Shuangdan Jiedu Decoction improved LPS-induced acute lung injury by regulating both cGAS-STING pathway and inflammasome.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.

Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms. MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1G93A NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway. RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1ß mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-ß mRNA, but also the levels of cGAS and STING protein in hSOD1G93A NSC-34 cells. CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.

DNA PAMPs as Molecular Tools for the cGAS-STING Signaling Pathways.

Beyond its role as the bearer of genetic material, DNA also plays a crucial role in the activation phase of innate immunity. Pathogen recognition receptors (PRRs) and their homologs, pathogen-associated molecular patterns (PAMPs), form the foundation for driving innate immune activation and the induction of immune responses during infection. In the context of DNA viruses or bacterial infections, specific DNA sequences are recognized and bound by DNA sensors, marking the DNA as a PAMP for host recognition and subsequent activation of innate immunity. The primary DNA sensor pathway known to date is cGAS-STING, which can induce Type I interferons (IFN) and innate immune responses against viruses and bacteria. Additionally, the cGAS-STING pathway has been identified to mediate functions in autophagy and senescence. Herein, we introduce methods for using DNA PAMPs as molecular tools to study the role of cGAS-STING and its signaling pathway in regulating innate immunity, both in vitro and in vivo.

cGAS regulates metabolic reprogramming independently of STING pathway in colorectal cancer.

BACKGROUND: Cyclic GMP-AMP synthase (cGAS) is widely acknowledged for detecting cytosolic chromatin fragments and triggering innate immune responses through the production of the second messenger cGAMP, which subsequently activates the adaptor protein STING. However, the role of cGAS in regulating metabolic reprogramming independently of STING activation has not yet been explored. METHODS: Gene set enrichment pathway analysis (GSEA) based on TCGA transcriptomics, combined with Seahorse metabolic analysis of CRC cell lines and human normal colonic mucosa cell line FHC, was performed to profile the metabolic features in CRC. cGAS doxycycline- (dox) inducible knockout (iKO) CRC sublines were generated to investigate the role of cGAS in CRC. Transcriptome and proteome data from COAD cohorts were utilized to evaluate the RNA and protein expression levels of cGAS in COAD tissues and normal colon tissues. Overall survival information of patients with COAD was used to evaluate the prognostic value of cGAS expression. Colony formation assays were conducted to evaluate the clonogenicity of CRC cells under different situations. Flow cytometry detecting the signal of fluorogenic reactive oxygen species (ROS) probes was performed to evaluate the total cellular and mitochondrial oxidative stress level in CRC cells. A propidium iodide (PI) staining assay was used to evaluate the cell death level in CRC cells. Quantitative PCR (qPCR) was conducted to detect the RNA level of STING pathway downstream target genes. Mass spectrometry was used for the identification of novel binding partners of cGAS in CRC cells. Co-immunoprecipitation (co-IP) was conducted to confirm the interaction between cGAS and NDUFA4L2. RESULTS: By integrating metabolic pathway analysis based on TCGA transcriptomics with Seahorse metabolic analysis of a panel CRC cell lines and the human normal colonic mucosa cell line FHC, we demonstrated that CRC cells exhibit typical characteristics of metabolic reprogramming, characterized by a shift from oxidative phosphorylation (OXPHOS) to glycolysis. We found that cGAS is critical for CRC cells to maintain this metabolic switch. Specifically, the suppression of cGAS through siRNA-mediated knockdown or doxycycline-inducible knockout reversed this metabolic switch, resulting in increased OXPHOS activity, elevated production of OXPHOS byproduct reactive oxygen species (ROS), and consequently caused oxidative stress. This disruption induced oxidative stress, ultimately resulting in cell death and reduced cell viability. Moreover, significant upregulation of cGAS in CRC tissues and cell lines and its association with poor prognosis in CRC patients was observed. Subsequently, we demonstrated that the role of cGAS in regulating metabolic reprogramming does not rely on the canonical cGAS-STING pathway. Co-immunoprecipitation combined with mass spectrometry identified NDUFA4L2 as a novel interactor of cGAS. Subsequent functional experiments, including mitochondrial respiration and oxidative stress assays, demonstrated that cGAS plays a crucial role in sustaining elevated levels of NDUFA4L2 protein expression. The increased expression of NDUFA4L2 is essential for cGAS-mediated regulation of metabolic reprogramming and cell survival in CRC cells. CONCLUSION: cGAS regulates metabolic reprogramming and promotes cell survival in CRC cells through its interaction with NDUFA4L2, independently of the canonical cGAS-STING pathway.

