Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting t...Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.展开更多
BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characte...BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characterize the microbiome in patients with IL10 RA mutations and to explore the association between gut dysbiosis and disease severity.METHODS Fecal samples were collected from patients who were diagnosed with loss-offunction mutations in the IL10 RA gene between January 2017 and July 2018 at the Children’s Hospital of Fudan University.Age-matched volunteer children were recruited as healthy controls.Patients with Crohn’s disease(CD) were used as disease controls to standardize the antibiotic exposure.Microbial DNA was extracted from the fecal samples.All analyses were based on the 16 S rRNA gene sequencing data.RESULTS Seventeen patients with IL10 RA mutations(IL10 RA group),17 patients with pediatric CD, and 26 healthy children were included.Both patients with IL10 RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability.The relative abundance of Firmicutes was substantially increased in the IL10 RA group(P=0.02).On further comparison of the relative abundance of taxa between patients with IL10 RA mutations and healthy children,13 taxa showed significant differences.The IL10 RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD.CONCLUSION In patients with IL10 RA mutations and early onset inflammatory bowel disease,gut dysbiosis shows a moderate association with disease severity.展开更多
This work aimed to find quantitative phenotypic traits that can be used to discriminate the levels of resistance/susceptibility to B. bovis and B. bigemina in two groups of cattle presenting the highest (H) or lowest ...This work aimed to find quantitative phenotypic traits that can be used to discriminate the levels of resistance/susceptibility to B. bovis and B. bigemina in two groups of cattle presenting the highest (H) or lowest (L) infection levels and Rhipicephalus microplus ticks count. The animals were selected from a previous study of 50 Canchim (5/8 Charolais/zebu) heifers raised in an endemic area for these parasites. These animals were evaluated regarding their TNFα, IL10, IFN-γ, IL12 and iNOS mRNA levels. No differences were found between these groups regarding TNFα, IFN-γ, IL12β or iNOS transcripts. However, the IL10 transcripts were significantly higher in the H group compared to the L group. Moreover, significant correlation coefficients were observed between B. bovis loads and both IL10 and IFN-γ transcripts, while no correlations were found for B. bigemina loads and all tested immune-related transcripts, suggesting that differential IL10 mRNA profiles were closely associated to B. bovis loads. Our results have contributed to a better understanding of the immune responses against Babesia infection, as we demonstrated that the IL10 cytokine levels might also influence or be influenced by parasitemia levels in persistently infected animals.展开更多
Background:Dengue fever is a major public health problem in Burkina Faso.Some people infected by dengue virus develop a severe dengue(SD)and po-tentially fatal form of the disease which are dengue hemorrhagic syndrome...Background:Dengue fever is a major public health problem in Burkina Faso.Some people infected by dengue virus develop a severe dengue(SD)and po-tentially fatal form of the disease which are dengue hemorrhagic syndrome or dengue shock syndrome.Host genetic factors may be relevant,predisposing some individuals to severe disease.Polymorphisms of pro-inflammatory cy-tokines have been associated with the pathogenesis of dengue fever(DF).The aim of this study was to assess the involvement of IL10 cytokine gene poly-morphisms to restriction sequence(rs),rs1800872 and rs1800896 in the path-ogenesis of dengue fever and even in its progression to severe forms of the disease in Burkina Faso.We conducted a descriptive and analytical case-con-trol study.A total of 246 subjects were recruited including,with 117 people who had never been in contact with the dengue virus considered as controls and 129 dengue disease patients.Polymorphisms in the IL10-592 and IL10-1082 genes were obtained by restriction fragment length polymorphism(PCR-RFLP).We found that the AA genotype(46.81%/DF,53.57%/DS and 23.08%/control)of the IL10-592 polymorphism was a risk factor associated with the DS form and the CA heterozygote(21.31%)tended not to favor DF infection.The GG genotype of IL10-1082 was associated with dengue fever and possible progression from DF to DS,while the AG genotype was associ-ated with a higher risk of DF infection.The A allele of IL10-1082(OR=1.521 CI[1.046-2.215],p-value=0.027)was associated with the development of dengue and would not be indifferent in the progression to the DS form.Poly-morphisms in the IL10-1082 and IL10-592 genes seems to be associated with the pathogenesis of dengue disease and also with progression to the severe form of the disease.展开更多
