Extracellular matrix-degrading STING nanoagonists for mild NIR-II photothermal-augmented chemodynamic-immunotherapy

AbstractRegulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome. Graphical Abstract

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Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

Rheumatology and Immunology Research ◽

10.2478/rir-2021-0023 ◽

2021 ◽

Vol 2 (3) ◽

pp. 173-184

Author(s):

Audrey M. Hagiwara ◽

Richard E. Moore ◽

Daniel J. Wallace ◽

Mariko Ishimori ◽

Caroline A. Jefferies

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Type I ◽

Systemic Lupus ◽

Downstream Signaling ◽

Potential Therapeutic Application ◽

Sting Pathway

Abstract Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the “interferonopathies.” Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.

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miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

Vaccines ◽

10.3390/vaccines7040197 ◽

2019 ◽

Vol 7 (4) ◽

pp. 197 ◽

Cited By ~ 2

Author(s):

Abid Ullah Shah ◽

Yanan Cao ◽

Naila Siddique ◽

Jian Lin ◽

Qian Yang

Keyword(s):

Dendritic Cells ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Mouse Bone Marrow ◽

Cytokine Detection ◽

Sting Pathway ◽

Factor Α ◽

Antigen Presenting ◽

And Control

The Cytosine–phosphate–guanosine (CpG) motif, which is specifically recognized intracellularly by dendritic cells (DCs), plays a crucial role in regulating the innate immune response. MicroRNAs (miRNAs) can strongly influence the antigen-presenting ability of DCs. In this study, we examine the action of miRNAs on CpG-stimulated and control DCs, as well as their effect on cyclic guanosine monophosphate-adenosine monophosphate (GMP–AMP) synthase (cGAS) and the stimulator of interferon genes (STING) signal pathway. Firstly, we selected miRNAs (miR-29a and miR-378b) based on expression in CpG-stimulated mouse bone marrow-derived dendritic cells (BMDCs). Secondly, we investigated the functions of miR-29a and miR-378b on CpG-stimulated and unstimulated BMDCs. The results showed that miR-29a and miR-378b increased expression of both the immunoregulatory DC surface markers (CD86 and CD40) and the immunosuppressive molecule CD273 by DCs. Thirdly, cytokine detection revealed that both miR-29a and miR-378b enhanced interferon-β (IFN-β) expression while suppressing tumor necrosis factor-α (TNF-α) production. Finally, our results suggest that miR-378b can bind TANK-binding kinase binding protein 1 (TBKBP1) to activate the cGAS/STING signaling pathway. By contrast, miR-29a targeted interferon regulatory factor 7 (IRF7) and promoted the expression of STING. Together, our results provide insight into the molecular mechanism of miRNA induction by CpG to regulate DC function.

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The cGAS–STING pathway: more than fighting against viruses and cancer

Cell & Bioscience ◽

10.1186/s13578-021-00724-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Terigen Bao ◽

Jia Liu ◽

Jiyan Leng ◽

Lu Cai

Keyword(s):

Inflammatory Diseases ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Type I ◽

Antiviral Responses ◽

Inflammatory Conditions ◽

Inflammatory Status ◽

Sting Pathway ◽

Inflammatory Molecules

AbstractIn the classic Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, downstream signals can control the production of type I interferon and nuclear factor kappa-light-chain-enhancer of activated B cells to promote the activation of pro-inflammatory molecules, which are mainly induced during antiviral responses. However, with progress in this area of research, studies focused on autoimmune diseases and chronic inflammatory conditions that may be relevant to cGAS–STING pathways have been conducted. This review mainly highlights the functions of the cGAS–STING pathway in chronic inflammatory diseases. Importantly, the cGAS–STING pathway has a major impact on lipid metabolism. Different research groups have confirmed that the cGAS–STING pathway plays an important role in the chronic inflammatory status in various organs. However, this pathway has not been studied in depth in diabetes and diabetes-related complications. Current research on the cGAS–STING pathway has shown that the targeted therapy of diseases that may be caused by inflammation via the cGAS–STING pathway has promising outcomes.