A Single-Atom Mn/MoO3- x Nanoagonist for Cascade cGAS/STING Activation in Tumor-Specific Catalytic Metalloimmunotherapy.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway plays a crucial role in initiating anti-tumor immunity. Despite the development of various STING agonists, their effectiveness is often limited by suboptimal activation efficiency and poor sustainability. To address this, a Mn/MoO3- x nanoagonist featuring Mn single-atom sites is presented, designed for cascade cGAS/STING activation in tumor-specific catalytic metalloimmunotherapy. The single-atom nanoagonist (SANA) is meticulously crafted by doping Mn atoms into defective molybdenum oxide (MoO3- x), enabling robust peroxidase-mimicking catalysis and inducing severe double-stranded DNA (dsDNA) damage in tumors. Of note, Mn2+ and MoO4 2- can be responsively released from Mn/MoO3- x SANA and enhance the sensitivity of cGAS to dsDNA. Importantly, MoO4 2- with a relatively slow-release profile and facile cellular accumulation compensates for Mn2+ that has poor cellular accumulation due to continuous efflux, thus continuatively triggering the secretion of type I interferon for beyond 72 h. Remarkably, Mn/MoO3- x SANA significantly inhibits tumor growth and metastasis without supplementary STING agonists or external stimulation. This study offers a promising cascade cGAS/STING activation approach to enhance the efficacy and sustainability of catalytic metalloimmunotherapy.

SUCNR 1 promotes atherosclerosis by inducing endoplasmic reticulum stress mediated ER-mito crosstalk.

Atherosclerosis is a progressive inflammatory disease within the large and medium arteries. SUCNR1(Succinate receptor 1) has been reported to regulate the inflammatory response in cardiovascular diseases, but how it works in atherosclerosis remains unclear. In this study, we observed that SUCNR1 is upregulated in endothelial cells within human atherosclerotic lesions. The deletion of SUCNR1 in vascular endothelial cells can mitigate the progression of atherosclerotic lesions in high-fat diet ApoE-/- mice. The overexpression or activation of SUCNR1 intensified endoplasmic reticulum stress and mitochondria-endoplasmic reticulum interactions. Moreover, SUCNR1 exacerbated mitochondrial injury, mtDNA leakage, and the activation of cGAS-STING signaling. Elevated mitochondrial damage, ER-mitochondrial interactions, and inflammation induced by SUCNR1 activation were blocked by the endoplasmic reticulum stress inhibitor. Collectively, these findings suggest that SUCNR1 promotes atherosclerosis through endoplasmic reticulum stress signaling mediated ER-mitochondrial crosstalk and its downstream cGAS-STING pathway. Our results provide new insights into the mechanism of SUCNR1 in atherosclerosis and inhibiting endoplasmic reticulum stress signaling may provide a promising strategy to prevent and treat atherosclerosis.

Naringenin loaded fucoidan/polyvinylpyrrolidone nanoparticles protect against folic acid induced acute kidney injury in vitro and in vivo.

