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Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

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Bioactive Materials 2023年第6期24卷 37-53页

作者： Haotian Shen Lulu Jin Qiangqiang Zheng Ziqiang Ye Linxiang Cheng Yuxu Wu Honghao Wu Tae Gyong Jon Wenduo Liu Zongyou Pan Zhengwei Mao Yue Wang Department of Orthopedic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou310003China MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhou310027China Dr.Li Dak Sum&Yip Yio Chin Center for Stem Cells and Regenerative Medicine Zhejiang University School of MedicineHangzhou310000China International Institutes of Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineN1 Shangchen RoadYiwuZhejiang322000China

Rheumatoid arthritis(RA)is a common autoimmune disease leading to pain,disability,and even death.Although studies have revealed that aberrant activation of STING was implicated in various autoimmune diseases,the role of STING in RA remains unclear.In the current study,we demonstrated that STING activation was pivotal in RA pathogenesis.As the accumulation of dsDNA,a specific stimulus for STING,is a feature of RA,we developed a spherical polyethyleneimine-coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176(PEI-PDA@C-176 NPs)for treating RA.The fabricated NPs with biocompatibility had high DNA adsorption ability and could effectively inhibit the STING pathway and inflammation in macrophages.Intra-articular administration of PEI-PDA@C-176 NPs could effectively reduce joint damage in mice models of dsDNA-induced arthritis and collagen-induced arthritis by inhibiting STING pathway.We concluded that materials with synergistic effects of STING inhibition might be an efficacious strategy to treat RA.

关键词： Mesoporous nanoparticles STING Inflammation Drug delivery Rheumatoid arthritis

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair

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Cellular & Molecular Immunology 2022年第11期19卷 1251-1262页

作者： Christopher O.Audu William J.Melvin Amrita D.Joshi Sonya J.Wolf Jadie Y.Moon Frank M.Davis Emily C.Barrett Kevin D.Mangum Hongping Deng Xianying Xing Rachel Wasikowski Lam C.Tsoi Sriganesh B.Sharma Tyler M.Bauer James Shadiow Matthew A.Corriere Andrea TObi Steven LKunkel Benjamin Levi Bethany BMoore Johann EGudjonsson Andrew MSmith Katherine A.Gallagher Department of Surgery Section of Vascular SurgeryUniversity of MichiganAnn ArborMIUSA Department of Microbiology and Immunology University of MichiganAnn ArborMIUSA Department of Medicinal Chemistry University of MichiganAnn ArborMIUSA Department of Surgery Section of General SurgeryUniversity of MichiganAnn ArborMIUSA Department of Bioengineering University of IllinoisUrbana-ChampaignChampaignILUSA Department of Dermatology University of MichiganAnn ArborMIUSA Department of Pathology University of MichiganAnn ArborMIUSA Department of Surgery University of Texas Southwestern Medical CenterDallasTXUSA

Macrophage plasticity is critical for normal tissue repair following injury.In pathologic states such as diabetes,macrophage plasticity is impaired,and macrophages remain in a persistent proinflammatory state;however,the reasons for this are unknown.Here,using single-cell RNA sequencing of human diabetic wounds,we identified increased JMJD3 in diabetic wound macrophages,resulting in increased inflammatory gene expression.Mechanistically,we report that in wound healing,JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling.However,in the diabetic state,we found that IL-6,a cytokine increased in diabetic wound tissue at later time points post-injury,regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism.IntereSTINGly,RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells(Jmjd3f/fLyz2Cre+)identified that the STING gene(Tmem173)is regulated by JMJD3 in wound macrophages.STING limits inflammatory cytokine production by wound macrophages during healing.However,in diabetic mice,its role changes to limit wound repair and enhance inflammation.This finding is important since STING is associated with chronic inflammation,and we found STING to be elevated in human and murine diabetic wound macrophages at late time points.Finally,we demonstrate that macrophage-specific,nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING.Taken together,this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

关键词： wound healing epigenetics diabetes JMJD3 STING

STING signaling in islet macrophages impairs insulin secretion in obesity

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Science China(Life Sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti Haiping Hao Peng Cao Haiyang Hu Chen Wang School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Natural Medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China School of Life Sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune diseases.Innate immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully understood.Here,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)feeding.STING^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of macrophages.Mechanically,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in macrophages.Additionally,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory granules.Pharmacologically inhibiting STING activation enhances insulin secretion to control hyperglycemia.Together,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

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Acta Pharmaceutica Sinica B 2022年第1期12卷 50-75页

作者： Patrick Kwabena Oduro Xianxian Zheng Jinna Wei Yanze Yang Yuefei Wang Han Zhang Erwei Liu Xiumei Gao Mei Du Qilong Wang Institute of Traditional Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China State Key Laboratory of Component-Based Chinese Medicine Ministry of EducationTianjin 301617China Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure,myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns(mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism.Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

关键词： STING cGAS Cardiovascular diseases Metabolic diseases Damage-associated molecular patterns Inflammation ER stress Mitochondria

