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关键词： cytokines   uveitis   multiple-sclerosis   EAU   EAE   JAK/STAT   exosomes   nanobody  

摘要： Cytokines influence cell-fate decisions of na & iuml;ve lymphocytes and determine outcome of immune responses by transducing signals that regulate the initiation, intensity and duration of immune responses. However, aberrant regulation of physiological levels of cytokines contribute to the development of autoimmune and other inflammatory diseases. The Interleukin 6 (IL-6)/IL-12 superfamily of cytokines have a profound influence on all aspects of host immunity and our focus in this review is on the signaling pathways that mediate their functions, with emphasis on how this enigmatic family of cytokines promote or suppress inflammation depending on the physiological context. We also describe regulatory lymphocyte populations that suppress neuroinflammatory diseases by producing cytokines, such as IL-27 (i27-Breg) or IL-35 (i35-Breg and iTR35). We conclude with emerging immunotherapies like STAT-specific Nanobodies, Exosomes and Breg therapy that ameliorate CNS autoimmune diseases in preclinical studies.

关键词： IL-6   Cardiac fibroblasts   Purinergic signalling   Myocardial infarction   Adenosine  

摘要： Elevated interleukin-6 (IL-6) levels are linked to an increased risk of cardiovascular mortality in myocardial infarction (MI). Targeting IL-6 and its downstream signalling pathways represents a therapeutic strategy;however, its cellular sources and regulatory mechanisms of IL-6 remain incompletely understood. In this study, Alter and colleagues investigated the primary cell type that produces IL-6 in post-MI murine heart and the role of purinergic signalling in regulating IL-6 formation. Using cellular and mouse models, the authors identified cardiac fibroblasts as the predominant source of IL-6. Further analysis revealed that the IL-6 formation in cardiac fibroblasts is regulated by adenosine A2B receptors. Of further importance, they elucidated that T cells highly express CD73, leading to significant adenosine formation, which in turn enhances IL-6 production via Gq activation in cardiac fibroblasts following MI. These findings reveal a dynamic interplay between immune cells and fibroblasts in shaping the post-MI inflammatory response. This study suggests the adenosine-A2B receptor-IL6 axis as a potential therapeutic target to mitigate inflammation and improve cardiomyocytes salvage in MI.

关键词： 茯苓多糖   环磷酰胺   免疫   BTLA/HVEM  

摘要： 目的 探讨茯苓多糖（PCP）对免疫抑制小鼠的免疫调节作用及其潜在机制。方法 采用物理化学方法分析PCP进行结构表征；建立环磷酰胺（CTX）诱导的免疫抑制小鼠模型，评价PCP对免疫抑制模型小鼠免疫器官、免疫细胞和免疫因子的调节作用。结果 PCP分子量约为13.10 kDa，主要由半乳糖、葡萄糖、甘露糖、岩藻糖组成。PCP对CTX诱导的免疫抑制小鼠具有免疫保护作用。PCP能增加免疫抑制模型小鼠体重，改善其脾脏和胸腺损伤，提高脏器指数；能提高T淋巴细胞CD4+/CD8+比值，提高小鼠血清白细胞介素（IL）-2、IL-4、IL-10、IL-12、肿瘤坏死因子-α(TNF-α)和干扰素-γ(IFN-γ)的表达；PCP能降低免疫抑制小鼠脾脏组织中B/T淋巴细胞弱化因子（BTLA）和疱疹病毒侵入介质（HVEM）的表达，促进T淋巴细胞的增殖和分化。结论 PCP可能通过抑制BTLA/HVEM通路，提高免疫抑制小鼠的免疫功能，本研究提示PCP可作为新型免疫调节剂进行深入研究。

关键词： interleukin-10   interleukin-18   meta-analysis   nasopharyngeal carcinoma   polymorphism  