Acute kidney injury (AKI) is a common clinical problem with no effective treatment. Excessive folic acid (FA) induced kidney tubular injury is characterized by oxidative stress and inflammation, and is a common model of AKI. The excellent pharmacological activity of naringenin (NAR) makes it a potential agent for treating AKI, but its poor solubility limits its application. This study prepared NAR loaded nanoparticles (FU/PVP-NAR) using fucoidan (FU) and polyvinylpyrrolidone (PVP) as carriers, with a particle size of 23.96 ± 2.77 nm. In vitro studies showed that FU/PVP-NAR inhibited excessive FA induced proliferation inhibition, accumulation of reactive oxygen species (ROS), and disruption of mitochondrial membrane potential (MMP) of HK-2 cells. Further confirmed that FU/PVP-NAR inhibited FA induced DNA damage and Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. In vivo studies showed that excessive FA induced AKI features in mice, such as elevated serum creatinine (SCr) and blood urea nitrogen (BUN) levels, accompanied by pathological damage to kidney tissues. The above AKI characteristics induced by FA were alleviated by FU/PVP-NAR. FU/PVP-NAR also inhibited the decrease in antioxidant enzyme levels in kidney tissues induced by FA. Furthermore, in vivo mechanism studies indicated that FU/PVP-NAR inhibited the release of inflammatory factors by inhibiting DNA damage-cGAS-STING pathway. In summary, this study provided the possibility for FU/PVP-NAR as a potential candidate drug for treating FA induced AKI.

Overexpression of FBP1 enhances dendritic cell activation and maturation by inhibiting glycolysis and promoting the secretion of IL33 in lung adenocarcinoma.

Fructose 1,6-diphosphatase 1 (FBP1) is an enzyme involved in gluconeogenesis and glycolysis inhibition. Dendritic cells (DCs) are antigen-presenting cells, and antigens presented to T cells activate the immune response. FBP1 inhibits the development of several tumors, and high FBP1 expression inhibits the proliferation, migration, and invasion of lung cancer cells. However, the mechanism through which FBP1 mediates the tumor immune microenvironment is unclear. This study mainly analyzed the role of FBP1 in regulating the function of DCs through metabolic reprogramming and immune microenvironment using in vitro and in vivo experiments. The positive association of FBP1 with DCs was found by bioinformatic analysis. The in vitro experiments revealed that the extracellular acidification rate and lactate level were lower in the FBP1 overexpression cells than in the control cells and that the lower lactate level reduced the inhibition of DC function. In addition, high FBP1 expression promoted the secretion of IL33 by activating the cGAS/STING/NF-κB/IL33 pathway, which was identified and verified via high-throughput sequencing and in vitro experiments. FBP1 activated the cGAS/STING pathway by increasing the degree of DNA damage, as revealed by the level of γH2AX and comet assay. IL33 enhanced the expression of the DC costimulatory molecules CD86 and HLA-DR as well as that of the functional factor IL-1ß. The results demonstrated that FBP1 promoted the activation and maturation of DCs by inhibiting glycolysis and promoting the secretion of IL33 as well as by further activating the function of CD8+T cells. Finally, the humanized immune system mouse models confirmed the above role of FBP1. Thus, FBP1 may serve as a new target to cure lung adenocarcinoma, and IL33 may improve the efficiency of immune therapy in lung adenocarcinoma.

TBPH-induced lung injury is induced by mitochondrial-derived ds-DNA-mediated inflammatory response.

Due to the ban on the use of traditional brominated flame retardants, new brominated flame retardants, such as Bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), have been developed as alternatives to traditional brominated flame retardants to replace the old ones, and TBPH has been widely used. Therefore, we need to systematically evaluate the toxicological effects of TBPH. In the current work, we analyzed the effects of TBPH on lung. In vivo model, we found that TBPH treatment caused damage to lung tissues through H&E staining, immunohistochemistry, and western-blot analysis. Furthermore, in vitro model, our study found that TBPH treatment led to a decrease in the proliferative capacity of lung cells. Furthermore, TBPH treatment led to inflammatory responses and oxidative stress in lung cells. Molecular mechanism studies showed that under exposure to TBPH, the biological function of mitochondria was disrupted, leading to the release of endogenous ds-DNA from mitochondria into the cytosol. This released ds-DNA acts as a danger signal molecule, effectively activating the cGAS-STING signaling pathway and subsequent inflammatory responses. Further research showed that the disruption of mitochondrial homeostasis by TBPH is closely related to lung injury. The current research findings not only enrich our understanding of the potential toxicological effects of new brominated flame retardants as environmental pollutants, but also provide a research foundation for further understanding TBPH toxicology.