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The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer

Journal of Experimental Medicine ◽

10.1084/jem.20180139 ◽

2018 ◽

Vol 215 (5) ◽

pp. 1287-1299 ◽

Cited By ~ 269

Author(s):

Tuo Li ◽

Zhijian J. Chen

Keyword(s):

Dna Damage ◽

Inflammatory Responses ◽

Adaptor Protein ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Host Immune System ◽

Detection Mechanism ◽

Microbial Infections ◽

Sting Pathway

Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.

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Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

Frontiers in Immunology ◽

10.3389/fimmu.2021.637399 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eloi R. Verrier ◽

Christelle Langevin

Keyword(s):

Nucleic Acid ◽

Current Knowledge ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Innate Immune ◽

Guanosine Monophosphate ◽

Type I ◽

Nucleic Acid Binding ◽

Sting Pathway ◽

Molecular Patterns

Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.

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cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model

Frontiers in Immunology ◽

10.3389/fimmu.2020.583251 ◽

2021 ◽

Vol 11 ◽

Author(s):

Elena V. Vassilieva ◽

Song Li ◽

Heorhiy Korniychuk ◽

Dahnide M. Taylor ◽

Shelly Wang ◽

...

Keyword(s):

Mouse Model ◽

Influenza Vaccine ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Aged Mouse ◽

Protective Response ◽

H1n1 Vaccine ◽

Adult Mice ◽

Sting Pathway

Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2’3 cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.

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Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:34-38 ◽

2019 ◽

Vol 18 (1) ◽

pp. 34-38

Author(s):

Chen Lei ◽

Pan Xiang ◽

Shen Yonggang ◽

Song Kai ◽

Zhong Xingguo ◽

...

Keyword(s):

Protein Kinase ◽

Guinea Pig ◽

Smooth Muscles ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Dependent Manner ◽

Underlying Mechanisms ◽

Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

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Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.748485 ◽

2021 ◽

Vol 9 ◽

Author(s):

Kunli Zhang ◽

Sutian Wang ◽

Hongchao Gou ◽

Jianfeng Zhang ◽

Chunling Li

Keyword(s):

Signaling Pathway ◽

Adenosine Monophosphate ◽

Degradation Process ◽

Guanosine Monophosphate ◽

Type I Interferons ◽

Research Progress ◽

Type I ◽

Type I Ifn ◽

Major Pathway ◽

Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

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Effects of Haima Duobian Pill in a Rat Model of Kidney Yang Deficiency Syndrome

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6696234 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yijia Zeng ◽

Tingna Li ◽

Xiaorui Zhang ◽

Yuanyuan Ren ◽

Qinwan Huang ◽

...

Keyword(s):

Rat Model ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Deficiency Syndrome ◽

Guanosine Monophosphate ◽

Network Pharmacology ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Effects ◽

Kidney Yang Deficiency

Objective. Modern research shows that Haima Duobian pill (HDP) can relieve the kidney yang deficiency syndrome (KYDS), but the mechanism is still unclear. The aim of this work was to study the effects of HDP in a rat model of KYDS. Materials and Methods. The network pharmacology methods were used to predict the therapeutic effects of Haima Duobian pill. Adenine was used to establish the rat model of kidney yang deficiency syndrome. The general physical signs of rats were observed after different doses of Haima Duobian pill (HDP) were given. Serum cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2), and gonadotropin-releasing hormone (GnRH) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Then, the histopathologic changes and sperm activity were detected. Results. HDP could improve the general signs of kidney yang deficiency syndrome rats. After the rats were treated with HDP, the expression of cGMP and E2 was significantly inhibited and the expression of cAMP and T was significantly increased. The pathological damage of testis, epididymis, and seminal vesicle was alleviated, and the sperm activity was improved. Conclusion. For adenine-induced kidney yang deficiency syndrome in rats, HDP had a significant therapeutic effect.

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