摘要： Objective To evaluate the possible association of the cytokine polymorphisms with the risk of nasopharyngeal carcinoma (NPC). Methods We performed a comprehensive search of electronic databases from PubMed, Web of Science, Embase, and CNKI. Articles related to the cytokine polymorphisms in patients with NPC and healthy controls from inception to 1 April 2024 were included. The results were analysed independently by two reviewers using RevMan 5.4 software. Summary odds ratio (OR) and 95% confidence interval (CI) were used to evaluate cancer risk. Results Our results showed that IL-10 1082A>G showed a significant difference only in the Dominant model, but in the Asian population, a significant difference was shown in all models. IL-18 607C>A polymorphism showed significant differences in the Allele model, Heterozygote model, and Homozygote model. In addition, the IL-18 137G>C polymorphism showed significant differences in all models. No statistically significant association was found between IL-8 251A>T, IL-10 819T>C polymorphism, and the risk of NPC. Conclusion Our meta-analysis results suggest that the IL-18 607C>A and IL-18 137G>C polymorphism are associated with the increased risk of NPC, and IL-10-1082 A/G polymorphism is associated with the increased risk of NPC in Asian populations.

关键词： periprosthetic osteolysis   wear particle   gene therapy   TNF-alpha   Wnt3a  

摘要： Wear particle-induced periprosthetic osteolysis is a prevalent issue that frequently leads to the failure of joint replacements, necessitating the development of effective therapeutic strategies. In this study, we established a mouse model of prosthetic loosening and evaluated the therapeutic effects of targeting tumor necrosis factor-alpha (TNF-alpha) and wingless-type MMTV integration site family, member 3A (Wnt3a) on osteolysis. TNF-alpha knockdown reduced inflammation and osteoclast-related gene expression, while Wnt3a overexpression increased osteoblast-related gene expression. Notably, the combination of these interventions showed superior efficacy in inhibiting osteolysis compared to monotherapy. Biomechanical imaging and histological staining revealed that combined therapy enhanced bone density and minimized the gaps between the peri-prosthetic bone and the prosthesis, reducing fibrous connective tissue proliferation. Adeno-associated virus-mediated gene therapy was found to be safe, with no adverse effects observed in liver, brain, spleen, and kidney tissues. Our findings suggest that combining TNF-alpha silencing with Wnt3a overexpression may be a promising approach for treating particle-induced peri-implant osteolysis and warrants further clinical investigation.

关键词： 疏肝益胃汤   瑞巴派特   肝郁脾虚证   慢性萎缩性胃炎   胃镜组织学   炎性细胞因子  

摘要： 目的：分析疏肝益胃汤辩证加减与瑞巴派特联合用药在慢性萎缩性胃炎(chronic atrophic gastritis，CAG)肝郁脾虚证诊疗中的实践效果，并观察疗程结束后胃镜组织学及炎性细胞因子改变情况。方法：选择我院近期收治114例CAG肝郁脾虚证患者，根据治疗方案将其分为对照组54例，观察组60例；其中对照组单用瑞巴派特口服，观察组加用疏肝益胃汤辩证加减，以3个月为治疗周期，疗程结束后观察两组中医症状积分、胃镜组织学积分、炎性因子指标变化情况，并对两组总临床疗效做对比分析。结果：治疗前，两组患者的中医症状积分、胃镜组织学积分、炎性因子指标对比，未见明显统计差异，P＞0.05；疗程结束后，与治疗前相比114例CAG肝郁脾虚证患者中医症状积分、胃镜组织学积分、炎性因子指标均明显下降，且观察组下降程度高于对照组；观察组临床总有效率明显高于对照组，P＜0.05。结论：应用疏肝益胃汤辩证加减联合瑞巴派特口服对CAG肝郁脾虚证患者具有确切临床疗效，能够修复胃镜组织学，调节体内血清炎性因子指标水平，提升临床治疗效果，应予以广泛推广。

