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The NETs-cGAS-STING Axis in Ischemic Stroke: Linking Neutrophil-Microglia Crosstalk, Immunothrombosis, and Neuroinflammation.

The immune and inflammatory responses following ischemic stroke involve aberrant DNA exposure, immunothrombosis, and innate immune activatio … tential link connecting vascular inflammation, immunothrombosis, and intracerebral DNA sensing. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a key DNA-sensing axis, mediates distinct inflammatory and stress responses across various stroke-associated cell types. This review summarizes the mechanisms of DNA recognition, NET- …

Boosting the immune response and protective efficacy of inactivated PRV vaccine using cGAMP as a mucosal adjuvant.

BACKGROUND: The respiratory mucosa serves as the primary site for Pseudorabies Virus (PRV) invasion, which can elicit both local mucosal and systemic immune responses. However, due to the presence of mucosal barrier, nasal immunization with inactivated vaccines typically results in a limited immune response; thus, a mucosal adjuvant is necessary to enhance this response. Cyclic GMP-AMP (cGAMP) acts as a potent agonist of STING, exhibiting significant mucosal adjuvant properties. It plays a vital role in the regulation of innate immune responses to DNA viruses. RESULTS: In this study, we devel…

Pharmacological Stimulator of Interferon Genes Activation Enhances Autophagy-Mediated Clearance of <italic>Mycobacterium tuberculosis</italic> in Human Macrophages.

INTRODUCTION: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a critical sensor in the innate immune response to intracellular pathogens, yet its therapeutic potential for augmenting macrophage-mediated control of Mycobacterium tuberculosis (Mtb) remains incompletely understood. This study investigated whether pharmacological activation of the STING pathway could enhance autophagy to promote Mtb clearance in human macrophages. METHODS: Human THP-1 monocytes were differentiated into macrophages and infected with Mtb. The effects of the STING agonist MIW815 …

Suppressed cGAS-STING DNA Sensing Drives Immune Evasion in Anaplastic Thyroid Cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a highly lethal malignancy with poor survival and limited therapeutic options. The mechanisms driving immune evasion in ATC remain poorly understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a key mediator of innate immune sensing and antitumor immunity. METHODS: We investigated the role of cGAS-STING signaling in ATC using three complementary models (i) a genetically engineered mouse model harboring triple mutations in Thrb1, Trp53, and Pten (RU3 model); (ii) an orthotopic tumor model derived from Trp53-…

Aberrant STING signalling promotes endothelial dysfunction and neurovascular injury in diabetic retinopathy.

AIMS/HYPOTHESIS: Diabetic retinopathy is a common complication of diabetes mellitus that is characterised by neurovascular dysfunction and c … mice. CONCLUSIONS/INTERPRETATION: Our findings demonstrate endothelial-intrinsic activation of the cyclic GMP-AMP synthase (cGAS)/STING/IFN pathway as a key driver of retinal inflammation and neurovascular dysfunction in diabetes. Targeting this pathway may offer a potential therapeutic approach for early intervention in diabetic retinopathy.

Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress.

Malaria, caused by intracellular Plasmodium parasites, remains a major global health concern. These parasites reside and replicate within a vacuole in host red blood cells. Egress of daughter parasites out of the vacuolar and host membranes is tightly regulated via a complex mechanism. Prior studies have suggested that a cyclic-GMP driven calcium signaling pathway leads to the signal-dependent exocytosis of egress-specific vesicles that discharge several proteases into the parasitophorous vacuole. However, signal-dependent exocytosis during egress has not yet been observed in live parasitized

Multifunctional nanoparticle-mediated targeting of metabolic reprogramming and DNA damage response pathways to treat drug-resistant triple-negative breast cancer.

Multi-drug resistance and immunosuppressive triple-negative breast cancer (TNBC) is triggered by the Warburg effect, which promotes homologo … in, fostering the cytoplasmic accumulation of DNA damage fragments, which induced activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway. Experimental results show that iPR@M1/Se nanoparticles effectively promote dendritic cell maturation and T lymphocyte activation, which elicits long-term immune memory responses, and …

Remdesivir alleviates joint damage in collagen-induced arthritis and inhibits inflammatory cell death of RA synovial fibroblasts.

BACKGROUND: The antiviral agent, remdesivir, is adenosine analogue which is currently also used as anti-coronavirus disease 2019. Remdesivir also had anti-inflammatory effect which reduced pro-inflammatory cytokine production, and inhibition of the cyclic GMP-AMP synthase-STING pathway. METHODS: We evaluated the antiarthritic effects of remdesivir in a mouse model of High-fat diet (HFD) collagen-induced arthritis (CIA) and in fibroblast-like synoviocytes from patients with RA. Type II collagen was administered to DBA/1J mice to induce CIA. Vehicle or remdesivir was injected subcutaneously thr…

Phagosomal escape and sabotage: The role of ESX-1 and PDIMs in Mycobacterium tuberculosis pathogenesis.

Mycobacterium tuberculosis (M. tb) employs diverse virulence factors to evade immune defenses and persist intracellularly. The ESAT-6 secret … evades degradation by manipulating autophagic flux. Simultaneously, M. tb-derived DNA activates the cyclic GMP-AMP synthase-stimulator of interferon response cGAMP interactor 1 (CGAS-STING1) axis, leading to type I interferon (IFN) signaling and inflammasome activation, which drive IL-1B and IL-18 secretion, necrosis, and pyroptosis, facilitating bacterial d …

Ребалансировка гомеостаза: ключевой регулятор пути CGAS-STING в аутоиммунных болезнях.

