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Fangchinoline induces antiviral response by suppressing STING degradation
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作者 Jinyong Wang Fang Xie +10 位作者 Xin Jia Xuejiao Wang Lingdong Kong Yiying Li b Xue Liang Meiqi Zhang Yuting He Wandi Feng Tong Luo Yao Wang Anlong Xu 《Journal of Pharmaceutical Analysis》 SCIE CAS CSCD 2024年第6期902-913,共12页
The stimulator of interferon genes(STING),an integral adaptor protein in the DNA-sensing pathway,plays a pivotal role in the innate immune response against infections.Additionally,it presents a valuable therapeutic ta... The stimulator of interferon genes(STING),an integral adaptor protein in the DNA-sensing pathway,plays a pivotal role in the innate immune response against infections.Additionally,it presents a valuable therapeutic target for infectious diseases and cancer.We observed that fangchinoline(Fan),a bis-benzylisoquinoline alkaloid(BBA),effectively impedes the replication of vesicular stomatitis virus(VSV),encephalomyocarditis virus(EMCV),influenza A virus(H1N1),and herpes simplex virus-1(HSV-1)in vitro.Fan treatment significantly reduced the viral load,attenuated tissue inflammation,and improved survival in a viral sepsis mouse model.Mechanistically,Fan activates the antiviral response in a STING-dependent manner,leading to increased expression of interferon(IFN)and interferon-stimulated genes(ISGs)for potent antiviral effects in vivo and in vitro.Notably,Fan interacts with STING,preventing its degradation and thereby extending the activation of IFN-based antiviral responses.Collectively,our findings highlight the potential of Fan,which elicits antiviral immunity by suppressing STING degradation,as a promising candidate for antiviral therapy. 展开更多
关键词 FANGCHINOLINE VIRUS Type I interferons Stimulator of interferon genes Protein degradation
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Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways 被引量:21
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作者 Rong-Juan Pei Xin-Wen Chen Meng-Ji Lu 《World Journal of Gastroenterology》 SCIE CAS 2014年第33期11618-11629,共12页
Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at... Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-&#x003b1; has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-&#x003b1; are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized. 展开更多
关键词 Hepatitis B virus interferon Toll-like receptor interferon stimulated genes Innate immune response
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Involvement of 2'-5'oligoadenylate synthetase-like proteinin the survivalof Mycobacterium tuberculosis avirulent strain in macrophages
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作者 Aikebaier Reheman Xiaojian Cao +8 位作者 Yifan Wang Xi Nie Gang Cao Wei Zhou Bing Yang Yingying Lei Weipan Zhang Muhammad Ahsan Naeem Xi Chen 《Animal Diseases》 CAS 2023年第4期275-285,共11页
Mycobacterium tuberculosis(M.tuberculosis)can replicate in the macrophage by interfering with many host protein functions.While it is far from known these host proteins for controlling M.tuberculosis infection.Herein,... Mycobacterium tuberculosis(M.tuberculosis)can replicate in the macrophage by interfering with many host protein functions.While it is far from known these host proteins for controlling M.tuberculosis infection.Herein,we infected macrophages including THP-1 and Raw264.7 cells with M.tuberculosis and identified the differentially expressed genes(DEGs)in the interferon signaling pathway.Among them,2'-5'oligoadenylate synthetase-like(OASL)underwent the greatest upregulation in M.tuberculosis-infected macrophages.Knockdown of the expression of OASL attenuated M.tuberculosis survival in macrophages.Further,bioinformatics analysis revealed the potential interaction axis of OASL-TAB3-RvO127,which was further validated by the yeast-two-hybrid(Y2H)assay and Co-IP.This interaction axis might regulate the M.tuberculosis survival and proliferation in macrophages.The study reveals a possible role of OASL during M.tuberculosis infection as a target to control its propagation. 展开更多
关键词 Mycobacterium tuberculosis interferon interferon stimulated genes OASL
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Computational modeling and inhibition of SARS-COV-2 Papain-like protease enzyme:A potential therapeutic approach for COVID-19
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作者 Auwal Rabiu Auwal Isa Abdullahi Baba +1 位作者 Evren Hincal Fathalla ARihan 《Journal of Biosafety and Biosecurity》 2024年第3期211-221,共11页
