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Glioma-derived ANXA1 suppresses the immune response to tlr3 ligands by promoting an anti-inflammatory tumor microenvironment

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Cellular & Molecular Immunology 2024年第1期21卷 47-59页

作者： Yu Zheng Haihui Jiang Naixue Yang Shaoping Shen Daosheng Huang Lemei Jia Jing Ling Longchen Xu Mingxiao Li Kefu Yu Xiaohui Ren Yong Cui Xun Lan Song Lin Xin Lin Institute for Immunology and School of Medicine Tsinghua UniversityBeijing100084China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityChina.National Clinical Research Center for Neurological DiseasesCenter of Brain TumorBeijing Institute for Brain Disorders and Beijing Key Laboratory of Brain TumorBeijing100070China Department of Neurosurgery Peking University Third HospitalPeking UniversityBeijing100191China Tsinghua-Peking Center for Life Sciences Beijing100084China

A highly immunosuppressive tumor microenvironment(TME)and the presence of the blood‒brain barrier are the two major obstacles to eliciting an effective immune response in patients with high-grade glioma(HGG).Here,we tried to enhance the local innate immune response in relapsed HGG by intracranially injecting poly(I:C)to establish a robust antitumor immune response in this registered clinical trial(NCT03392545).During the follow-up,12/27(44.4%)patients who achieved tumor control concomitant with survival benefit were regarded as responders in our *** found that the T-cell receptor(TCR)repertoire in the TME was reshaped after poly(I:C)*** on the RNA-seq analysis of tumor samples,the expression of annexin A1(ANXA1)was significantly upregulated in the tumor cells of nonresponders,which was further validated at the protein *** vitro and in vivo experiments showed that ANXA1 could induce the production of M2-like macrophages and microglia via its surface receptor formyl peptide receptor 1(FPR1)to establish a Treg cell-driven immunosuppressive TME and suppress the antitumor immune response facilitated by poly(I:C).The ANXA1/FPR1 signaling axis can inhibit the innate immune response of glioma patients by promoting an anti-inflammatory and Treg-driven ***,ANXA1 could serve as a reliable predictor of response to poly(I:C),with a notable predictive accuracy rate of 92.3%.In light of these notable findings,this study unveils a new perspective of immunotherapy for gliomas.

关键词： glioma ANXA1 tlr3 poly(I:C) immunotherapy

The zinc-finger protein ZFYVE1 modulates tlr3-mediated signaling by facilitating tlr3 ligand binding

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Cellular & Molecular Immunology 2020年第7期17卷 741-752页

作者： Xuan Zhong Lu Feng Wen-Hua Xu Xin Wu Yi-Di Ding Yan Zhou Cao-Qi Lei Hong-Bing Shu College of Life Sciences Wuhan UniversityWuhan 430072China Department of Infectious Diseases Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430072China Medical Research Institute Wuhan UniversityWuhan 430072China

Recognition of viral dsRNA by Toll-like receptor 3(tlr3)leads to the induction of downstream antiviral effectors and the innate antiviral immune ***,we identified the zinc-finger FYVE domain-containing protein ZFYVE1,a guanylate-binding protein(GBP),as a positive regulator of tlr3-mediated *** of ZFYVE1 promoted the transcription of downstream antiviral genes upon stimulation with the synthetic tlr3 ligand poly(I:C).Conversely,ZFYVE1 deficiency had the opposite ***1^(−/−) mice were less susceptible than wild-type mice to inflammatory death induced by poly(I:C)but not ***1 was associated with tlr3,and the FYVE domain of ZFYVE1 and the ectodomain of tlr3 were shown to be responsible for their ***1 was bound to poly(I:C)and increased the binding affinity of tlr3 to poly(I:C).These findings suggest that ZFYVE1 plays an important role in the tlr3-mediated innate immune and inflammatory responses by promoting the ligand binding of tlr3.

关键词： tlr3 ZFYVE1 ligand binding immune response

ZCCHC3 modulates tlr3-mediated signaling by promoting recruitment of TRIF to tlr3

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Journal of Molecular Cell Biology 2020年第4期12卷 251-262页

作者： Ru Zang Huan Lian Xuan Zhong Qing Yang Hong-Bing Shu Department of Infectious Diseases Frontier Science Center for Immunology and MetabolismMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430071China