The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.

Oxygen self-supplying nanoradiosensitizer activates cGAS-STING pathway to enhance radioimmunotherapy of triple negative breast cancer.

Radiotherapy (RT)-mediated immune activation is insufficient for effective therapy of triple-negative breast cancer (TNBC) due to the immunosuppressive tumor microenvironment. Herein, we developed an oxygen self-supplying nanoradiosensitizer to activate immunogenic cell death (ICD) and the cGAS-STING signaling pathway, elevating the anti-tumor immune response and improving radioimmunotherapy for TNBC. The nanoradiosensitizer was fabricated using astragaloside liposome-encapsulated FePt alloy and MnO nanocrystals (ALFM). The ALFM targeted the glucose transporter-1 (GLUT-1) receptor in TNBC and effectively entered tumor cells. Subsequently, the ALFM responded to the weakly acidic tumor microenvironment and degraded, releasing FePt and Mn2+ ions. The released Mn2+ ions not only elevated cellular ROS levels via a Fenton-like reaction but also activated the cGAS-STING signaling pathway, which stimulated the anti-tumor immune response. In addition, the FePt alloy catalyzed a cascade reaction, producing ROS and O2 in tumor cells, alleviating tumor hypoxia, and enhancing the RT effect. Besides, ROS-mediated cell damage induced the ICD effect in TNBC, promoted dendritic cell maturation and the infiltration of cytotoxic T lymphocytes, ultimately eliciting cancer immunotherapy. In vivo experimental results demonstrated that ALFM effectively activated the antitumor immune response and improved the radioimmunotherapy effect for TNBC. Overall, this work presents an effective strategy for enhanced radioimmunotherapy of TNBC. Subsequently, the ALFM responded to weak acidic tumor microenvironment, and then degraded along with the release of FePt and Mn2+ ions. The released Mn2+ ions not only elevated cellular ROS level via Fenton-like reaction, but also activated cGAS-STING signal pathway, which activated anti-tumor immune response. In addition, FePt alloy catalyzed cascade reaction and then produced ROS and O2 in tumor cells, relieving tumor hypoxia and enhancing RT effect. Besides, ROS-mediated cell damage induced ICD effect of TNBC, promoted dendritic cells maturation and the infiltration of cytotoxic T lymphocytes, eventually elicited antitumor immunotherapy. In vivo experimental results demonstrated that ALFM effectively activated antitumor immune response, improved radioimmunotherapy effect of TNBC. Overall, this work provided a complete new strategy for enhanced radioimmunotherapy of TNBC.

DKN-01 Suppresses Gastric Cancer Progression Through Activating cGAS-STING Pathway to Block Macrophage M2 Polarization.

Dickkopf-1 (DKK1) is a secretory antagonist that can bind with the Wnt coreceptor to desensitize cells to canonical Wnt ligands. DKN-01 is a specific antibody targeting secreted DKK1, which has been investigated as a monotherapy or combination therapy for various malignant tumors, including gastric cancer (GC). Tumor-associated macrophages (TAMs) with high plasticity usually present M2 phenotype, which can promote tumor progression. The aim of this study was to investigate the effect of DKN-01 on macrophage polarization in GC and the underlying molecular mechanism. To ascertain the effect of DKN-01 on GC tumor growth, we established a tumor-bearing mouse model and found that DKN-01 treatment suppressed tumor growth efficiently. Through RNA-seq and pathway enrichment analysis, we identified that the differentially expressed genes after DKN-01 treatment are associated with tumor immune-related pathways. Macrophage polarization was assessed using immunohistochemistry and quantitative real-time polymerase chain reaction. DKN-01 and knockdown of DKK1 promoted M1 polarization and inhibited M2 polarization of macrophages, while DKK1 overexpression got the opposite results. Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization.

Dual-tDCS Ameliorates Cerebral Injury and Promotes Motor Function Recovery via cGAS-STING Signaling Pathway in a Rat Model of Ischemic Stroke.

