Environmentally responsive hydrogel promotes vascular normalization to enhance STING anti-tumor immunity.

The immunosuppressive microenvironment of malignant tumors severely hampers the effectiveness of anti-tumor therapy. Moreover, abnormal tumor vasculature interacts with immune cells, forming a vicious cycle that further interferes with anti-tumor immunity and promotes tumor progression. Our pre-basic found excellent anti-tumor effects of c-di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy. We chose to load these two drugs on PVA-TSPBA hydrogel scaffolds that expressly release drugs within the tumor microenvironment by in situ injection. Studies have shown that c-di-AMP activates the STING pathway, enhances immune cell infiltration, and reverses tumor immunosuppression. Meanwhile, RRx-001 releases nitric oxide, which increases oxidative stress injury in tumor cells and promotes apoptosis. Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy.

A phytomedicine extract exerts an anti-inflammatory response in the lungs by reducing STING-mediated type I interferon release.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an acute respiratory disease characterized by bilateral chest radiolucency and severe hypoxemia. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE), which is prepared from the traditional Chinese respiratory anti-inflammatory natural herb Quzhou Fructus Arantii, has the potential to alleviate ARDS. In this work, we aimed to investigate the potential and mechanism underlying the action of QFAEE on ARDS and how QFAEE modulates the STING pathway to reduce type I interferon release to alleviate the inflammatory response. METHODS: Lipopolysaccharide (LPS), a potential proinflammatory stimulant capable of causing pulmonary inflammation with edema after nasal drops, was employed to model ARDS in vitro and in vivo. Under QFAEE intervention, the mechanism of action of QFAEE to alleviate ARDS was explored in this study. TREX1-/- mice were sued as a research model for the activation of the congenital STING signaling pathway. The effect of QFAEE on TREX1-/- mice could explain the STING-targeted effect of QFAEE on alleviating the inflammatory response. Our explorations covered several techniques, Western blot, histological assays, immunofluorescence staining, transcriptomic assays and qRT-PCR to determine the potential mechanism of action of QFAEE in antagonizing the inflammatory response in the lungs, as well as the mechanism of action of QFAEE in targeting the STING signaling pathway to regulate the release of type I interferon. RESULTS: QFAEE effectively alleviates ARDS symptoms in LPS-induced ARDS. We revealed that the mechanism underlying LPS-induced ARDS is the STING-TBK1 signaling pathway and further elucidated the molecular mechanism of QFAEE in the prevention and treatment of ARDS. QFAEE reduced the release of type I interferons by inhibiting the STING-TBK1-IRF3 axis, thus alleviating LPS-induced pneumonia and lung cell death in mice. Another key finding is that activation of the STING pathway by activators or targeted knockdown of the TREX1 gene can also induce ARDS. As expected, QFAEE was found to be an effective protective agent in alleviating ARDS and the antagonistic effect of QFAEE on ARDS was achieved by inhibiting the STING signaling pathway. CONCLUSIONS: The main anti-inflammatory effect of QFAEE was achieved by inhibiting the STING signaling pathway and reducing the release of type I interferons. According to this mechanism of effect, QFAEE can effectively alleviate ARDS and can be considered a potential therapeutic agent. In addition, the STING pathway plays an essential role in the development and progression of ARDS, and it is a potential target for ARDS therapy.

Phase separation as a new form of regulation in innate immunity.

Innate immunity is essential for the host against pathogens, cancer, and autoimmunity. The innate immune system encodes many sensor, adaptor, and effector proteins and relies on the assembly of higher-order signaling complexes to activate immune defense. Recent evidence demonstrates that many of the core complexes involved in innate immunity are organized as liquid-like condensates through a mechanism known as phase separation. Here, we discuss phase-separated condensates and their diverse functions. We compare the biochemical, structural, and mechanistic details of solid and liquid-like assemblies to explore the role of phase separation in innate immunity. We summarize the emerging evidence for the hypothesis that phase separation is a conserved mechanism that controls immune responses across the tree of life. The discovery of phase separation in innate immunity provides a new foundation to explain the rules that govern immune system activation and will enable the development of therapeutics to treat immune-related diseases properly.

Glucagon-like peptide-1 receptor agonists rescued diabetic vascular endothelial damage through suppression of aberrant STING signaling.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases.

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.

Mitochondria-Regulated Information Processing Nanosystem Promoting Immune Cell Communication for Liver Fibrosis Regression.

Liver fibrosis is a coordinated response to tissue injury that is mediated by immune cell interactions. A mitochondria-regulated information-processing (MIP) nanosystem that promotes immune cell communication and interactions to inhibit liver fibrosis is designed. The MIP nanosystem mimics the alkaline amino acid domain of mitochondrial precursor proteins, providing precise targeting of the mitochondria. The MIP nanosystem is driven by light to modulate the mitochondria of hepatic stellate cells, resulting in the release of mitochondrial DNA into the fibrotic microenvironment, as detected by macrophages. By activating the STING signaling pathway, the developed nanosystem-induced macrophage phenotype switches to a reparative subtype (Ly6Clow) and downstream immunostimulatory transcriptional activity, fully restoring the fibrotic liver to its normal tissue state. The MIP nanosystem serves as an advanced information transfer system, allowing precise regulation of trained immunity, and offers a promising approach for effective liver fibrosis immunotherapy with the potential for clinical translation.

