation. Moreover, we find that IFI27 increases PKR function in cells infected with different RNA viruses such as Severe Acute Respiratory virus 2 (SARS-CoV-2), and Vesicular Stomatitis virus (VSV), and in cells transfected with the dsRNA analog poly(I:C), suggesting a broad effect of IFI27 on PKR activation. Moreover, we show that IFI27 expression increases the formation of stress granules (SGs) at the cell cytoplasm, correlating with the increased PKR activation mediated by IFI27, as it has been shown that the translational arrest induced by activated PKR leads to the formation of SGs. Mechanistically, we describe that this ability of IFI27 to activate PKR is dependent on its interaction with PACT. Further understanding of the regulation of PKR activity will allow us to develop new antiviral

摘要： Metastatic colorectal cancer (CRC) has the dismal 5-year survival rate of only 14%, and immunotherapies fail to improve the patient outcome. One reason for the poor response rate is the slightly acidic (~ 6.5) immunosuppressive microenvironment. Interleukin 12 (IL-12) is a highly potent pro-inflammatory cytokine that can stimulate tumor immune cells and reverse immunosuppression by inducing interferon gamma (IFN-γ) expression. However, its clinical applications are hindered by systemic side effects. In this study, we developed pH-responsive polymeric nanoparticles (NPs) encapsulating IL-12 to enhance its therapeutic efficacy into the tumor microenvironment (TME). IL-12-loaded pH-responsive NPs induced antitumoral pro-inflammatory response in macrophages at pH ~ 6.5, determined by increased IFN-γ levels and nitric oxide (NO) release, without affecting metabolic activity. In contrast, IL-12-loaded pH non-responsive PLGA NPs showed much lower macrophage activation. To validate the specificity and efficacy in a complex immune-rich microenvironment, we developed a novel CRC 3D immuno-spheroid by incorporating human monocyte-derived macrophages with tumor cells in collagen, mimicking CRC spatial organization and extracellular matrix. The interaction of IL-12 pH-responsive NPs induced macrophage polarization, by providing a reduction of M2-like markers (CD14 + CD163+) while increasing pro-inflammatory M1-like counterparts (CD14 + CD86+). Moreover, IL-12 pH-responsive NPs increased IFN-γ levels and reduced anti-inflammatory IL-10 secretion. Overall, this study provides two major findings (1) a pH-responsive NP system to effectively deliver IL-12 to the TME and reprogram local macrophages into pro-inflammatory phenotype; (2) a macrophage-enriched human 3D immuno-spheroid in vitro system as a tool to test the effectivity of immunomodulatory NPs.