Background Bronchiolitis is the most common infection leading to hospitalization in infancy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and in our previous study, IL10 gene rs1800896 (-1082A/G) polymorph...Background Bronchiolitis is the most common infection leading to hospitalization in infancy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and in our previous study, IL10 gene rs1800896 (-1082A/G) polymorphism was associated with viral etiology of infant bronchiolitis. The objective of this study was to evaluate the associations between IL10 single nucleotide polymorphisms (SNPs) at rs1800890 (-3575A/T), rs1800871 (-819C/T) or rs1800872 (-592C/A) either alone or combined with the SNP at rs1800896 (-1082G/A), and the etiology and severity of infant bronchiolitis. Methods Data on four IL10 SNPs were available from 135 full-term infants, hospitalized for bronchiolitis at age less than 6 months, and from 378 to 400 controls. Viral etiology was studied, and oxygen support, feeding support and the length of stay in hospital were recorded during bronchiolitis hospitalization. Results Infants with rhinovirus bronchiolitis had the IL10 rs1800890 variant AT or TT genotype less often (18.2%) than controls (63.3%, P=0.03), and likewise, had the IL10 rs1800896 variant AG or GG genotype less often (27.3%) than con-trols (65.5%, P=0.009). Twenty-eight infants with bronchiolitis had the variant–variant Grs1800896Trs1800890 haplotype, and none of them had rhinovirus infection. The IL10 rs1800871 or rs1800872 genotypes showed no associations with viruses. No association was found between any genotypes and bronchiolitis severity measures. Conclusion IL10 rs1800890 and rs1800896 polymorphisms differed between infants with rhinovirus bronchiolitis and con-trols, but not between infants with respiratory syncytial virus bronchiolitis and controls.展开更多
烧伤疼痛是影响烧伤患者康复及生活质量的关键因素,其机制复杂,涉及多种炎症与免疫信号通路。本研究整合生物信息学和实验验证,旨在筛选鉴定与烧伤疼痛密切相关的关键基因,探索其作为潜在治疗靶点的临床价值。通过GEO数据库获取烧伤患...烧伤疼痛是影响烧伤患者康复及生活质量的关键因素,其机制复杂,涉及多种炎症与免疫信号通路。本研究整合生物信息学和实验验证,旨在筛选鉴定与烧伤疼痛密切相关的关键基因,探索其作为潜在治疗靶点的临床价值。通过GEO数据库获取烧伤患者与健康对照的表达谱数据(GSE19743作训练集,GSE37069作验证集),结合GeneCaRNA数据库筛选疼痛相关基因。运用差异分析、GO与KEGG富集分析、构建可视化PPI网络,以及LASSO回归、SVM和RF三种机器学习方法识别关键基因,构建诊断模型,利用ROC曲线与DCA评估诊断效能。最终经RT-qPCR对外周血样本中候选基因表达水平进行实验验证。本研究筛选出117个烧伤疼痛相关差异表达基因,富集于PI3K-Akt、MAPK等炎症信号通路,IFNG、IL10和TLR4被三种机器学习方法共同识别为关键特征基因。基于此三基因构建的诊断模型在GSE37069验证集中表现优异,AUC达0.959。RT-qPCR验证表明,烧伤患者中IL10显著上调,IFNG表达下降,TLR4表达无显著差异,部分结果与生物信息学分析一致。IFNG、IL10和TLR4或通过调控免疫与炎症反应参与烧伤疼痛的发生维持,有望成为诊断生物标志物及治疗靶点,未来研究需进一步探讨其信号通路机制及临床干预价值。Burn pain is a critical factor affecting the recovery and quality of life of burn patients. Its underlying mechanisms are complex, involving multiple inflammatory and immune signaling pathways. This study integrates bioinformatics and experimental validation to identify key genes closely associated with burn pain and to explore their potential clinical value as therapeutic targets. Gene expression profiles (GSE19743 as the training set and GSE37069 as the validation set) were retrieved from the GEO database, and pain-related genes were screened via the GeneCaRNA database. Subsequent analyses included differential analysis, GO and KEGG enrichment analyses, and PPI network construction and visualization. Three machine learning algorithms—LASSO regression, SVM, and RF—were employed to identify key genes, following which a diagnostic model was established and evaluated using ROC curves and DCA. RT-qPCR validated candidate gene expression in peripheral blood samples. A total of 117 differentially expressed burn pain-related genes were identified, primarily enriched in inflammatory signaling pathways such as PI3K-Akt and MAPK. IFNG, IL10, and TLR4 were consistently identified as key feature genes across all three machine-learning methods. The diagnostic model based on these genes demonstrated excellent performance in the GSE37069 validation set, achieving an AUC of 0.959. RT-qPCR validation indicated that IL10 was significantly upregulated in burn patients, IFNG expression was decreased, while TLR4 expression showed no significant difference, partially in line with bioinformatics predictions. These findings suggest that IFNG, IL10, and TLR4 may be involved in burn pain occurrence and maintenance by modulating immune and inflammatory responses, thus showing promise as diagnostic biomarkers and therapeutic targets. Further research into their signaling pathway mechanisms and clinical intervention value is warranted.展开更多
文摘Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
基金Supported by the Jiujiu Charitable Trust-PIBD China.
