Cytokine最新文献_第10页

Delving deeper in the eye of the hurricane: Immunopathogenesis & molecular characterization of cytokine storm in COVID-19, association with disease severity & the therapeutic regimens 深入研究飓风眼：COVID-19细胞因子风暴的免疫发病机制和分子特征，与疾病严重程度和治疗方案的关联

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-09-12 DOI: 10.1016/j.cyto.2025.157025

Umaiya Muzaffar , Kamal Shaik Fakiruddin , Yasaman Talebiashtiany , Syahril Abdullah

The COVID-19 pandemic elicited by SARS-CoV-2 has led to a world-wide crisis, affecting a substantial percentage of the entire global population, and has engendered profound morbidity and fatalities. SARS-CoV-2 mediates its entry into human respiratory epithelial cells via interaction between viral Spike protein (S) and ACE2 receptor and enacts the host cell tropism by numerous molecular factors and inflammatory signaling pathways. The complex molecular immunopathogenesis involves loss of regulatory control of the generation & release of proinflammatory cytokines at both local as well as systemic levels. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system leading to the cytokine storm. Owing to the enormous release of inflammatory factors and active mediators, cytokine storm induces severe damage to secondary tissues, leading to Acute Respiratory Distress Syndrome (ARDS) or multiple-organ failure, which evokes aggravation of the disease and eventually death. Comparisons amid COVID-19 cytokine storm and several other types of cytokine storm associated diseases, gives proper insights about the etiology of cytokine storm in COVID-19. Various genetic and physiological factors contribute to severe disease progression and aggravation of the disease. In that view, several immunoregulatory therapies have been tailored to curb the cytokine storm, which might be crucial in improving the success rates of various treatment strategies as well as in lowering the mortality rate in COVID-19 patients. This review elucidates the hallmarks of COVID-19 cytokine storm, immunopathogenesis, disease progression, biomarkers, and therapeutic interventions.

由SARS-CoV-2引发的COVID-19大流行导致了一场全球性危机，影响了全球相当大比例的人口，并造成了严重的发病率和死亡率。SARS-CoV-2通过病毒刺突蛋白（Spike protein， S）与ACE2受体的相互作用介导进入人呼吸道上皮细胞，并通过多种分子因子和炎症信号通路介导宿主细胞趋向性。复杂的分子免疫发病机制涉及局部和全身水平上对促炎细胞因子的产生和释放的调节控制的丧失。促炎细胞因子和趋化因子的过度分泌导致先天免疫系统失调，导致细胞因子风暴。由于炎症因子和活性介质的大量释放，细胞因子风暴对继发性组织造成严重损伤，导致急性呼吸窘迫综合征（Acute Respiratory Distress Syndrome， ARDS）或多器官功能衰竭，引起疾病加重，最终导致死亡。比较COVID-19细胞因子风暴和其他几种类型的细胞因子风暴相关疾病，为COVID-19细胞因子风暴的病因提供了正确的见解。各种遗传和生理因素导致疾病的严重进展和加重。根据这种观点，已经定制了几种免疫调节疗法来抑制细胞因子风暴，这可能对提高各种治疗策略的成功率以及降低COVID-19患者的死亡率至关重要。本文综述了COVID-19细胞因子风暴的特征、免疫发病机制、疾病进展、生物标志物和治疗干预措施。

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引用次数: 0

Inactivation of LHAVglut2 neurons relieves stress-induced intestine inflammation by sympathetic nerve- intestinal epithelial cell Cxcl1 communication LHAVglut2神经元失活可通过交感神经-肠上皮细胞Cxcl1通讯缓解应激性肠炎症

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-09-03 DOI: 10.1016/j.cyto.2025.157024

Keyi Liu , Xinyan Tan , Lianguo Fu , Fengfeng Mo

Purpose

This study aimed to elucidate the role of lateral hypothalamic area (LHA) Vglut2 neurons in stress-induced intestinal inflammation and to investigate the underlying mechanisms involving neuro-immune interactions. Specifically, we hypothesized that LHA Vglut2 neuron activation exacerbates intestinal inflammation via sympathetic-driven IL-1β and Cxcl1 signaling.

Methods

Transgenic mice (Vglut2-cre) and wild-type controls were subjected to chronic restraint stress (CRS). Chemogenetic silencing of LHA Vglut2 neurons was achieved using hM4Di DREADD receptors. Techniques included qPCR, RNA sequencing, pseudorabies virus (PRV) retrograde tracing, immunofluorescence, and histopathology. Sympathetic ablation (6-OHDA) and vagotomy were performed to dissect neural pathways.