Ischemic stroke is one of the leading causes of death and disability. Dual transcranial direct current stimulation (dual-tDCS) is a promising intervention to treat ischemic stroke, but its efficacy and underlying mechanism remain to be verified. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has recently emerged as a key mediator in cerebral injury. However, little is known about the effect of cGAS-STING on neuronal damage in ischemic stroke, and it remains to be studied whether the cGAS-STING pathway is involved in tDCS intervention for ischemic stroke. Therefore, we aimed to investigate whether dual-tDCS can alleviate ischemic brain injury in a rat model of ischemic stroke and if so, whether via cGAS-STING pathway. Middle cerebral artery occlusion (MCAO) was employed to induce a rat model of ischemic stroke. Male SD rats weighing 250-280 g were randomly assigned to the Sham, MCAO, Dual-tDCS, Dual-tDCS + RU.521, and Dual-tDCS + 2'3'-cGAMP groups, with 10 rats in each group completing the experiment. Behavioral, morphological, MRI, and molecular biological methods were performed. We found that the cGAS-STING pathway was activated and expressed in neurons after MCAO. Dual-tDCS improved motor function and infarct volume, inhibited neuronal apoptosis, promoted the expression of neurotrophins (BDNF and NGF), CD31, and VEGF, and suppressed inflammation reaction after MCAO via the cGAS-STING pathway. Taken together, dual-tDCS may improve MCAO-induced brain injury and promote the recovery of motor function, resulting from the inhibition of neuronal apoptosis and inflammation reaction, as well as promotion of the expression of nerve plasticity- and angiogenesis-related proteins, via cGAS-STING pathway.

Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy.

Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.

Recent advancements in cGAS-STING activation, tumor immune evasion, and therapeutic implications.

The cGAS-STING signaling pathway is indeed a pivotal component of the immune system and serve as a crucial link between innate and adaptive immune responses. STING is involved in the cellular response to pathogen invasion and DNA damage, and which has important consequences for host defense mechanisms and cancer regulation. Ongoing research aiming to modulate the cGAS-STING pathway for improved clinical outcomes in cancer and autoimmune diseases is underway. Indeed, the interaction between the cGAS-STING pathway and immune evasion mechanisms is a complex and critical aspect of cancer biology. Pathogens and various host factors can exploit this pathway to reduce the effectiveness of cancer therapies, particularly immunotherapies. Thus, immunotherapies or combination therapies may assist in overcoming the immune suppression and improving clinical outcomes. This review explores recent advancements in understanding the cGAS-STING signaling pathway, with particular emphasis on its activation mechanisms and role in tumor immune evasion. The dual role of the pathway in boosting immune responses while simultaneously enabling tumors to evade the immune system makes it a crucial target for innovative cancer treatment approaches.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 2 Given name: [Md Mazedul] Last name [Islam], Author 3 Given name: [Mst Rubaiat Nazneen] Last name [Akhand] and Author 5 Given name: [Md Rashedunnabi] Last name [Akanda]. Also, kindly confirm the details in the metadata are correct.AQ1: Here Author 4 given name: [Byung-Yong] Last name [Park] is missing. Metadata are correct.

Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects.

The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant to traditional therapies. This scholarly review examines the diverse categories of STING agonists, encompassing CDN analogues, non-CDN chemotypes, CDN-infused exosomes, engineered bacterial vectors, and hybrid structures of small molecules-nucleic acids. We highlight their mechanisms, clinical trial progress, and therapeutic outcomes. While these agents offer significant promise, challenges such as toxicity, tumor heterogeneity, and delivery methods remain obstacles to their broader clinical use. Ongoing research and innovation are essential to overcoming these hurdles. STING agonists could play a transformative role in cancer treatment, particularly for patients with hard-to-treat malignancies, by harnessing the body's immune system to target and eliminate cancer cells.

Age-associated changes in innate and adaptive immunity: role of the gut microbiota.

Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.

The Role of STING-Mediated Activation of Dendritic Cells in Cancer Immunotherapy.