文摘BACKGROUND Several studies have employed animal models to explore the association between microbiota and interleukin(IL) 10 signaling;however,limited information is available about the human microbiome.AIM To characterize the microbiome in patients with IL10 RA mutations and to explore the association between gut dysbiosis and disease severity.METHODS Fecal samples were collected from patients who were diagnosed with loss-offunction mutations in the IL10 RA gene between January 2017 and July 2018 at the Children’s Hospital of Fudan University.Age-matched volunteer children were recruited as healthy controls.Patients with Crohn’s disease(CD) were used as disease controls to standardize the antibiotic exposure.Microbial DNA was extracted from the fecal samples.All analyses were based on the 16 S rRNA gene sequencing data.RESULTS Seventeen patients with IL10 RA mutations(IL10 RA group),17 patients with pediatric CD, and 26 healthy children were included.Both patients with IL10 RA mutations and those with CD exhibited a reduced diversity of gut microbiome with increased variability.The relative abundance of Firmicutes was substantially increased in the IL10 RA group(P=0.02).On further comparison of the relative abundance of taxa between patients with IL10 RA mutations and healthy children,13 taxa showed significant differences.The IL10 RA-specific dysbiosis indices exhibited a significant positive correlation with weighted pediatric CD activity index and simple endoscopic score for CD.CONCLUSION In patients with IL10 RA mutations and early onset inflammatory bowel disease,gut dysbiosis shows a moderate association with disease severity.
文摘This work aimed to find quantitative phenotypic traits that can be used to discriminate the levels of resistance/susceptibility to B. bovis and B. bigemina in two groups of cattle presenting the highest (H) or lowest (L) infection levels and Rhipicephalus microplus ticks count. The animals were selected from a previous study of 50 Canchim (5/8 Charolais/zebu) heifers raised in an endemic area for these parasites. These animals were evaluated regarding their TNFα, IL10, IFN-γ, IL12 and iNOS mRNA levels. No differences were found between these groups regarding TNFα, IFN-γ, IL12β or iNOS transcripts. However, the IL10 transcripts were significantly higher in the H group compared to the L group. Moreover, significant correlation coefficients were observed between B. bovis loads and both IL10 and IFN-γ transcripts, while no correlations were found for B. bigemina loads and all tested immune-related transcripts, suggesting that differential IL10 mRNA profiles were closely associated to B. bovis loads. Our results have contributed to a better understanding of the immune responses against Babesia infection, as we demonstrated that the IL10 cytokine levels might also influence or be influenced by parasitemia levels in persistently infected animals.
基金The World Academy of Sciences and the Swedish Inter-national Development Cooperation Agency(Sida)for funding this research through the grant No.17-403 RG/BIO/AF/AC_I-FR3240297757.
文摘Background:Dengue fever is a major public health problem in Burkina Faso.Some people infected by dengue virus develop a severe dengue(SD)and po-tentially fatal form of the disease which are dengue hemorrhagic syndrome or dengue shock syndrome.Host genetic factors may be relevant,predisposing some individuals to severe disease.Polymorphisms of pro-inflammatory cy-tokines have been associated with the pathogenesis of dengue fever(DF).The aim of this study was to assess the involvement of IL10 cytokine gene poly-morphisms to restriction sequence(rs),rs1800872 and rs1800896 in the path-ogenesis of dengue fever and even in its progression to severe forms of the disease in Burkina Faso.We conducted a descriptive and analytical case-con-trol study.A total of 246 subjects were recruited including,with 117 people who had never been in contact with the dengue virus considered as controls and 129 dengue disease patients.Polymorphisms in the IL10-592 and IL10-1082 genes were obtained by restriction fragment length polymorphism(PCR-RFLP).We found that the AA genotype(46.81%/DF,53.57%/DS and 23.08%/control)of the IL10-592 polymorphism was a risk factor associated with the DS form and the CA heterozygote(21.31%)tended not to favor DF infection.The GG genotype of IL10-1082 was associated with dengue fever and possible progression from DF to DS,while the AG genotype was associ-ated with a higher risk of DF infection.The A allele of IL10-1082(OR=1.521 CI[1.046-2.215],p-value=0.027)was associated with the development of dengue and would not be indifferent in the progression to the DS form.Poly-morphisms in the IL10-1082 and IL10-592 genes seems to be associated with the pathogenesis of dengue disease and also with progression to the severe form of the disease.