Results

CRS upregulated IL-1β and Cxcl1 in the gut, increased c-Fos expression in LHA neurons, and impaired intestinal barrier integrity (reduced ZO-1/Occludin, elevated MUC2). Silencing LHA Vglut2 neurons reversed these effects, reducing inflammation and restoring barrier proteins. RNA sequencing revealed IL-1β-Cxcl1 as a key pathway. Sympathetic ablation mirrored these improvements, while vagotomy showed no effect, indicating a predominant sympathetic-mediated mechanism.

Conclusion

LHA Vglut2 neurons drive stress-induced intestinal inflammation via sympathetic activation of the IL-1β-Cxcl1 axis. Targeting this hypothalamic-sympathetic circuit may offer therapeutic potential for stress-related gastrointestinal disorders.

目的研究下丘脑外侧区（LHA） Vglut2神经元在应激性肠道炎症中的作用，并探讨其神经免疫相互作用的潜在机制。具体来说，我们假设LHA Vglut2神经元激活通过交感神经驱动的IL-1β和Cxcl1信号通路加剧肠道炎症。方法对转基因小鼠（Vglut2-cre）和野生型小鼠进行慢性抑制应激（CRS）。利用hM4Di DREADD受体实现LHA Vglut2神经元的化学发生沉默。技术包括qPCR， RNA测序，伪狂犬病毒（PRV）逆行示踪，免疫荧光和组织病理学。采用交感神经消融术（6-OHDA）和迷走神经切开术解剖神经通路。结果scrs上调肠道IL-1β和Cxcl1，增加LHA神经元中c-Fos的表达，损害肠屏障完整性（ZO-1/Occludin降低，MUC2升高）。沉默LHA Vglut2神经元逆转了这些作用，减少了炎症并恢复了屏障蛋白。RNA测序显示IL-1β-Cxcl1是关键通路。交感神经消融术反映了这些改善，而迷走神经切开术没有效果，表明交感神经介导的机制占主导地位。结论lha Vglut2神经元通过激活IL-1β-Cxcl1轴驱动应激性肠道炎症。以这种下丘脑-交感神经回路为目标，可能为应激相关的胃肠道疾病提供治疗潜力。

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引用次数: 0

Genetic evidence for a causal relationship between oral bacterial taxa and asthma in east Asian population 东亚人群口腔细菌分类群与哮喘因果关系的遗传证据

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-09-01 DOI: 10.1016/j.cyto.2025.157021

Wenyan Wei , Zejing Qiu , Lu Xiao , Yanlin Huang , Min Chen

Background

Emerging evidence highlights the significant role of microbiota (lung and gut) in the development of asthma. However, the potential effect between oral microbiota and asthma remains poorly understood.

Methods

This study performed a bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of oral microbiota, immune cell traits and asthma. Various MR analysis methods were employed, including inverse variance weighted (IVW), constrained maximum likelihood model averaging-based method (cML-MA-BIC), maximum likelihood (ML), weighted mode, weighted median, and MR-robust adjusted profile score (MR-RAPS). Additionally, mediation analyses were performed to identify the immune cell traits that mediate these effects.

Results

This study identified 12 oral bacterial taxa and 36 inflammatory cytokines associated with asthma. After identifying the oral microbiota and immune cell characteristics associated with asthma, we applied a mediation MR framework to investigate whether immune cell traits mediate the effect of microbiota on asthma. Finally, we identified eight immune cell traits that mediate asthma caused by bacteria.

Conclusions

Our results highlight the causal associations between oral bacterial taxa, immune cell traits, and asthma, providing evidence that various immune cell traits serve as critical mediators between the oral microbiota and asthma. The link between the oral microbiome and asthma has important implications for clinical practice.

新出现的证据强调了微生物群（肺和肠道）在哮喘发展中的重要作用。然而，口服微生物群与哮喘之间的潜在影响仍然知之甚少。方法本研究采用双向孟德尔随机化（MR）研究，利用口腔微生物群、免疫细胞特征和哮喘全基因组关联研究的汇总统计数据。采用了各种磁共振分析方法，包括逆方差加权（IVW）、基于约束的最大似然模型平均方法（cML-MA-BIC）、最大似然（ML）、加权模式、加权中位数和磁共振稳健调整剖面评分（MR- raps）。此外，还进行了中介分析，以确定介导这些影响的免疫细胞特性。结果本研究鉴定出12个口腔细菌分类群和36个与哮喘相关的炎症因子。在确定与哮喘相关的口腔微生物群和免疫细胞特征后，我们应用中介MR框架来研究免疫细胞特征是否介导微生物群对哮喘的影响。最后，我们确定了介导由细菌引起的哮喘的8种免疫细胞特征。结论口腔细菌类群、免疫细胞特性与哮喘之间存在因果关系，表明多种免疫细胞特性在口腔微生物群与哮喘之间起着重要的调节作用。口腔微生物组与哮喘之间的联系对临床实践具有重要意义。