Toll-like receptor 3(tlr3)-mediated signaling is important for host defense against RNA *** viral RNA stimulation,toll and interleukin-1 receptor domain-containing adaptor inducing IFN-p(TRIF)is recruited to tlr3 and then undergoes oligomerization,which is required for the recruitment of downstream molecules to transmit ***,we identified zinc finger CCHC-type containing 3(ZCCHC3)as a positive regulator of tlr3-mediated *** of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic tlr3 ligand poly(I:C).ZCCHC3-deficiency markedly inhibited tlr3-but not tlr4-mediated induction of type I interferons(IFNs)and proinflammatory ***/7c3-/-mice were more resistant to poly(l:C)-but not lipopolysaccharide-induced inflammatory ***,ZCCHC3 promoted recruitment of TRIF to tlr3 after poly(l:C)*** findings reveal that ZCCHC3 plays an important role in tlr3-mediated innate immune response by promoting the recruitment of TRIF to tlr3 after ligand stimulation.

关键词： tlr3 TRIF ZCCHC3 innate immune response signaling

E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting and degrading tlr3 in murine cells

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Cellular & Molecular Immunology 2020年第8期17卷 865-874页

作者： Xiaoqi Song Shuo Liu Wendie Wang Zhongfei Ma Xuetao Cao Minghong Jiang National Key Laboratory of Medical Molecular Biology Department of Immunology&Center for ImmunotherapyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical College100005BeijingChina National Key Laboratory of Medical Immunology&Institute of Immunology Second Military Medical University200433ShanghaiChina School of Medicine Nankai University300071TianjinChina

Upon recognition of dsRNA,toll-like receptor 3(tlr3)recruits the adaptor protein TRIF to activate IRF3 and NF-κB signaling,initiating innate immune *** ubiquitination of tlr3 downstream signaling molecules and their roles in the innate response have been discovered;however,whether tlr3 itself is ubiquitinated and then functionally involved remains to be *** immunoprecipitating tlr3-binding proteins in macrophages,we identified ring finger protein 170(RNF170)as a tlr3-binding E3 ***170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of tlr3 and promoted the degradation of tlr3 through the proteasome *** genetic ablation of RNF170 selectively augmented tlr3-triggered innate immune responses both in vitro and in *** results reveal a novel role for RNF170 in selectively inhibiting tlr3-triggered innate immune responses by promoting tlr3 degradation.

关键词： tlr3 RNF170 Ubiquitination Degradation Innate immunity

Acute exacerbation of chronic obstructive pulmonary disease was associated with respiratory syncytial virus infection and the upregulation of tlr3

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BIOCELL 2022年第4期46卷 1025-1032页

作者： LING GONG HUAJUN YANG YING HUANG ZHU LI JIN NIE MENG YE PENG XIE DAISHUN LIU Department of Respiratory Medicine The First People’s Hospital of Zunyi(The Third Affiliated Hospital of Zunyi Medical University)Zunyi563000China Zunyi Medical University Zunyi563000China Department of Respiratory Medicine The Affiliated Hospital of Zunyi Medical UniversityZunyi563000China Scientific Research Center The First People’s Hospital of Zunyi(The Third Affiliated Hospital of Zunyi Medical University)Zunyi563000China Department of Critical Care Medicine The First People’s Hospital of Zunyi(The Third Affiliated Hospital of Zunyi Medical University)Zunyi563000China

Respiratory syncytial virus(RSV)infection is known as a risk factor for chronic obstructive pulmonary disease(COPD).RSV infection induces the upregulation of Toll-like receptor 3(tlr3).This study aimed to investigate the association of tlr3 with RSV induced acute exacerbations of chronic obstructive pulmonary disease(AECOPD).Serum/sputum samples from AECOPD patients,stable chronic obstructive pulmonary disease(SCOPD)patients,and healthy controls were *** PCR was used to detect *** lung function parameters were assessed by blood gas and lung function *** expression levels of inflammatory factors in sputum and serum samples were determined by enzyme-linked immunosorbent ***-2B cell lines were infected with RSV,and the expression of tlr3 mRNA was determined by PCR and the levels of inflammatory factors were also *** presence of RSV was detected in 3 SCOPD and 8 AECOPD patients,but not in healthy *** expression levels of TNF-αand IRF-3 in both sputum and serum samples of RSV-positive group were significantly higher than in RSV-negative ***3 mRNA levels in RSV-positive group were significantly higher than those in RSVnegative ***,the level of tlr3 mRNA expression was negatively correlated with oxygenation index and lung function ***,BEAS-2B cells infected with RSV led to significant increase of the expression of tlr3 mRNA and inflammatory factors IFN-β,IL-13,IL-32,and TNF-α.Our observations indicate that AECOPD is associated with RSV infection and the upregulation of tlr3.