摘要： RATIONALE:IL-33 is a key driver of type 2 inflammation relevant to airway epithelial biology. However, the mechanisms for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. OBJECTIVES:We sought to define how a disease associated isoform IL-33d34 that escapes nuclear sequestration and is tonically secreted from epithelial cells can be recruited to non-canonical secretory pathways. METHODS:IL-33d34 interaction with HSP70 was assessed and validated by affinity purification, mass-spectrometry and miniTurboID proximity labeling. Secretion and activity reporter assays were used to probe the effect of HSP70 on epithelial IL-33d34 secretion and receptor binding. Human airway disease biospecimens were analyzed for dysregulation of heat shock pathways revealing modulation of TCP1 complex intermediates. MEASUREMENTS AND MAIN RESULTS:We confirmed that HSP70 interacts directly with IL-33d34, recruits the cytokine to a vesicular compartment and enhances stability upon secretion. IL-33, HSP70 and other key mediators of proteostasis were found to be dysregulated in airway disease biospecimens and secreted extracellular vesicles. The IL-33d34 interactome was characterized and novel secretion modulators were identified. CONCLUSIONS:This study confirms a role for HSP70 in non-canonical IL-33d34 secretion and function that may be amenable for therapeutic targeting in airway diseases.

关键词： osteoarthritis   SIK1   chondrocyte apoptosis   inflammation   CRTC2/CREB1 signaling  

摘要： Osteoarthritis (OA) is a chronic degenerative joint disease that affects 70-90% of individuals over the age of 75 and over 100 million people globally. Current treatments primarily offer symptomatic relief and do not effectively halt disease progression, highlighting the need for improved therapeutic strategies. Salt-inducible kinase 1 (SIK1) plays a role in regulating key physiological processes, including gluconeogenesis, glycolysis, and bone metabolism. Despite these insights, the specific role and underlying mechanisms of SIK1 in OA pathogenesis remain inadequately understood. This study aims to elucidate the function of SIK1 in OA cells. We observed that SIK1 was downregulated in a cell model of OA. The overexpression of SIK1 was found to inhibit IL-1 beta-induced chondrocyte apoptosis and inflammation. Additionally, SIK1 overexpression enhanced the activation of the CRTC2/CREB1 axis, suggesting a protective role for SIK1 in cartilage cells. In summary, SIK1 exerts a protective effect against IL-1 beta-induced cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling axis.

关键词： IL-17   route design   imidazopyridazine   biocatalysis   stereoselective hydrogenation  

摘要： The chemical development and production of sufficient amounts of IL-17A inhibitor LY3509754 to enable preclinical toxicology studies is described. LY3509754 is a complex small molecule that features three stereocenters, which comprised much of the synthetic challenge. Stereoselective hydrogenation and biocatalysis enabled access to all stereocenters. The most significant challenge was installation of the chiral methoxymethyl side chain, specifically, formation of the sp2-sp3 C-C bond from reasonable raw materials and establishment of the benzylic amine stereocenter. Given prior experience with structural analogs, we were able to use a hybrid approach to the synthesis, with key building blocks being available on large-scale from the previous efforts. Historical knowledge combined with rapid route scouting and development allowed us to invent a scalable route to LY3509754 in about seven months and deliver 430 g to accelerate the preclinical toxicology studies.

关键词： NK cells   tumor immunology   IL-13   cytokines   ILC   allergy   HNSCC  

摘要： Natural killer (NK) cells are innate immune effectors with considerable heterogeneity and potent antitumor capabilities. Intraepithelial ILC1 (ieILC1)-like NK cells, a population of cytotoxic tissue-resident innate lymphoid cells, have recently been documented in the microenvironment of head and neck squamous cell carcinomas (HNSCC) and other solid tumors. These cells have antitumor cytolytic potential and are potent producers of type 1 cytokines, including IFN gamma. Here, we identify a subpopulation of ex vivo differentiated ieILC1-like NK cells that produce IL-13 upon stimulation. Functional characterization revealed that these cells co-expressed IFN gamma and IL-13 while maintaining an ILC1 transcriptional signature. IL-13 was induced either upon co-culture with tumor cell lines, or in response to TGF-beta and IL-15. IL-13-expressing ieILC1-like NK cells were identified among tumor infiltrating lymphocytes expanded from patient HNSCC tumors, in support of their in vivoexistence in primary tumors. These data demonstrate additional heterogeneity within the ieILC1-like NK cell population than previously appreciated and highlight a unique form of ILC plasticity in which cells with clear ILC1 transcriptional profiles express a type 2 cytokine. With the known roles of IL-13 in cancer cell growth dynamics and immunoregulation, the identification of this subset within tumor microenvironments presents a potential target for therapeutic manipulation.