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引用次数: 0

Long non-coding RNA MEG3 rs7158663 polymorphism confers susceptibility to the development of sepsis and is associated with sepsis-induced inflammatory responses 长链非编码RNA MEG3 rs7158663多态性与脓毒症的发展易感性有关，并与脓毒症诱导的炎症反应有关

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-29 DOI: 10.1016/j.cyto.2025.157019

Xiemuziya Maimaitirexiati , Minxin Wang , Huijing Zhao

Background

The polymorphism of long non-coding RNA (lncRNA) can influence the susceptibility of patients to certain diseases.

Objectives

This study compared the genotype distribution of lncRNA MEG3 rs7158663 polymorphism in sepsis patients and controls. Furthermore, it elaborated on the relationship between rs7158663 and prognosis as well as the inflammatory response of the patients.

Materials and methods

350 sepsis patients and 320 controls were incorporated to conduct genotyping of the rs7158663 locus and to measure the serum MEG3 levels. The connection between genotypes and prognosis was appraised via the construction of K-M curves. The levels of serum inflammatory factors were measured with ELISA.

Results

Rs7158663 GG genotype occurred more frequently in sepsis patients than the control group, whereas the frequencies of the GA and AA genotypes were lower in the former. MEG3 rs7158663 GA and AA genotypes were non-susceptible genotypes for sepsis, and a similar genetic association was observed in the dominant model. Stratified analysis indicated that the genetic association between rs7158663 and sepsis was more significant in cases with non-smoking, non-drinking, older age, and low BMI. MEG3 rs7158663 GG genotype carriers had increased MEG3, excessive release of inflammatory factors, and poor prognosis in patients with sepsis.

Conclusion

MEG3 rs7158663 GG genotype may be a susceptibility genotype for sepsis and is associated with patients' poor prognosis. It might be related to rs7158663-mediated increase of MEG3 expression and excessive release of inflammatory cytokines.

长链非编码RNA （lncRNA）的多态性可以影响患者对某些疾病的易感性。目的比较脓毒症患者和对照组中lncRNA MEG3 rs7158663多态性的基因型分布。进一步阐述了rs7158663与预后及患者炎症反应的关系。材料与方法选取350例脓毒症患者和320例对照组，对rs7158663位点进行基因分型，测定血清MEG3水平。通过构建K-M曲线来评价基因型与预后的关系。采用ELISA法检测血清炎症因子水平。结果rs7158663 GG基因型在脓毒症患者中的发生率高于对照组，而GA和AA基因型在脓毒症患者中的发生率低于对照组。MEG3 rs7158663 GA和AA基因型是脓毒症的非易感基因型，在优势模型中也观察到类似的遗传关联。分层分析显示，rs7158663与脓毒症的遗传相关性在不吸烟、不饮酒、年龄较大、BMI较低的人群中更为显著。MEG3 rs7158663 GG基因型携带者脓毒症患者MEG3升高，炎症因子释放过多，预后较差。结论meg3 rs7158663 GG基因型可能是脓毒症的易感基因型，与患者预后不良相关。可能与rs7158663介导的MEG3表达升高、炎性细胞因子过度释放有关。

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引用次数: 0

Differential chemokine profiles between lacrimal and salivary glands in a murine model of primary Sjögren disease 原发性Sjögren疾病小鼠模型中泪腺和唾液腺的差异趋化因子谱

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-29 DOI: 10.1016/j.cyto.2025.157023

Ruka Nagao , Kunihiro Otsuka , Shigefumi Matsuzawa , Aya Ushio , Takaaki Tsunematsu , Naozumi Ishimaru

Background

Primary Sjögren disease (pSjD) is an autoimmune disorder that primarily targets the lacrimal glands (LGs) and salivary glands (SGs). However, the differences in immune pathogenesis between LGs and SGs remain poorly understood. In this study, we investigated LG-specific immune responses in comparison to SGs using a murine model of pSjD. Histopathological analyses of LGs and SGs were conducted in control and pSjD model mice.