关键词： tlr3 Chronic obstructive pulmonary disease RSV Inflammation

Polarization of M1 tumor associated macrophage promoted by the activation of tlr3 signal pathway

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Asian Pacific Journal of Tropical Medicine 2016年第5期9卷 470-474页

作者： Bo Liu Xia Wang Tai-Zhong Chen Guang-Liang Li Chang-Chun Tan Yong Chen Shao-Qiang Duan Department of Pediatric Surgery Yongchuan hospital of chongqing medical university

Objective: To investigate the correlation between activation of toll-like receptors 3(tlr3) signaling pathway and tumor-associated macrophage and its effect on the tumor growth. Methods: The mice Lewis lung cancer cell lines 3LL and melanoma B16H10 were used to construct the subcutaneous transplantation tumor models and then they were treated with Poly-ICLC. The curative effect was observed and then the T cell and macrophage phenotypes infiltrated in local tumor were detected by flow cytometry. After the in vitro culture of mouse bone marrow-derived macrophage, the real-time PCR and western blot were applied to detect the expression of macrophage activation markers and the activation of intracellular signaling pathways. Results: The survival time of mice with brown tumor treated with Poly-ICLC significantly increased and the tumor growth was inhibited. The ratio of local tumor-infiltrated Treg decreased, while the ratio of CD8+ T cell increased significantly. The macrophages surface CD206 expression was down-regulated while the expression of i NOS increased. The Poly-ICLC could promote the expression of M1 markers(IL-1毬, TNF-α毩 and i NOS) in bone marrow-derived macrophage and inhibited the expression of M2 molecules(Arg-1, YM-1 and CD206). The phosphorylation level of downstream p65, TBK1 and IRF3 increased significantly. Conclusions: The Poly-ICLC can activate the tlr3 downstream signaling pathway to induce a M1 polarization of tumor associated macrophage, thereby inhibiting the tumor growth.

关键词： Tumor-associated macrophage tlr3 Poly-ICLC M1

和解抗敏煎对呼吸道合胞病毒感染诱发哮喘小鼠tlr3及NF-κB/IRF3信号通路调控的研究

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中国现代应用药学 2020年第23期37卷 2839-2844页

作者：李岚余陈欢陈雅琴陈梅王其莉应华忠浙江中医药大学附属第一医院杭州310006 浙江省医学科学院动物实验中心杭州310013

目的探讨和解抗敏煎对呼吸道合胞病毒(respiratory syncytial virus,RSV)感染诱发哮喘小鼠tlr3及NF-κB/IRF3信号通路的调控作用。方法将BALB/c小鼠随机分为对照组,模型组,地塞米松组(0.5 mg·kg^-1),和解抗敏煎低、中、高剂量组(17.5,3... 详细信息

目的探讨和解抗敏煎对呼吸道合胞病毒(respiratory syncytial virus,RSV)感染诱发哮喘小鼠tlr3及NF-κB/IRF3信号通路的调控作用。方法将BALB/c小鼠随机分为对照组,模型组,地塞米松组(0.5 mg·kg^-1),和解抗敏煎低、中、高剂量组(17.5,35.0,70.0 g·kg^-1),每组10只。RSV诱发合并卵白蛋白致敏建立哮喘小鼠模型。末次激发后24 h,乙酰甲胆碱吸入测定气道相对阻力;麻醉小鼠,制备肺泡灌洗液,检测炎症细胞数(巨噬细胞、嗜酸性粒细胞、淋巴细胞、中性粒细胞)和IgE、CD31、IL-4、TNF-α、MPO含量。取肺组织石蜡包埋切片行HE染色观察肺组织炎症浸润,免疫组化染色观察tlr3表达。qRT-PCR检测肺组织tlr3、NF-κB、IRF3 mRNA的表达。结果与模型组相比,和解抗敏煎各剂量组能有效降低哮喘小鼠气道高反应性,改善肺组织损伤和炎症细胞浸润,降低肺泡灌洗液中巨噬细胞、嗜酸性粒细胞、淋巴细胞、中性粒细胞数量和IgE、CD31、IL-4、TNF-α、MPO的含量,并有效降低肺组织tlr3、NF-κB、IRF3的表达。结论和解抗敏煎对病毒诱发的支气管哮喘具有治疗效果,且可能与介导tlr3及NF-κB/IRF3信号通路有关。

关键词：和解抗敏煎支气管哮喘呼吸道合胞病毒气道炎症 tlr3 NF-κB/IRF3

tlr3在大鼠心肌缺血再灌注损伤中的表达及其意义

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免疫学杂志 2014年第9期30卷 768-772,791页