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

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Zoological Research 2023年第1期44卷 183-218页

作者： Jing Pan Chen-Jie Fei Yang Hu Xiang-Yu Wu Li Nie Jiong Chen State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityNingboZhejiang 315211China Laboratory of Biochemistry and Molecular Biology School of Marine SciencesMeishan CampusNingbo UniversityNingboZhejiang 315832China Zhejiang Key Laboratory of Marine Bioengineering Ningbo UniversityNingboZhejiang 315832China

The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway,comprised of cyclic GMP-AMP synthase(cGAS),stimulator of interferon genes(STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases.After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2’3’-c GAMP for the activation of endoplasmic reticulum(ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosoliclocalized cGAS. Detailed delineation of this pathway,including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

关键词： cGAS STING Structure Signaling Post-translational modification Diseases

Phase separation in cGAS-STING signaling

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Frontiers of Medicine 2023年第5期17卷 855-866页

作者： Quanjin Li Pu Gao CAS Key Laboratory of Infection and Immunity National Laboratory of BiomacromoleculesCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100049China

Biomolecular condensates formed by phase separation are widespread and play critical roles in many physiological and pathological processes.cGAS-STING signaling functions to detect aberrant DNA signals to initiate anti-infection defense and antitumor immunity.At the same time,cGAS-STING signaling must be carefully regulated to maintain immune homeostasis.IntereSTINGly,exciting recent studies have reported that biomolecular phase separation exists and plays important roles in different steps of cGAS-STING signaling,including cGAS condensates,STING condensates,and IRF3 condensates.In addition,several intracellular and extracellular factors have been proposed to modulate the condensates in cGAS-STING signaling.These studies reveal novel activation and regulation mechanisms of cGAS-STING signaling and provide new opportunities for drug discovery.Here,we summarize recent advances in the phase separation of cGAS-STING signaling and the development of potential drugs targeting these innate immune condensates.

关键词： biomolecular condensates phase separation cGAS-STING pathway cGAS STING cGAMP interferon

Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu Maosheng Cheng Gaofei Wei Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Research&Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China Key Laboratory of Structure-Based Drug Design and Discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum Chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

Tetrahedral DNA nanostructures synergize with MnO_(2) to enhance antitumor immunity via promoting STING activation and M1 polarization

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2494-2505页

作者： Siping Liang Jiaying Li Zhengyu Zou Miao Mao Siqi Ming Fan Lin Ziyan Zhang Can Cao Jinyu Zhou Yuanqing Zhang Jiaping Li Minhao Wu Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510080China Department of Laboratory Medicine Guangdong Second Provincial General HospitalGuangzhou 510317China Guangdong Key Laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Interventional Oncology The First Afﬁliated HospitalSun Yat-sen UniversityGuangzhou 510080China

Stimulator of interferon genes(STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here,we showed that tetrahedral DNA nanostructures(TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn^(2+) to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn^(2+),we constructed a TDN-MnO_(2) complex and found that it displayed a much higher efficacy than TDN plus Mn^(2+) to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO_(2).These findings provide new therapeutic opportunities for cancer therapy.

关键词： Tetrahedral DNA nanostructure Manganese MnO_(2) STING M1 polarization Antigen presentation Anti-tumor immunity Cancer therapy

Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4765-4784页

作者： Xuesong Li Xiang Chen Longbin Zheng Minghong Chen Yunjia Zhang Ruigong Zhu Jiajing Chen Jiaming Gu Quanwen Yin Hong Jiang Xuan Wu Xian Ji Xin Tang Mengdie Dong Qingguo Li Yuanqing Gao Hongshan Chen Key Laboratory of Cardiovascular and Cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing 211166China Department of Anesthesiology Sir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of Pharmacy Huashan HospitalFudan UniversityShanghai 200040China Department of Cardiothoracic Surgery the Second Affliated Hospital of Nanjing Medical UniversityNanjing 211166China Key Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of Cardiology Huai'an First People's Hospital Affliated with Nanjing Medical UniversityHuai'an 223399China

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis,while the underlying mechanism remains elusive.Here,we report that the non-canonical stimulator of interferon genes(STING)-PKR-like ER kinase(PERK)pathway was significantly activated in both human and mice atherosclerotic arteries.Typically,STING activation leads to the activation of interferon regulatory factor 3(IRF3)and nuclear factor-kappa B(NF-κB)/p65,thereby facilitating IFN signals and infammation.In contrast,our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4(BRD4)expression,which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines,thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process.Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation.Mechanistically,this pathway is triggered by leaked mitochondrial DNA(mtDNA)via mitochondrial permeability transition pore(mPTP),formed by voltage-dependent anion channel 1(VDAC1)oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation.Especially,compared to macrophages,endothelial STING activation plays a more pronounced role in atherosclerosis.We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3,NF-κB and BRD4 in inflammatory responses,which provides emerging therapeutic modalities for vascular endothelial dysfunction.

关键词： Endothelial dysfunction Infiammation Mitochondrial DNA STING ROS PERK BRD4 Atherosclerosis