Methods

The mRNA expression levels of 18 chemokines associated with T-cell migration were evaluated by quantitative PCR. Gene expression of selected chemokines was further examined in LG tissues by in situ hybridization. The phenotype and function of T-cells were assessed using flow cytometry and in vitro migration assays.

Results

Lymphocytic infiltration was observed earlier in LGs than in SGs in pSjD model mice. Among the chemokines analyzed, C-X-C motif chemokine ligand 4 (CXCL4) was specifically upregulated in LGs. Cxcl4 expression was localized to macrophages within LG tissues. Moreover, CXCR3 expression on CD4⁺ T-cells in lymphoid tissues was significantly higher in pSjD model mice compared to controls. T-bet was more highly expressed in CXCR3⁺CD4⁺ T cells than in CXCR3⁻CD4⁺ T cells in pSjD model mice. Finally, CXCL4 enhanced the migration of CD4⁺ T cells derived from pSjD model mice more effectively than those from control mice.

Conclusions

These findings suggest that CXCL4-producing macrophages may promote the recruitment of CXCR3⁺ Th1 cells into the LGs in pSjD, thereby contributing to LG-specific autoimmune inflammation. This mechanism may represent a potential therapeutic target for managing dry eye in pSjD.

原发性Sjögren疾病（pSjD）是一种主要以泪腺（LGs）和唾液腺（SGs）为靶点的自身免疫性疾病。然而，LGs和SGs在免疫发病机制上的差异仍然知之甚少。在这项研究中，我们利用小鼠pSjD模型研究了lg特异性免疫反应与SGs的比较。对对照组和pSjD模型小鼠进行LGs和SGs的组织病理学分析。方法采用定量PCR方法检测18种与t细胞迁移相关的趋化因子的mRNA表达水平。通过原位杂交进一步检测LG组织中所选趋化因子的基因表达。使用流式细胞术和体外迁移试验评估t细胞的表型和功能。结果pSjD模型小鼠LGs的淋巴细胞浸润时间早于SGs。在分析的趋化因子中，C-X-C基序趋化因子配体4 （CXCL4）在LGs中特异性上调。Cxcl4的表达局限于LG组织内的巨噬细胞。此外，pSjD模型小鼠淋巴组织CD4+ t细胞上CXCR3的表达明显高于对照组。在pSjD模型小鼠中，T-bet在CXCR3+CD4+ T细胞中的表达高于CXCR3 - CD4+ T细胞。最后，CXCL4对pSjD模型小鼠CD4+ T细胞的迁移作用比对照组小鼠更有效。结论产生cxcl4的巨噬细胞可能促进pSjD中CXCR3+ Th1细胞募集到LGs，从而参与LGs特异性自身免疫性炎症。这一机制可能是治疗干眼症的潜在治疗靶点。

{"title":"Differential chemokine profiles between lacrimal and salivary glands in a murine model of primary Sjögren disease","authors":"Ruka Nagao , Kunihiro Otsuka , Shigefumi Matsuzawa , Aya Ushio , Takaaki Tsunematsu , Naozumi Ishimaru","doi":"10.1016/j.cyto.2025.157023","DOIUrl":"10.1016/j.cyto.2025.157023","url":null,"abstract":"<div><h3>Background</h3><div>Primary Sjögren disease (pSjD) is an autoimmune disorder that primarily targets the lacrimal glands (LGs) and salivary glands (SGs). However, the differences in immune pathogenesis between LGs and SGs remain poorly understood. In this study, we investigated LG-specific immune responses in comparison to SGs using a murine model of pSjD. Histopathological analyses of LGs and SGs were conducted in control and pSjD model mice.</div></div><div><h3>Methods</h3><div>The mRNA expression levels of 18 chemokines associated with T-cell migration were evaluated by quantitative PCR. Gene expression of selected chemokines was further examined in LG tissues by <em>in situ</em> hybridization. The phenotype and function of T-cells were assessed using flow cytometry and <em>in vitro</em> migration assays.</div></div><div><h3>Results</h3><div>Lymphocytic infiltration was observed earlier in LGs than in SGs in pSjD model mice. Among the chemokines analyzed, C-X-C motif chemokine ligand 4 (CXCL4) was specifically upregulated in LGs. <em>Cxcl4</em> expression was localized to macrophages within LG tissues. Moreover, CXCR3 expression on CD4<sup>+</sup> T-cells in lymphoid tissues was significantly higher in pSjD model mice compared to controls. T-bet was more highly expressed in CXCR3<sup>+</sup>CD4<sup>+</sup> T cells than in CXCR3<sup>−</sup>CD4<sup>+</sup> T cells in pSjD model mice. Finally, CXCL4 enhanced the migration of CD4<sup>+</sup> T cells derived from pSjD model mice more effectively than those from control mice.</div></div><div><h3>Conclusions</h3><div>These findings suggest that CXCL4-producing macrophages may promote the recruitment of CXCR3<sup>+</sup> Th1 cells into the LGs in pSjD, thereby contributing to LG-specific autoimmune inflammation. This mechanism may represent a potential therapeutic target for managing dry eye in pSjD.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"195 ","pages":"Article 157023"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Global transcriptomic profiling reveals nicotinamide metabolism as a key regulator of nitric oxide-modulated interferon-γ responses in macrophages 全球转录组学分析显示，在巨噬细胞中，烟酰胺代谢是一氧化氮调节的干扰素-γ反应的关键调节因子