Аутоиммунные заболевания (АД) возникают в результате нарушения иммунной терпимости к самоантигенам, что приводит к патологическому повреждению тканей. Избыток цитокина, вызывающий воспаление, нарушает перепроизводство гомеостаза в различных популяциях клеток, вызывая окислительный стресс, вызывающий повреждение ДНК с помощью различных механизмов. Изменения, вызванные окисляющим стрессом в проницаемости мембран и повреждениях ДНК, могут привести к выявлению двойной структуры ДНК (dsDNA), митохондриальной ДНК (mtDNA) и микронукли-DNA (MN-DNA) с помощью датчиков ДНК, что инициирует активацию цикл

Совпадение в аннотации оригинала
Autoimmune diseases (ADs) arise from the breakdown of immune tolerance to self-antigens, leading to pathological tissue damage. Proinflammat … drial DNA (mtDNA) and micronuclei-DNA (MN-DNA) by DNA sensors, thereby initiating activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. While previous reviews have characterized cGAS-STING activation in autoimmunity, the reciprocal regulation between redox homeostasis and cGAS-STING activation remains insufficiently d …

FGF21 attenuates neuroinflammation following subarachnoid hemorrhage through promoting mitophagy and inhibiting the cGAS-STING pathway.

BACKGROUND: Subarachnoid hemorrhage (SAH) represents a form of cerebrovascular event characterized by a notable mortality and morbidity rate … itochondrial DNA (mtDNA) release into the cytoplasm and dampening the activation of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Conditional knockout of STING in microglia markedly ameliorated the inflammatory response and mitigated secondary brain injuries post-SAH. CONCLUSION: Our results present …

Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer.

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoin … ociated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tu …

Lymph node-targeted STING agonist nanovaccine against chronic HBV infection.

Chronic hepatitis B virus (HBV) infection is a global health problem that substantially increases the risk of developing liver disease. The development of a novel strategy to induce anti-HB seroconversion and achieve a long-lasting immune response against chronic HBV infection remains challenging. Here, we found that chronic HBV infection affected the signaling pathway involved in STING-mediated induction of host immune responses in dendritic cells (DCs) and then generated a lymph node-targeted nanovaccine that co-delivered hepatitis B surface antigen (HBsAg) and cyclic diguanylate monophospha

Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors.

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO2)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (mPEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesi…

Inhibition of cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury.

Acute glaucoma is a vision-threatening disease characterized by a sudden elevation in intraocular pressure (IOP), followed by retinal ganglion cell (RGC) death. Cytosolic double-stranded DNA (dsDNA)-a damage-associated molecular pattern (DAMP) that triggers inflammation and immune responses-has been implicated in the pathogenesis of IOP-induced RGC death, but the underlying mechanism is not entirely clear. In this study, we investigated the effect of the inflammatory cascade on dsDNA recognition and examined the neuroprotective effect of the cyclic GMP-AMP (cGAMP) synthase (cGAS) antagonist A1…

Borrelia burgdorferi Engages Mammalian Type I IFN Responses via the cGAS-STING Pathway.

Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multisy … ure, and we document that internalized spirochetes colocalize with the pattern recognition receptor cyclic GMP-AMP synthase (cGAS). Moreover, we report that IFN-I responses in mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence of cGAS or its adaptor stimulator of IFN genes (STING), which function to sense and respo …

The STING pathway: Therapeutic vulnerabilities in ovarian cancer.

Ovarian cancer is the leading cause of mortality due to gynecologic malignancy. The majority of women diagnosed with the most common subtype … option. Of the several type I interferon (IFN-1) stimulating therapies, exogenously activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is emerging as a promising avenue. Herein, we highlight our current understanding of how constitutive and induced cGAS-STING pathway activation influences the ovarian tumour microenvir …

Inhibition of cGAS in Paraventricular Nucleus Attenuates Hypertensive Heart Injury Via Regulating Microglial Autophagy.

Neuroinflammation in the cardiovascular center plays a critical role in the progression of hypertensive heart disease. And microglial autophagy is involved in the regulation of neuroinflammation. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, senses mitochondrial DNA (mtDNA) and regulates autophagy. The detailed mechanisms of central cGAS affects neuroinflammatory response in hypertensive heart disease via regulating autophagy remain unknown. Angiotensin II (Ang II, 1.5 mg·kg-1·12 h-1, 2 weeks) was intraperitoneally injected to induce hypertension in mice. The cGAS-STING pathway was a…

High glucose-induced ROS accumulation is a critical regulator of ERK1/2-Akt-tuberin-mTOR signalling in RGC-5 cells.

Hyperglycemia and oxidative stress are the primary stressors that elicit mitochondria specific cell stress in diabetes. Here we hypothesized … ion. Furthermore, fragmented mtDNA escape from mitochondria into the cytosol, where it engaged with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN gene (STING) phosphorylation and activate interferon regulatory factor 3 (IRF3) via ERK1/2-Akt-tuberin-mTOR dependent pathways. Our results further indicate that siRNA-mediated gene silencing of tuberin supp …

Inhibition of mTOR suppresses IFNα production and the STING pathway in monocytes from systemic lupus erythematosus patients.

OBJECTIVE: Increased IFNα is important in the pathogenesis of SLE. Plasmacytoid dendritic cells are considered the main producer of IFNα upon Toll-like receptor pathway activation. However, which cells produce IFNα following stimulation with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) in SLE remains unknown. We investigated the IFNα producing capacity of myeloid cells under cGAS-STING pathway stimulation. METHODS: IFNα levels in peripheral blood mononuclear cells from SLE patients and healthy controls stimulated with 2'3'c-GAMP, a stimulator of cGAS-STING, were measured…