This study aims to investigate the potential impact of inhibitors targeting the papain-like protease(PLpro)of SARS-CoV-2 on viral replication and the host immune response.A mathematical model was developed to simulate... This study aims to investigate the potential impact of inhibitors targeting the papain-like protease(PLpro)of SARS-CoV-2 on viral replication and the host immune response.A mathematical model was developed to simulate the interaction among susceptible cells,infected cells,PLpro,and immune cells,incorporating data on PLpro inhibition.Through numerical simulations using MATLAB,the model parameters were estimated based on available statistical data.The results indicate that strategically positioned inhibitors could impede the virus’s access to host cellular machinery,thereby enhancing the immune response and gradually reducing susceptible and infected cells over time.The dynamics of the viral enzyme PLpro showed reduced activity with the introduction of the inhibitor,leading to a decline in viral replication.Moreover,the immune cell population exhibited functional recovery as the inhibitor suppressed PLpro activity.These findings suggest that inhibitors targeting PLpro may serve as therapeutic interventions against SARS-CoV-2 by inhibiting viral replication and bolstering the immune response. 展开更多
关键词 COVID-19 Viral replication Papain-like protease(PLpro) Mathematical modeling Noncovalent inhibitors Immune response interferon stimulated gene product 15(ISG-15)
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Advances in the prerequisite and consequence of STING downstream signalosomes
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作者 Xinliang Lu Xiaobing Li +2 位作者 Lili Li Chuanhui Han Sirui Li 《Medical Review》 2024年第5期435-451,共17页
The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.As... The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING. 展开更多
关键词 stimulator of interferon genes signalosomes cellular heterogeneity cancer therapeutics
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Update on the STING Signaling Pathway in Developing Nonalcoholic Fatty Liver Disease
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作者 Wei Liu Zhili Zhang Chen +4 位作者 Chenhui Yang Yaofu Fan Liang Qiao Shaofeng Xie Lin Cao 《Journal of Clinical and Translational Hepatology》 SCIE 2024年第1期91-99,共9页
Nonalcoholic fatty liver disease(NAFLD)is a prevalent chronic liver condition with limited treatment options.Inflammation caused by metabolic disturbances plays a significant role in NAFLD development.Stimulator of in... Nonalcoholic fatty liver disease(NAFLD)is a prevalent chronic liver condition with limited treatment options.Inflammation caused by metabolic disturbances plays a significant role in NAFLD development.Stimulator of interferon gene(STING),a critical regulator of innate immunity,induces the production of interferons and other pro-inflammatory factors by recognizing cytoplasmic DNA to defend against pathogen infection.The STING-mediated signaling pathway appears to play a vital role in hepatic inflammation,metabolic disorders,and even carcinogenesis.Promisingly,pharmacological interventions targeting STING have shown improvements in the pathological state of NAFLD.Macrophages,dendritic cells,natural killer cells,and T cell pathways regulated by STING present potential novel druggable targets for NAFLD treatment.Further research and development in this area may offer new therapeutic options for managing NAFLD effectively. 展开更多
关键词 Stimulator of interferon gene MACROPHAGE Innate immunity Nonalcoholic fatty liver disease
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Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer 被引量:3
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作者 Yang Liu William N.Crowe +3 位作者 Lulu Wang W.Jeffrey Petty Amyn A.Habib Dawen Zhao 《Nano Research》 SCIE EI CSCD 2023年第4期5300-5310,共11页
Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of im... Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it. 展开更多
关键词 locally advanced non-small cell lung cancer(LANSCLC) nanoparticle immunotherapeutic aerosol inhalation stimulator of interferon genes programmed death 1/programmed death-ligand 1(PD-1/PD-L1)blockade
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Novel STING-targeted PET radiotracer for alert and therapeutic evaluation of acute lung injury 被引量:1
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作者 Duo Xu Fan Yang +9 位作者 Jiayao Chen Tianxing Zhu Fen Wang Yitai Xiao Zibin Liang Lei Bi Guolong Huang Zebo Jiang Hong Shan Dan Li 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第5期2124-2137,共14页
Acute lung injury(ALI),as a common clinical emergency,is pulmonary edema and diffuse lung infiltration caused by inflammation.The lack of non-invasive alert strategy,resulting in failure to carry out preventive treatm... Acute lung injury(ALI),as a common clinical emergency,is pulmonary edema and diffuse lung infiltration caused by inflammation.The lack of non-invasive alert strategy,resulting in failure to carry out preventive treatment,means high mortality and poor prognosis.Stimulator of interferon genes(STING)is a key molecular biomarker of innate immunity in response to inflammation,but there is still a lack of STING-targeted strategy.In this study,a novel STING-targeted PET tracer,[~(18)F]FBTA,was labeled with high radiochemical yield(79.7±4.3%)and molar activity(32.5±2.9 GBq/μmol).We confirmed that[~(18)F]FBTA has a strong STING binding affinity(K_d=26.86±6.79 nmol/L)and can be used for PET imaging in ALI mice to alert early lung inflammation and to assess the efficacy of drug therapy.Our STING-targeted strategy also reveals that[~(18)F]FBTA can trace ALI before reaching the computed tomography(CT)diagnostic criteria,and demonstrates its better specificity and distribution than[~(18)F]fluorodeoxyglucose([~(18)F]FDG). 展开更多