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-28 DOI: 10.1016/j.cyto.2025.157015

Avik Chattopadhyay , Sai Shyam , Shreyasee Das , Dipankar Nandi

Interferon-gamma (IFN-γ) is a key regulator of immune responses. A hallmark of IFN-γ responses is inducible nitric oxide (NO), driven primarily by nitric oxide synthase (NOS)2. In this study, we investigated the influence of NO on the IFN-γ-induced transcriptomic and metabolic changes in the RAW 264.7 macrophage cell line. IFN-γ activation led to NO-dependent lactate production and lower cell survival. Bulk RNA sequencing analysis identified genes differentially expressed early by IFN-γ that were either NO-independent or NO-dependent. Inhibition of NO modulated a minor subset of the transcriptome, notably affecting Klf6 (a tumor suppressor) and Zfp36 (a regulator of pro-inflammatory cytokines). Interestingly, both Klf6 and Zfp36 correlatively showed high expression in most cancers. The protein-protein interaction (PPI) network exhibited dense clustering with scale-free and small-world properties, identifying Stat1, Irf7, Irf1, Cxcl10, and Isg15 as top five hubs. Interestingly, the RNA seq analysis identified IFN-γ upregulated genes, Nampt, Pnp and Pnp2, to be involved in nicotinamide metabolism. This novel aspect was experimentally tested to show that IFN-γ induced NAD⁺ amounts in a NO-dependent manner. Importantly, the inhibition of purine nucleoside phosphorylase (PNP) which is involved in the endogenous pathway for NAD⁺ generation, lowered IFN-γ-induced nitrite and increased cell survival, demonstrating biological relevance of this study. Interestingly, NAMPT and PNP are expressed in multiple organs in humans and Epstein Barr Virus (EBV)-transformed lymphocytes. In addition, polymorphisms in NAMPT and PNP are associated with several diseases. Functionally, enriched nicotinamide metabolism by IFN-γ may regulate inflammatory responses and the implications of our findings are discussed.

干扰素γ (IFN-γ)是免疫应答的关键调节因子。IFN-γ反应的一个标志是诱导型一氧化氮（NO），主要由一氧化氮合酶（NOS）2驱动。在本研究中，我们研究了NO对IFN-γ诱导的RAW 264.7巨噬细胞转录组学和代谢变化的影响。IFN-γ激活导致no依赖性乳酸生成和细胞存活率降低。大量RNA测序分析鉴定了IFN-γ早期差异表达的基因，这些基因要么是no独立的，要么是no依赖的。NO的抑制调节了转录组的一小部分，特别是影响了Klf6（一种肿瘤抑制因子）和Zfp36（一种促炎细胞因子的调节因子）。有趣的是，Klf6和Zfp36在大多数癌症中都有高表达。蛋白质相互作用（PPI）网络具有密集的聚类，具有无标度和小世界特性，其中Stat1、Irf7、Irf1、Cxcl10和Isg15为前5个枢纽。有趣的是，RNA序列分析发现IFN-γ上调的基因Nampt、Pnp和Pnp2参与烟酰胺代谢。这一新的方面经过实验测试，表明IFN-γ以no依赖的方式诱导NAD+的量。重要的是，抑制参与内源性NAD+生成途径的嘌呤核苷磷酸化酶（PNP），降低IFN-γ诱导的亚硝酸盐，提高细胞存活率，证明了本研究的生物学相关性。有趣的是，NAMPT和PNP在人类的多个器官和eb病毒转化淋巴细胞中表达。此外，NAMPT和PNP的多态性与几种疾病有关。功能上，IFN-γ丰富的烟酰胺代谢可能调节炎症反应，并讨论了我们研究结果的意义。

