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Over-activation of tlr5 signaling by high-dose flagellin induces liver injury in mice

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Cellular & Molecular Immunology 2015年第6期12卷 729-742页

作者： Yang Xiao Fang Liu Jingyi Yang Maohua Zhong Ejuan Zhang Yaoming Li Dihan Zhou Yuan Cao Wei Li Jie Yu Yi Yang Huimin Yan Mucosal immunity Research Group State Key Laboratory of Virology Wuhan institute of Virology Chinese Academy of Sciences Wuhan China

Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for vaccines, and it might function as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated flagellin in the occurrence of some inflammatory diseases, such as acute lung inflammation, cardiovascular collapse and inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-tlr5 signaling activation plays a role in the pathophysiology of liver or whether some other flagellin activity also contributes to liver injury either via bacterial infections or during clinical applications. Recombinant flagellin proteins with or without tlr5-stimulating activity were used to evaluate the role of flagellin-tlr5 signaling in liver injury in wild-type and tlr5 KO mice. Gross lesions and large areas of hepatocellular necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 pg flagellin （FliC） in a dose-and time-dependent manner in wild-type mice, but not in tlr5 KO mice. Deletion of the N-terminal or tlr5 binding domain of flagellin inhibited flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that flagellin is an essential determinant of liver injury and demonstrated that the over-activation of tlr5 signaling by high-dose flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of flagellin-induced liver injury.

关键词： flagellin liver injury pathological effect tlr5

Salmonella flagella confer anti-tumor immunological effect via activating Flagellin/tlr5 signalling within tumor microenvironment

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3165-3177页

作者： Jianxiang Chen Yiting Qiao Guo Chen Cunjie Chang Heng Dong Bo Tang Xiawei Cheng Xiufeng Liu Zichun Hua School of Life Sciences Nanjing UniversityNanjing 210023China Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc. Changzhou 213164China College of Pharmacy School of MedicineHangzhou Normal UniversityHangzhou 311100China Department of Hepatology the Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of Surgerythe First Affiliated HospitalSchool of MedicineZhejiang University School of Biopharmacy China Pharmaceutical UniversityNanjing 211198China

Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains *** this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma *** flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer *** results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion *** mainly activate immune cells via Flagellin/Toll-like receptor 5(tlr5)signalling ***,we showed that exogenous activation of tlr5 signalling by recombinant Flagellin and exogenous expression of tlr5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against *** study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/tlr5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of tlr5 agonists in the cancer immune therapy.

关键词： Bacteria-mediated cancer therapy Salmonella VNP20009 Flagellum Flagellin tlr5 NF-kB Cancer immune therapy

Activation of NLRC4 downregulates tlr5-mediated antibody immune responses against flagellin

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Cellular & Molecular Immunology 2016年第4期13卷 514-523页

作者： Wei Li Jingyi Yang Ejuan Zhang Maohua Zhong Yang Xiao Jie Yu Dihan Zhou Yuan Cao Yi Yang Yaoming Li Huimin Yan Mucosal Immunity Research Group State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences Wuhan 430071 People's Republic of China

Bacterial flagellin is a unique pathogen-associated molecular pattern （PAMP）, which can be recognized by surface localized Toll-like receptor 5 （tlr5） and the cytosolic NOD-like receptor （NLR） protein 4 （NLRC4） receptors. Activation of the tlr5 and/or NLRC4 signaling pathways by flagellin and the resulting immune responses play important roles in anti-bacterial immunity. However, it remains unclear how the dual activities of flagellin that activate the tlr5 and/or NLRC4 signaling pathways orchestrate the immune responses. In this study, we assessed the effects of flagellin and its mutants lacking the ability to activate tlr5 and NLRC4 alone or in combination on the adaptive immune responses against flagellin. Flagellin that was unable to activate NLRC4 induced a significantly higher antibody response than did wild-type flagellin. The increased antibody response could be eliminated when macrophages were depleted in vivo. The activation of NLRC4 by flagellin downregulated the flagellin-induced and tlr5-mediated immune responses against flagellin.

关键词： flagellin NLRC4 tlr5 macrophage adaptive immunity

rFliC prolongs allograft survival in association with the activation of recipient Tregs in a tlr5-dependent manner

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Cellular & Molecular Immunology 2014年第2期11卷 206-214页

作者： Jing Hao Chao Zhang Jing Song Guihua Hou Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine Shandong University MedicalSchool Jinan 250012 China