关键词 Acute lung injury(ALI) Stimulator of interferon genes(STING) PET imaging [~(18)F]FBTA
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Peptide nanotube loaded with a STING agonist,c-di-GMP,enhance cancer immunotherapy against melanoma 被引量:1
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作者 Ziyuan Zhang Juan Liu +5 位作者 Min Xiao Quanfeng Zhang Zhonghua Liu Meiyan Liu Peng Zhang Youlin Zeng 《Nano Research》 SCIE EI CSCD 2023年第4期5206-5215,共10页
The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonis... The activation of the stimulating factor of the interferon gene(STING)pathway can enhance the immune response within the tumor.Cyclic diguanylate monophosphate(c-di-GMP)is a negatively charged,hydrophilic STING agonist,however,its effectiveness is limited due to the poor membrane permeability and low bioavailability.Herein,we introduced KL-7 peptide derived from Aβamyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP,which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust“in situ immunity”to kill melanoma cells.KL-7 peptide nanotube,also called PNT,was loaded with negatively charged c-di-GMP via electrostatic interaction,which prepared a nanocomposite named c-di-GMP-PNT.Treatment of RAW 264.7 cells(leukemia cells in mouse macrophage)with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-βalong with phospho-STING(Ser365)protein expression,indicating the activation of the STING pathway.In the unilateral flank B16-F10(murine melanoma cells)tumor-bearing mouse model,compared to PNT and cdi-GMP,c-di-GMP-PNT can promote the expression of INF-β,TNF-α,IL-6,and IL-1β.At the same time,up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues,resulting in significant inhibition of tumor growth in tumor-bearing mice.More importantly,in a bilateral flank B16-F10 tumor model,both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT.Moreover,c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs(heart,liver,spleen,lung,and kidney)and biochemical indexes of mice.In summary,our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity. 展开更多
关键词 cyclic diguanylate monophosphate stimulating factor of the interferon gene(STING) peptide nanotubes in situ immunity tumor immunotherapy
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Nano-STING agonist-decorated microrobots boost innate and adaptive anti-tumor immunity
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作者 Yixin Wang Zhaoting Li +3 位作者 Yu Chen Allie Barrett Fanyi Mo Quanyin Hu 《Nano Research》 SCIE EI CSCD 2023年第7期9848-9858,共11页
Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathwa... Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists. 展开更多
关键词 drug delivery mitochondrial DNA(mtDNA) Fenton reaction stimulator of interferon genes(STING) tumor immunotherapy bacteria
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High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors 被引量:10
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作者 Yao Zhao Xiaoyu Du +23 位作者 Yinkai Duan Xiaoyan Pan Yifang Sun Tian You Lin Han Zhenming Jin Weijuan Shang Jing Yu Hangtian Guo Qianying Liu Yan Wu Chao Peng Jun Wang Chenghao Zhu Xiuna Yang Kailin Yang Ying Lei Luke W.Guddat Wenqing Xu Gengfu Xiao Lei Sun Leike Zhang Zihe Rao Haitao Yang 《Protein & Cell》 SCIE CSCD 2021年第11期877-888,共12页
A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identif... A new coronavirus(SARS-CoV-2)has been identified as the etiologic agent for the COVID-19 outbreak.Currently,effective treatment options remain very limited for this disease;therefore,there is an urgent need to identify new anti-COVID-19 agents.In this study,we screened over 6,000 compounds that included approved drugs,drug candidates in clinical trials,and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease(PLpro).Together with main protease(Mpro),PLpro is responsible for processing the viral replicase polyprotein into functional units.There-fore,it is an attractive target for antiviral drug develop-ment.Here we discovered four compounds,YM155,cryptotanshinone,tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 pmol/L.These compounds also exhibit strong antiviral activities in cell-based assays.YM155,an anti-cancer drug candidate in clinical trials,has the most potent antiviral activity with an EC50 value of 170 nmol/L.In addition,we have determined the crystal structures of this enzyme and its complex with YM155,revealing a unique binding mode.YM155 simultaneously targets three"hot"spots on PLpro,including the substrate-binding pocket,the interferon stimulating gene product 15(ISG15)binding site and zinc finger motif.Our results demonstrate the efficacy of this screening and repur-posing strategy,which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments. 展开更多
关键词 SARS-CoV-2 papain-like protease YM155 interferon stimulating gene product 15 drug repurposing