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引用次数: 0

Serum levels of leucine-rich α–2 glycoprotein 1 (LRG1), pro-neurotensin (PNT), fatty acid-binding protein 4 (FABP4) and furin in pediatric growth hormone deficiency before and after 1-year growth hormone replacement therapy 生长激素缺乏儿童1年生长激素替代治疗前后血清富亮氨酸α-2糖蛋白1 （LRG1）、前神经紧张素（PNT）、脂肪酸结合蛋白4 （FABP4）和furin水平的变化

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-28 DOI: 10.1016/j.cyto.2025.157022

Zhibo Zhou , Yuxin Sun , Zeyan Zheng , Xiaoyuan Guo , Hongbo Yang , Shi Chen , Hui Pan , Huijuan Zhu

Objective

To investigate serum levels of leucine-rich α–2 glycoprotein 1 (LRG1), pro-neurotensin (PNT), fatty acid-binding protein 4 (FABP4), and furin in children with growth hormone deficiency (GHD) compared to idiopathic short stature (ISS) and healthy children, and to evaluate their changes and clinical relevance after 1-year growth hormone replacement therapy (GHRT).

Methods

The prospective cohort study was conducted in 32 idiopathic GHD, 32 ISS and 32 healthy children. Serum LRG1, PNT, FABP4, furin and clinical parameters were measured at baseline and after 6 and 12 months of GHRT. Correlation analyses were used to assess the associations between these adipokines and clinical variables. Restricted cubic spline curves and multivariable logistic regressions were used to assess the relationships between adipokines and GHD risk.

Results

At baseline, PNT and furin levels were significantly higher, while LRG1 was lower in GHD children compared to ISS and healthy controls. After 1-year GHRT, LRG1, PNT, FABP4, and furin levels significantly decreased in GHD patients. PNT levels were higher in male and GHD patients, and FABP4 levels were positively related with GV_SDS, BMI_SDS and negatively with FBG. Higher PNT levels were associated with increased GHD risks (OR = 15.545, P < 0.001), while and higher LRG1 levels were associated with decreased GHD risks (OR = 0.291, P = 0.034).

Conclusion

GHD children have higher PNT and furin levels and lower LRG1 levels. During GHRT, LRG1, PNT, FABP4 and furin levels significantly decline, suggesting favorable metabolic effects and potential long-term benefits of GHRT.

目的探讨生长激素缺乏症（GHD）患儿血清富白氨酸α-2糖蛋白1 （LRG1）、前神经紧张素（PNT）、脂肪酸结合蛋白4 （FABP4）、furin水平与特发性身材矮小（ISS）及健康儿童的比较，并评价其在1年生长激素替代治疗（GHRT）后的变化及其临床意义。方法对32例特发性GHD、32例ISS和32例健康儿童进行前瞻性队列研究。在基线及GHRT治疗6个月和12个月后测定血清LRG1、PNT、FABP4、furin及临床参数。相关分析用于评估这些脂肪因子与临床变量之间的关联。使用限制性三次样条曲线和多变量logistic回归来评估脂肪因子与GHD风险之间的关系。结果与ISS和健康对照组相比，GHD儿童的sat基线、PNT和furin水平显著升高，而LRG1水平较低。ght治疗1年后，GHD患者的LRG1、PNT、FABP4和furin水平显著降低。男性和GHD患者PNT水平较高，FABP4水平与GVSDS、BMISDS呈正相关，与FBG呈负相关。较高的PNT水平与GHD风险增加相关（OR = 15.545, P < 0.001），而较高的LRG1水平与GHD风险降低相关（OR = 0.291, P = 0.034）。结论hd患儿PNT、furin水平较高，LRG1水平较低。在GHRT期间，LRG1、PNT、FABP4和furin水平显著下降，提示GHRT具有良好的代谢作用和潜在的长期益处。

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引用次数: 0

The NLRP3 inflammasome activation boosts lung injury, inflammation, and macrolide resistance in mycoplasma pneumoniae pneumonia NLRP3炎性小体激活促进肺炎支原体肺炎的肺损伤、炎症和大环内酯类药物耐药性

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-26 DOI: 10.1016/j.cyto.2025.157014