The signaling pathway that comprises cyclic guanosine monophosphate-adenosine monophosphate (cGAMP or GMP-AMP) synthase (cGAS) and Stimulator of Interferon Genes (STING) is emerging as a druggable target for immunotherapy, with tumor-resident dendritic cells (DC) playing a critical role in mediating its effects. The STING receptor is part of the DNA-sensing cellular machinery, that can trigger the secretion of pro-inflammatory mediators, priming effector T cells and initiating specific antitumor responses. Yet, recent studies have highlighted the dual role of STING activation in the context of cancer: STING can either promote antitumor responses or enhance tumor progression. This dichotomy often depends on the cell type in which cGAS-STING signaling is induced and the activation mode, namely acute versus chronic. Of note, STING activation at the DC level appears to be particularly important for tumor eradication. This review outlines the contribution of the different conventional and plasmacytoid DC subsets and describes the mechanisms underlying STING-mediated activation of DCs in cancer. We further highlight how the STING pathway plays an intricate role in modulating the function of DCs embedded in tumor tissue. Additionally, we discuss the strategies being employed to harness STING activation for cancer treatment, such as the development of synthetic agonists and nano-based delivery systems, spotlighting the current techniques used to prompt STING engagement specifically in DCs.

Bidirectional regulation of the cGAS-STING pathway in the immunosuppressive tumor microenvironment and its association with immunotherapy.

Adaptive anti-tumor immunity is currently dependent on the natural immune system of the body. The emergence of tumor immunotherapy has improved prognosis and prolonged the survival cycle of patients. Current mainstream immunotherapies, including immune checkpoint blockade, chimeric antigen receptor T-cell immunotherapy, and monoclonal antibody therapy, are linked to natural immunity. The cGAS-STING pathway is an important natural immunity signaling pathway that plays an important role in fighting against the invasion of foreign pathogens and maintaining the homeostasis of the organism. Increasing evidence suggests that the cGAS-STING pathway plays a key role in tumor immunity, and the combination of STING-related agonists can significantly enhance the efficacy of immunotherapy and reduce the emergence of immunotherapeutic resistance. However, the cGAS-STING pathway is a double-edged sword, and its activation can enhance anti-tumor immunity and immunosuppression. Immunosuppressive cells, including M2 macrophages, MDSC, and regulatory T cells, in the tumor microenvironment play a crucial role in tumor escape, thereby affecting the immunotherapy effect. The cGAS-STING signaling pathway can bi-directionally regulate this group of immunosuppressive cells, and targeting this pathway can affect the function of immunosuppressive cells, providing new ideas for immunotherapy. In this study, we summarize the activation pathway of the cGAS-STING pathway and its immunological function and elaborate on the key role of this pathway in immune escape mediated by the tumor immunosuppressive microenvironment. Finally, we summarize the mainstream immunotherapeutic approaches related to this pathway and explore ways to improve them, thereby providing guidelines for further clinical services.

Toxoplasma gondii ROP5 Enhances Type I IFN Responses by Promoting Ubiquitination of STING.

Toxoplasma gondii is a widely spread opportunistic pathogen that can infect nearly all warm-blooded vertebrates and cause serious toxoplasmosis in immunosuppressed animals and patients. However, the relationship between the host's innate immune system and effector proteins is poorly understood, particularly with regard to how effectors antagonize cGAS-STING signaling during T. gondii infection. In this study, the ROP5 from the PRU strain of T. gondii was found to promote cGAS-STING-mediated immune responses. Mechanistically, ROP5 interacted with STING through predicted domain 2 and modulated cGAS-STING signaling in a predicted domain 3-dependent manner. Additionally, ROP5 strengthened cGAS-STING signaling by enhancing the K63-linked ubiquitination of STING. Consistently, ROP5 deficient PRU (PRUΔROP5) induced fewer type I IFN-related immune responses and replicated faster than the parental strain in RAW264.7 cells. Taken together, this study provides new insights into the mechanism by which ROP5 regulates T. gondii infection and provides new clues for strategies to prevent and control toxoplasmosis.