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STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation 被引量:1
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作者 Bo-Dou Zhang Jun-Jun Wu +5 位作者 Wen-Hao Li Hong-Guo Hu Lang Zhao Pei-Yang He Yu-Fen Zhao Yan-Mei Li 《Nano Research》 SCIE EI CSCD 2022年第7期6328-6339,共12页
Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity ... Immunostimulatory therapies based on pattern recognition receptors(PRRs)have emerged as an effective approach in the fight against cancer,with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment.The agonist cyclic dinucleotides(CDNs)of the stimulator of interferon gene(STING)are a group of very promising anticancer molecules that increase tumor immunogenicity by activating innate immunity.However,the tumor immune efficacy of CDNs is limited by several factors,including relatively narrow cytokine production,inefficient delivery to STING,and rapid clearance.In addition,a single adjuvant molecule is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect.To address this problem,two or more agonist molecules are often used together to synergistically enhance immune efficacy.In this work,we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8(TLR7/8)agonist 522 produced a broader cytokine response.Subsequently,we developed multicomponent nanovaccines(MCNVs)consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant molecules.These MCNVs activate bone marrow-derived dendritic cells(BMDCs)to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor Tcell responses.In in vivo experiments,we observed that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes,resulting in significant tumor regression and,notably,a 100%survival rate in mice through 25 days without other partnering therapies.These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency. 展开更多
关键词 nanovaccines stimulator of interferon gene(STING) Toll-like receptor 7/8 synergistic immune activation lymph node targeting
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A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy
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作者 Madiha Zahra Syeda Tu Hong +4 位作者 Min Zhang Yanfei Han Xiaoling Zhu Songmin Ying Longguang Tang 《Nano Research》 SCIE EI CSCD 2022年第10期9215-9222,共8页
Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challeng... Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials. 展开更多
关键词 PRODRUG esterase-responsive immunotherapy stimulator of interferon genes(STING) indoleamine 2 3 dioxygenase(IDO)
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STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
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作者 Hee-Jin ChoiTaylor Ticer Yongxia Wu +13 位作者 Chih-Hang Anthony Tang Corey Mealer David Bastian M.Hanief Sofi Linlu Tian Steven Schutt Hee-Jin Choi Taylor Ticer Mengmeng Zhang Xiaohui Sui Lei Huang Andrew L.Mellor Chih-Chi Andrew Hu Xue-Zhong Yu 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2021年第3期632-643,共12页
Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmuni... Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD mortality.In conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT. 展开更多
关键词 Stimulator of interferon genes antigen-presenting cells allogeneic hematopoietic cell transplantation graft-versushost diseases hematopoietic stem-cell transplantation T cells
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The multifaceted functions of cGAS
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作者 Haipeng Liu Fei Wang +2 位作者 Yajuan Cao Yifang Dang Baoxue Ge 《Journal of Molecular Cell Biology》 SCIE CAS CSCD 2022年第5期16-26,共11页
Pattern recognition receptors arecritical forthe sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of innate immunityandshaping ofadaptive immunity.The i... Pattern recognition receptors arecritical forthe sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of innate immunityandshaping ofadaptive immunity.The identification of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)synthase(cGAS)as a major cytosolic DNA receptor is a milestone in the field of DNA sensing.The engagement of cGAS by double-stranded DNA from different origins,including invading pathogens,damaged mitochondria,ruptured micronuclei,and genomic DNA results in the generation of cGAMP and activation of stimulator of interferon genes,which thereby activates innate immunity mainly characterized by the activation of type I interferon response.In recent years,great progress has been made in understanding the subcellular localization and novel functions of cGAS.In this review,we particularlyfocus on summarizingthe multifaceted roles ofcGAS in regulating senescence,autophagy,cell stemness,apoptosis,angiogenesis,cell proliferation,antitumor effect,DNA replication,DNA damage repair,micronucleophagy,as well as cell metabolism. 展开更多
关键词 cyclic GMP-AMP synthase(cGAS) stimulator of interferon genes(STING) DNA sensing innate immunity micronucleophagy
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