Meijun Zhu, Yan Lu, Yan Wei, Fei Hong, Juhua Ji, Lei Song

The increase in the number of macrolide-resistant Mycoplasma pneumoniae (MP) poses a threat to human health worldwide. The present research investigates the role of the NLRP3 inflammasome in mycoplasma pneumoniae pneumonia (MPP). MPP patient (n = 40) and healthy control (n = 20)-derived serum samples were collected. MP (strain ATCC15531)-infected C57BL/6 J or Nlrp3^−/− mice with or without MCC950 treatment were used to explore the role of the NLRP3 inflammasome. The concentrations of inflammatory cytokines were determined by enzyme-linked immunosorbent assay. Histomorphological changes were determined by hematoxylin-eosin staining. The transcriptional and translational levels of NLRP3 were detected with quantitative PCR and western blot. Serum interleukin (IL)-1β and IL-18 levels were higher in MPP patients, along with elevated NLRP3 mRNA and protein levels. High NLRP3 expression was associated with fever duration, duration of admission, c-reactive protein and lactate dehydrogenase levels, and macrolide resistance. During the progression of MP infection, the NLRP3 inflammasome was progressively activated in mice, accompanied by increasing lung injury and inflammation. However, MP-infected Nlrp3^−/− mice showed decreased lung injury and inflammation. Additionally, MCC950 weakened lung injury and inflammation in MPP mice, and the combination of azithromycin and MCC950 exerted a stronger effect than azithromycin or MCC950 alone. The NLRP3 inflammasome activation boosts lung injury, inflammation, and macrolide resistance in MPP, implying that interfering with the NLRP3 inflammasome may be a stratagem for MPP administration.

耐大环内酯肺炎支原体（MP）数量的增加对全球人类健康构成威胁。本研究探讨NLRP3炎性小体在肺炎支原体肺炎（MPP）中的作用。收集MPP患者（n = 40）和健康对照（n = 20）的血清样本。用MP（菌株ATCC15531）感染C57BL/6 J或Nlrp3 - / -小鼠，分别用或不加MCC950治疗，探讨Nlrp3炎症小体的作用。采用酶联免疫吸附法测定炎症细胞因子浓度。苏木精-伊红染色观察组织形态学变化。采用定量PCR和western blot检测NLRP3的转录和翻译水平。MPP患者血清白细胞介素(IL)-1β和IL-18水平升高，NLRP3 mRNA和蛋白水平升高。NLRP3高表达与发热持续时间、入院时间、c反应蛋白和乳酸脱氢酶水平以及大环内酯类药物耐药性有关。在MP感染的进展过程中，小鼠NLRP3炎性小体逐渐被激活，并伴有肺损伤和炎症的增加。然而，mp感染的Nlrp3−/−小鼠显示肺损伤和炎症减轻。此外，MCC950可以减弱MPP小鼠的肺损伤和炎症，阿奇霉素与MCC950联合使用的效果强于阿奇霉素或MCC950单独使用。NLRP3炎性小体激活可促进MPP患者的肺损伤、炎症和大环内酯类药物耐药，这意味着干扰NLRP3炎性小体可能是MPP给药的一种策略。

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引用次数: 0

Aspergillus fumigatus and Mycobacterium tuberculosis synergistically induce TNF and IL-1β via different pathways in human peripheral blood mononuclear cells 烟曲霉和结核分枝杆菌通过不同途径协同诱导人外周血单核细胞TNF和IL-1β

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-23 DOI: 10.1016/j.cyto.2025.157018

Intan M.W. Dewi , Mariolina Bruno , Nico A.F. Janssen , Mark S. Gresnigt , Arjan van Laarhoven , Reinout van Crevel , Frank L. van de Veerdonk

Aspergillus fumigatus may cause infections in individuals with underlying lung damage, such as those with pulmonary tuberculosis (TB). Simultaneous exposure to A. fumigatus and Mycobacterium tuberculosis may worsen lung tissue damage, but the combined immune response to these pathogens has not yet been fully characterized.

Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with A. fumigatus conidia, M. tuberculosis H37Rv lysate, or both combined. TNF and IL-1β were measured from culture supernatants. The role of different pattern recognition receptors (PRRs) important for the recognition of both pathogens were explored by using PRR inhibitors and PBMCs from donors deficient in certain pathways.

A. fumigatus and M. tuberculosis synergistically induced TNF and IL-1β release by PBMCs, and this response was independent of TLR2 and dectin-1. We found that the synergy is regulated through distinct intracellular pathways. The activation of the intracellular receptor NOD2 by M. tuberculosis and NADPH oxidase complex-dependent ROS production triggered by A. fumigatus mediate TNF but not IL-1β synergy.

Together, these findings indicate that A. fumigatus and M. tuberculosis jointly exacerbate proinflammatory responses. This may help to explain the persistent inflammation and immunopathology observed in patients with concurrent TB and aspergillosis.