作者：殷盼刘新伟重庆医科大学附属第一医院麻醉科 400016

目的观察Toll样受体3(Toll like receptor-3,tlr3)在大鼠心肌缺血再灌注损伤中表达的变化,探讨其在心肌缺血再灌注损伤中可能的作用与意义。方法 72只实验SD大鼠随机分3组(n=24):假手术组、缺血再灌注组、预处理缺血再灌注组。假手术组... 详细信息

目的观察Toll样受体3(Toll like receptor-3,tlr3)在大鼠心肌缺血再灌注损伤中表达的变化,探讨其在心肌缺血再灌注损伤中可能的作用与意义。方法 72只实验SD大鼠随机分3组(n=24):假手术组、缺血再灌注组、预处理缺血再灌注组。假手术组为冠状动脉左前降支(left anterior descending coronary artery,LAD)放置穿线但不结扎,缺血再灌注组压迫结扎LAD 30 min后再灌注2 h。预处理缺血再灌注组为压迫结扎LAD 5 min松开5 min,共3个循环,再停灌30 min,最后再灌注120 min。模型成功后进行心肌梗死面积(TTC)、RT-PCR、Western blots、ELISA、免疫组化学检测。结果假手术组tlr3 mRNA及蛋白呈微弱表达;缺血再灌注组中缺血区心肌细胞肿胀,周围大量中性粒细胞浸润,血清LDH(lactate dehyhrogenase)、CK(creatine kinase)活性及TNF-α水平升高(Ptlr3 mRNA及蛋白呈强烈高表达(Ptlr3 mRNA及蛋白表达明显减低(Ptlr3呈微弱表达于胞浆,而缺血区tlr3主要强烈表达分布于细胞核与细胞浆。同时免疫荧光结果提示,TNF-α与tlr3部分细胞有共表达。结论心肌缺血再灌注损伤模型中,tlr3的基因和蛋白表达水平明显升高,tlr3表达水平与心肌缺血再灌注损伤的进展有一定相关性。

关键词：固有免疫缺血再灌注炎症 tlr3

Efficacy of a Novel Antibody tlr3 Modulator in the Self-Treatment of Common Cold: The ESTUAR Trial

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Advances in Infectious Diseases 2015年第4期5卷 204-217页

作者： Andrey Martyushev-Poklad Jacques Bruhwyler Stéphane Heijmans Michel Thiry CONTRAFLU PTE LTD. Singapore City Singapore ECSOR Blanmont Belgium ResearchLink Linkebeek Belgium Theranor Trooz Belgium

Context: Since the discovery of toll-like receptor 3 (tlr3), no specific tools have been developed to modulate its activity in upper respiratory tract viral infections (URTIs). ContafluTM (antibodies to tlr3 cytoplasmic fragment) is the first specific tlr3 modulator that showed efficacy in a mouse model of influenza. Objective: To evaluate the efficacy of Contaflu in URTI. Methods: A double-blind randomized placebo-controlled trial in adults with self-reported URTI (the ESTUAR trial) was conducted in 2012/2013 in Belgium. Adult outpatients started a 7-day treatment course with oral tablets of Contaflu or placebo within 36 h after onset of at least one of 4 typical symptoms of URTI. Patients were examined twice by their general practitioners, on days 2-3 and 10-14 after start of treatment. The primary endpoint was the overall severity of URTI calculated as the sum of Wisconsin Upper Respiratory Symptom Survey (WURSS-21) scores over the follow-up. Independent Student’s t test was used to compare the disease severity between groups. Results: A total of 243 patients were enrolled by 32 investigators (121 Contaflu, 122 placebo);92% of cases matched ICD codes J00 or J06. Most patients had very mild (41.8%) or mild (18.2%) URTI symptoms. In the ITT cohort, neither primary nor secondary outcome measures (duration of URTI, day-to-day and overall functional impairments) showed statistically significant differences between groups. The rate of adverse events was similar in both groups. In patients with moderate to severe URTI symptoms, Contaflu tended to reduce the overall disease severity, daily symptoms, and to improve the functional state. Due to the small size of the corresponding subgroups, Contaflu efficacy on daily scores was statistically significant (p < 0.05) only 1, 2, and 5 days after start of treatment. Conclusion: Contaflu was ineffective in mild URTI and showed efficacy in moderate to severe URTI cases.

关键词： Common Cold Treatment Toll-Like Receptor 3 tlr3 Modulation Randomized Clinical Trial