AIIorejection remains an obstacle for successful organ transplantation. Although different types of immunosuppressive agents are effective for controlling rejection and prolonging graft survival, drug treatment is limited because of side effects and toxicity. Therefore, it is necessary and urgent to identify new candidate drugs for inducing allotolerance. Recently, it has been reported that bacterial flagellin induces the immunosuppressive activity of regulatory T cells （Tregs） in humans in vitro. In the present study, we analyzed the effects of recombinant flagellin （rFliC） on allograft survival and explored the underlying mechanisms associated with the activation of recipient Tregs in a murine skin allotransplantation model. The results showed that rFliC administration （3 mg/kg, once per day for 3 days, i.p.） prolonged allograft survival （mean survival time： 18.4--.1.1 days） compared to the control group （10___0.7 days, P〈O.01）. Additionally, higher positive expression of Toll-like receptor 5 （tlr5） was detected within the allograft administered with rFliC. The frequency of CD4＋CD25＋Foxp3＋ Tregs; the expression of Treg-related factors tlr5, Foxp3, TGF-I^I and IL-IO; and the proliferation and suppression of Tregs were increased following rFliC administration compared to the control. Moreover, the increased expression of tolerance-related molecules and the proliferation of Tregs induced by rFliC were attenuated by an anti-tlr5 blocking antibody both in vivo and in vitro. In conclusion, rFliC administration prolongs the survival of allografts, which is associated with the activation of recipient Tregs in a tlr5-dependent manner, rFliC may be a new candidate for anti-allorejection therapy.

关键词： allotransplantation flagellin regulatory T cells tlr5

tlr5: beyond the recognition of flagellin

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Cellular & Molecular Immunology 2017年第12期14卷 1017-1019页

作者： Jingyi Yang Huimin Yan Mucosal Immunity Research Group State Key Laboratory of VirologyWuhan Institute of VirologyChinese Academy of SciencesWuhanHubei 430071China

The innate immune system plays an essential role in the host defense against infections by initially sensing and recognizing diverse microbial pathogens and directing adaptive immune responses to their *** does the innate immune system sense and recognize pathogens?The identification of pattern recognition receptors(PRRs)during the past decades has brought us into a new era to explore this fundamental *** are an array of germline-encoded multifunctional proteins that do not recognize specific pathogens but rather recognize conserved molecular patterns associated with various classes of pathogens,leading to pathogen-associated molecular patterns(PAMPs).

关键词： initially tlr5 pattern

双峰驼tlr5抗体制备及其在淋巴结中的表达

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西北农林科技大学学报（自然科学版） 2023年第12期51卷 1-8页

作者：王亭玮刘转霞陆佳李沛轩刘柯江曾巍巍索南吉谢东旭王雯慧甘肃农业大学动物医学院甘肃兰州730070

【目的】制备兔抗双峰驼Toll样受体5(tlr5)的多克隆抗体并鉴定其活性。【方法】选择双峰驼tlr5基因序列,经软件分析选择其编码区的膜外区1~499氨基酸位为主要抗原位,再选取对应的核苷酸序列进行基因合成,并与pET-28a(+)载体连接构建重... 详细信息

【目的】制备兔抗双峰驼Toll样受体5(tlr5)的多克隆抗体并鉴定其活性。【方法】选择双峰驼tlr5基因序列,经软件分析选择其编码区的膜外区1~499氨基酸位为主要抗原位,再选取对应的核苷酸序列进行基因合成,并与pET-28a(+)载体连接构建重组质粒pET28a-tlr5,对其进行BamHⅠ和XhoⅠ双酶切鉴定。将pET28a-tlr5转染大肠杆菌原核表达系统,用IPTG进行诱导表达,对IPTG浓度(0.1,0.2,0.4,0.6,0.8,1.0 mol/L)和诱导时间(2,3,4,5,6,7,8,9 h)进行优化。将表达的蛋白经亲和层析法纯化后免疫新西兰白兔以制备多克隆抗体,采用ELISA法检测多抗效价,用Western blot检测和免疫组化验证评价多克隆抗体的特异性。【结果】成功构建了重组质粒pET28a-tlr5,经IPTG诱导后获得了重组蛋白(大小约为57 ku),且以包涵体的形式表达。IPTG最佳诱导表达条件为:IPTG浓度为1 mol/L,诱导时间为6 h。tlr5多抗血清效价为1∶128000。Western blot鉴定表明,tlr5多抗血清能特异性识别目的蛋白;免疫组化结果表明,tlr5多抗能很好地识别成年双峰驼十二指肠肠系膜淋巴中的tlr5阳性细胞。【结论】成功制备出特异性良好的兔抗双峰驼tlr5多克隆抗体,能够用于tlr5的检测。

关键词：双峰驼 tlr5 原核表达抗体制备表达定位

Amino acids 89–96 of Salmonella flagellin: a key site for its adjuvant effect independent of the tlr5 signaling pathway

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Cellular & Molecular Immunology 2017年第12期14卷 1023-1025页