烟曲霉可引起潜在肺损伤的个体感染，如肺结核患者。同时暴露于烟曲霉和结核分枝杆菌可能会加重肺组织损伤，但对这些病原体的联合免疫反应尚未得到充分表征。用烟曲霉分生孢子菌、结核分枝杆菌H37Rv裂解液或两者联合刺激健康志愿者外周血单个核细胞。从培养上清液中检测TNF和IL-1β。通过使用PRR抑制剂和来自某些途径缺乏的供体的pbmc，研究了不同模式识别受体（PRRs）在识别两种病原体中的重要作用。烟曲霉和结核分枝杆菌协同诱导PBMCs释放TNF和IL-1β，且该反应不依赖于TLR2和dectin-1。我们发现协同作用是通过不同的细胞内途径调节的。结核分枝杆菌对细胞内受体NOD2的激活和烟曲霉引发的NADPH氧化酶复合物依赖性ROS的产生介导TNF，但不介导IL-1β协同作用。总之，这些发现表明烟曲霉和结核分枝杆菌共同加剧了促炎反应。这可能有助于解释结核和曲霉病并发患者的持续炎症和免疫病理。

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引用次数: 0

Blocking Fpr3 ameliorates osteoarthritis by inhibiting NLRP3-mediated chondrocyte pyroptosis 阻断Fpr3可通过抑制nlrp3介导的软骨细胞热凋亡改善骨关节炎

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine

Pub Date : 2025-08-22 DOI: 10.1016/j.cyto.2025.157020

Bin Zhou, Yaobin Huang

Objective

Osteoarthritis (OA) is a chronic joint disorder that frequently diagnosed in elderly individuals. While formyl peptide receptor 3 (Fpr3) is known to play a significant role in inflammation, its involvement in OA progression and chondrocyte pyroptosis remains unclear.

Methods

Anterior cruciate ligament transection (ACLT) was used to create OA mouse model. Lipopolysaccharide (LPS) was utilized to induce inflammation in chondrocytes. We assessed the expression of Fpr3, chondrogenic markers (Collagen-II, SOX9, and Aggrecan), catabolic factors (MMP3, MMP13, and ADAMTS5), inflammatory cytokines (IL-1β, IL-18, and COX-2), and NLRP3 inflammasome members (NLRP3, ASC, Cleaved caspase1, and GSDMD-N) in cartilage from ACLT-induced mouse models and LPS-treated chondrocytes.

Results

Fpr3 expression was significantly increased in both ACLT-induced OA mice and LPS-induced chondrocytes. Fpr3 knockdown reduced chondrocyte injury in OA mice. Fpr3 knockdown promoted the expression of collagen-II, SOX9, and aggrecan, while suppressing the expression of MMP3, MMP13, ADAMTS5, IL-1β, IL-18, COX-2, NLRP3, ASC, cleaved caspase1, and GSDMD-N in both experimental models.

Conclusions

Blocking Fpr3 ameliorated extracellular matrix degradation and pyroptosis during OA progress through the NLRP3 inflammasome. Modulating Fpr3 expression may be a therapeutic target for OA.

目的骨关节炎（OA）是一种常见于老年人的慢性关节疾病。虽然已知甲酰基肽受体3 （Fpr3）在炎症中发挥重要作用，但其在OA进展和软骨细胞焦亡中的作用尚不清楚。方法采用前交叉韧带横断术（ACLT）建立OA小鼠模型。利用脂多糖（LPS）诱导软骨细胞炎症。我们评估了aclt诱导的小鼠模型和lps处理的软骨细胞中Fpr3、软骨生成标志物（Collagen-II、SOX9和Aggrecan）、分解代谢因子（MMP3、MMP13和ADAMTS5）、炎症因子（IL-1β、IL-18和COX-2）和NLRP3炎性体成员（NLRP3、ASC、Cleaved caspase1和GSDMD-N）的表达。结果aclt诱导的OA小鼠和lps诱导的软骨细胞中fpr3的表达均显著升高。Fpr3敲低可减少OA小鼠软骨细胞损伤。Fpr3敲低可促进胶原- ii、SOX9和aggrecan的表达，抑制MMP3、MMP13、ADAMTS5、IL-1β、IL-18、COX-2、NLRP3、ASC、cleaved caspase1和GSDMD-N的表达。结论阻断Fpr3可通过NLRP3炎性体改善OA进展过程中的细胞外基质降解和焦亡。调节Fpr3的表达可能是OA的治疗靶点。

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引用次数: 0