文摘Background Bronchiolitis is the most common infection leading to hospitalization in infancy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and in our previous study, IL10 gene rs1800896 (-1082A/G) polymorphism was associated with viral etiology of infant bronchiolitis. The objective of this study was to evaluate the associations between IL10 single nucleotide polymorphisms (SNPs) at rs1800890 (-3575A/T), rs1800871 (-819C/T) or rs1800872 (-592C/A) either alone or combined with the SNP at rs1800896 (-1082G/A), and the etiology and severity of infant bronchiolitis. Methods Data on four IL10 SNPs were available from 135 full-term infants, hospitalized for bronchiolitis at age less than 6 months, and from 378 to 400 controls. Viral etiology was studied, and oxygen support, feeding support and the length of stay in hospital were recorded during bronchiolitis hospitalization. Results Infants with rhinovirus bronchiolitis had the IL10 rs1800890 variant AT or TT genotype less often (18.2%) than controls (63.3%, P=0.03), and likewise, had the IL10 rs1800896 variant AG or GG genotype less often (27.3%) than con-trols (65.5%, P=0.009). Twenty-eight infants with bronchiolitis had the variant–variant Grs1800896Trs1800890 haplotype, and none of them had rhinovirus infection. The IL10 rs1800871 or rs1800872 genotypes showed no associations with viruses. No association was found between any genotypes and bronchiolitis severity measures. Conclusion IL10 rs1800890 and rs1800896 polymorphisms differed between infants with rhinovirus bronchiolitis and con-trols, but not between infants with respiratory syncytial virus bronchiolitis and controls.
文摘烧伤疼痛是影响烧伤患者康复及生活质量的关键因素,其机制复杂,涉及多种炎症与免疫信号通路。本研究整合生物信息学和实验验证,旨在筛选鉴定与烧伤疼痛密切相关的关键基因,探索其作为潜在治疗靶点的临床价值。通过GEO数据库获取烧伤患者与健康对照的表达谱数据(GSE19743作训练集,GSE37069作验证集),结合GeneCaRNA数据库筛选疼痛相关基因。运用差异分析、GO与KEGG富集分析、构建可视化PPI网络,以及LASSO回归、SVM和RF三种机器学习方法识别关键基因,构建诊断模型,利用ROC曲线与DCA评估诊断效能。最终经RT-qPCR对外周血样本中候选基因表达水平进行实验验证。本研究筛选出117个烧伤疼痛相关差异表达基因,富集于PI3K-Akt、MAPK等炎症信号通路,IFNG、IL10和TLR4被三种机器学习方法共同识别为关键特征基因。基于此三基因构建的诊断模型在GSE37069验证集中表现优异,AUC达0.959。RT-qPCR验证表明,烧伤患者中IL10显著上调,IFNG表达下降,TLR4表达无显著差异,部分结果与生物信息学分析一致。IFNG、IL10和TLR4或通过调控免疫与炎症反应参与烧伤疼痛的发生维持,有望成为诊断生物标志物及治疗靶点,未来研究需进一步探讨其信号通路机制及临床干预价值。Burn pain is a critical factor affecting the recovery and quality of life of burn patients. Its underlying mechanisms are complex, involving multiple inflammatory and immune signaling pathways. This study integrates bioinformatics and experimental validation to identify key genes closely associated with burn pain and to explore their potential clinical value as therapeutic targets. Gene expression profiles (GSE19743 as the training set and GSE37069 as the validation set) were retrieved from the GEO database, and pain-related genes were screened via the GeneCaRNA database. Subsequent analyses included differential analysis, GO and KEGG enrichment analyses, and PPI network construction and visualization. Three machine learning algorithms—LASSO regression, SVM, and RF—were employed to identify key genes, following which a diagnostic model was established and evaluated using ROC curves and DCA. RT-qPCR validated candidate gene expression in peripheral blood samples. A total of 117 differentially expressed burn pain-related genes were identified, primarily enriched in inflammatory signaling pathways such as PI3K-Akt and MAPK. IFNG, IL10, and TLR4 were consistently identified as key feature genes across all three machine-learning methods. The diagnostic model based on these genes demonstrated excellent performance in the GSE37069 validation set, achieving an AUC of 0.959. RT-qPCR validation indicated that IL10 was significantly upregulated in burn patients, IFNG expression was decreased, while TLR4 expression showed no significant difference, partially in line with bioinformatics predictions. These findings suggest that IFNG, IL10, and TLR4 may be involved in burn pain occurrence and maintenance by modulating immune and inflammatory responses, thus showing promise as diagnostic biomarkers and therapeutic targets. Further research into their signaling pathway mechanisms and clinical intervention value is warranted.