作者： Xilong Kang Zhiming Pan Xinan Jiao Jiangsu Key Laboratory of Zoonosis YangzhouUniversityYangzhouJiangsu 225009China Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses Yangzhou UniversityYangzhouJiangsu 225009China Key Laboratory of Prevention and Control of Biological Hazard Factors(Animal Origin)for Agrifood Safety and Quality MOAYangzhou UniversityYangzhouJiangsu 225009China Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education YangzhouJiangsu 225009China

Flagellin,the main component of bacterial flagella,is a well-known pathogen-associated molecular pattern(PAMP)that can be recognized by the cell surface-localized Toll-like receptor 5(tlr5)and the cytosolic NOD-like receptor protein 4(NLRC4)inflammasome receptor NAIP5/6.1 Hosts can detect flagellated bacteria using the dual sensors,tlr5 and NAIP5/6,to recognize flagellin,and these sensors then initiate innate immune responses to protect the host from bacterial *** by extracellular tlr5 can trigger the MyD88-dependent signaling pathway and activate nuclear factorκB,leading to the upregulation of several proinflammatory cytokines.

关键词： effect tlr5 initiate

鱼类tlr5与病原配体的识别和信号传导机制研究

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鱼类TLR5与病原配体的识别和信号传导机制研究

作者：孙晴宇河南师范大学

学位级别：硕士

Toll样受体是一类非常重要的模式识别受体,能够识别病原相关分子模式,引发免疫反应。泥鳅是我国以及亚洲沿岸各国重要的养殖鱼类,受高密度养殖和水质恶化影响,由细菌、病毒和寄生虫感染引起的病害给鱼类养殖业造成了巨大损失。嗜水气单... 详细信息

Toll样受体是一类非常重要的模式识别受体,能够识别病原相关分子模式,引发免疫反应。泥鳅是我国以及亚洲沿岸各国重要的养殖鱼类,受高密度养殖和水质恶化影响,由细菌、病毒和寄生虫感染引起的病害给鱼类养殖业造成了巨大损失。嗜水气单胞菌作为淡水鱼类传染病诱因之一,会引发泥鳅的败血症甚至死亡。目前泥鳅被嗜水气单胞菌感染后的研究主要集中于生化指标和免疫指标的检测,对致病菌影响鱼类生殖发育缺少系统研究。本实验以泥鳅为研究对象,利用三代测序技术构建了泥鳅不同发育时期性腺(原始生殖腺、已分化尚未成熟的雌雄性腺、成熟非繁殖期雌雄性腺和成熟繁殖期性腺)的转录组文库,通过分析筛选出了与泥鳅性腺发育相关的tlr基因。利用PCR技术扩增了泥鳅tlr5基因和MyD88基因,展开对其序列结构特征、在正常组织中表达以及免疫应答规律的研究。主要获得以下成果:1、tlr5和MyD88的cDNA全长分别是1785 bp和855 bp,推定编码594个、284个氨基酸。蛋白结构分析显示,tlr5具有一个信号肽、九个富含亮氨酸的重复结构域(LRR)、一个富含亮氨酸的重复C末端结构域(LRR-CT),三个富含亮氨酸的重复典型的亚家族结构域(LRR-TYP),跨膜结构域和细胞内Toll/白细胞介素-1受体结构域(TIR);MyD88具有一个死亡结构域和一个TIR结构域。序列分析和进化分析证实,泥鳅tlr5和MyD88序列具有保守性,且均与鲤形目鱼类聚为一大支。2、qPCR检测健康泥鳅tlr5基因的表达分布。结果表明,tlr5在所检组织(脑、鳃、皮肤、肠道、心脏、肾脏、肝脏和性腺)中呈组成型分布且具有性别二态性,在肠道表达量最高,鳃、肾脏和卵巢次之,在心脏中表达最低,这表明tlr5参与了机体各种生命活动。同时我们检测在不同发育时期的泥鳅性腺中不同tlr基因的表达,结果表明在卵巢中tlr5呈现高表达,在精巢中tlr5的表达要低于tlr9和tlr21。在不同发育时期的卵巢中tlr5的表达显著高于精巢。3、嗜水气单胞菌刺激后,在成熟性腺和二期性腺中tlr5以及tlr通路相关基因MyD88、TRAF6、TAK1、AP1、P50均发生了显著性的上调,而上调的tlr信号通路关键基因又可通过NF-κB信号通路和MAPK途径来促进细胞因子(IL-1β,IL-12,TNF-α)的分泌,导致泥鳅性腺中的炎症反应增加。以上结果提示tlr5在性腺组织的抗细菌感染过程中发挥着重要的免疫作用。4、为进一步了解tlr5识别病原体的分子机制,并鉴定不同的LRR结构域的功能,使用p ET30a原核表达系统,构建tlr5胞外结构域(p ET30a-tlr5-1和p ET30atlr5-2)重组蛋白。通过细菌结合实验和糖结合实验,发现p ET30a-tlr5-1和p ET30a-tlr5-2蛋白能够识别并结合多种细菌,并高饱和的识别脂多糖(LPS)和肽聚糖(PGN)。5、为了鉴定tlr5激活tlr信号通路的机制,构建p ET30a-MyD88和p GExtlr5-TIR原核重组质粒,利用Pull-down技术,探究Matlr5与MaMyD88蛋白互作关系。结果显示,Matlr5能与MaMyD88相互作用,表明tlr5可以通过识别MyD88激活tlr通路引发免疫反应。

关键词：泥鳅 tlr5 细菌结合糖结合 Pull-down

鱼类tlr5比较基因组及鲫鱼tlr5克隆表达与SNP分析

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鱼类TLR5比较基因组及鲫鱼TLR5克隆表达与SNP分析

作者：陈铭仲恺农业工程学院

学位级别：硕士

Toll样受体5(Toll-like receptor 5,tlr5)是toll样受体(Toll-like receptor,tlrs)家族的一员,是一种识别病原体相关分子模式的模式识别受体,能响应脊椎动物对细菌鞭毛蛋白的识别,激活机体的先天免疫反应。本研究以tlr5基因为研究对象,... 详细信息

Toll样受体5(Toll-like receptor 5,tlr5)是toll样受体(Toll-like receptor,tlrs)家族的一员,是一种识别病原体相关分子模式的模式识别受体,能响应脊椎动物对细菌鞭毛蛋白的识别,激活机体的先天免疫反应。本研究以tlr5基因为研究对象,通过比较基因组学的方法,首次对大范围鱼类物种的tlr5基因进行比较分析,探讨不同鱼类tlr5拷贝数与形成模式以及系统进化地位;针对主要经济养殖鱼类鲫鱼tlr5基因两个亚型tlr5Ma和tlr5Mb进行真核表达与抗体制备;同时基于两个亚型基因序列开展抗病相关联的SNP位点筛选。结果可为进一步研究鱼类tlr5基因适应性进化及鲫鱼tlr5基因的功能分析提供理论参考,具体结果如下:1、基于鱼类全基因组数据,对30种鱼类tlr5基因进行比较基因组学研究,比较不同鱼类tlr5基因类型、拷贝数变化与共线性分析,揭示不同进化地位的鱼类其tlr5基因亚型种类及拷贝数存在差异。首次发现鱼类的tlr5Mb具有两个亚型(tlr5Mb1和tlr5Mb2),认为硬骨鱼类中最多可能含有4个tlr5亚型(tlr5S、tlr5Ma、tlr5Mb1和tlr5Mb2),推测是全基因组复制事件和基因丢失导致不同鱼类tlr5基因拷贝数发生变化。分子系统进化树分析揭示不同进化地位的鱼类,其不同tlr5基因亚型能形成特异性的谱系分支。此外,tlr5亚型在鞭毛蛋白相互作用位点,在不同进化地位鱼类中具有特异性,表明tlr5可能产生功能化或亚功能化。嗜水气单胞菌感染实验也验证草鱼tlr5Ma和tlr5Mb两个亚型存在亚功能化可以感知细菌鞭毛蛋白。2、通过比较基因组分析首次发现鲫鱼tlr5基因存在tlr5Ma和tlr5Mb两种亚型,tlr5Ma蛋白编码序列为2649 bp,tlr5Mb蛋白编码序列为2637 bp,两个亚型序列共有458个碱基差异、221个氨基酸存在变异。分别制备鲫鱼tlr5Ma与tlr5Mb的兔源性多克隆抗体,分析了鲫鱼感染嗜水气单胞菌后tlr5Ma与tlr5Mb在转录水平和蛋白水平上表达模式的差异,结果显示两个亚型在三种免疫组织的表达模式较为相似,均在头肾的表达水平最高,其次是脾脏,最后是肝脏。且两个亚型在三种免疫组织中均感染嗜水气单胞菌6至12小时之间的表达量达到峰值,而后逐渐降低,揭示两个亚型存在功能同源。3、针对鲫鱼两个亚型tlr5Ma与tlr5Mb序列进行抗病性状相关联的SNP位点筛选及群体分型分析,在鲫鱼tlr5Ma上筛选出1个较为显著的与抗病性状相关联的SNP位点(A2271G)。基于这个SNP位点对6个不同地理分布及6个不同品种的鲫鱼群体进行检测及多样性分析揭示,不同地理群体中,广东、贵州、浙江、重庆群体相对于安徽、江苏群体拥有更多抗病关联的优势基因型。在不同品种鲫鱼群体中,“中科五号”、“中科三号”、工程鲫、白鲫等品种存在更多的抗病关联的优势基因型,但也有一定比例易染优势基因型,推测可能相关品种由于长期的人工繁育,种质可能存在退化,导致抗病能力下降。

关键词： tlr5 比较基因组学抗体制备 SNP位点抗病性状群体多样性