Exogenous non-coding dsDNA-dependent trans-activation of phagocytes augments anti-tumor immunity.

Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway. We observe that rHSVs expressing STING and/or cGAS replicate inefficiently yet retain in vivo anti-tumor activity, independent of oncolytic activity requisite on the trans-activation of extrinsic STING signaling in phagocytes by engulfed microbial dsDNA species. Accordingly, the in vivo effects of virotherapy could be simulated by nanoparticles incorporating non-coding dsDNA species, which comparably elicit the trans-activation of phagocytes and augment the efficacy of established cancer treatments including checkpoint inhibition and radiation therapy. Our results help elucidate mechanisms of virotherapeutic anti-tumor activity as well as provide alternate strategies to treat cancer.

The cGAS/STING signaling pathway is involved in sevoflurane induced neuronal necroptosis via regulating microglia M1 polarization.

OBJECTIVE: The specific mechanisms of sevoflurane-induced neurotoxicity are still undetermined. The aim of the current study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in sevoflurane-induced neuronal necroptosis. METHODS: BV2 microglial cells were divided into a control group and a 4% sevoflurane exposure group. Western blotting was used to detect expression of the M1 polarization marker inducible nitric oxide synthase (iNOS). RNA was collected for RNA sequencing analysis. After STING knockdown in microglia, western blotting was performed to examine expression of the pro-inflammatory markers CD16 and CD32. The tumor necrosis factor-α (TNF-α) level in media was detected using an enzyme-linked immunosorbent assay. BV2 microglia conditioned media was collected to incubate HT22 neuronal cells, and their cell activity was measured using a CCK8 assay. Calcium was observed by fluorescence. Western blotting was performed to evaluate receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) expression. Neuronal necroptosis rate were detected using flow cytometry. RESULTS: Sevoflurane exposure promoted microglial M1 polarization. The cGAS/STING pathway was screened and identified by RNA sequencing analysis of sevoflurane-exposed microglia and the control group. Compared with the control group, STING knockdown in microglia rescued the amoeboid morphology, inhibited TNF-α release, and significantly decreased iNOS, CD16, and CD32 expression. Moreover, calcium ions and necroptosis within neurons were decreased, and RIPK1, RIPK3, and p-MLKL expression was markedly decreased in microglia media culture with STING knockdown. CONCLUSION: These results suggest that sevoflurane can regulate microglial M1 polarization by activating the cGAS/STING signaling pathway and increasing immune factor release, thus accelerating the neuronal necroptosis induced by calcium overload.

Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.

The interplay between autophagy and cGAS-STING signaling and its implications for cancer.

Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.

mtDNA regulates cGAS-STING signaling pathway in adenomyosis.

In various hyperproliferative disorders, damaged mitochondria can release mitochondrial DNA (mtDNA) into the cytoplasm, activating the cGAS-STING signaling pathway and subsequent immune imbalances. Our previous research has demonstrated that hypoxia plays a role in the development of adenomyosis (AM) by inducing mitochondrial dysfunction. However, the precise involvement of the cGAS-STING signaling pathway and mtDNA in AM remains unclear. Therefore, this study aims to investigate the relationship between mtDNA secretion, changes in the cGAS-STING signaling pathway, and the abnormal cellular proliferation observed in AM. We found the cGAS, STING, TBK1, p-TBK1, IRF3, and p-IRF3 proteins levels were significantly elevated in the tissues of patients with AM compared to the control group. Additionally, there was an increase in the expression of the pro-inflammatory cytokines IL-6 and IFN-α in the AM tissues. Hypoxia-induced an increase in the proliferation and migration abilities of endometrial stromal cells (ESCs), accompanied by the activation of the cGAS-STING signaling pathway and elevated levels of IFN-α. Furthermore, hypoxia promoted the leakage of mtDNA into the cytoplasm in AM ESCs, and the deletion of mtDNA reduced the activation of the cGAS-STING pathway. Moreover, knockdown of the STING gene inhibited the expression of TBK1, p-TBK1, IRF3, and p-IRF3 and suppressed the secretion of the inflammatory cytokines IL-6 and IFN-α. Furthermore, the migration and invasion abilities of AM ESCs were significantly diminished after STING knockdown. These findings provide valuable insights into the role of mtDNA release and the cGAS-STING signaling pathway in the pathogenesis of AM.

Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling.

To evade immune surveillance, tumor cells express ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) on the surface of their membrane, which degrades extracellular cyclic GMP-AMP (cGAMP), thereby inhibiting the cyclic GMP-AMP synthase (cGAS) stimulator of interferon gene (STING) DNA-sensing pathway. To fully understand this tumor stealth mechanism, it is essential to determine whether other forms of ENPP1 with hydrolytic cGAMP activity also are present in the tumor microenvironment to regulate this innate immune pathway. Herein, it is reported that various tumor-derived exosomes carry ENPP1, and can hydrolyze synthetic 2'3'-cGAMP and endogenous 2'3'-cGAMP produced by cells to inhibit cGAS-STING pathway in immune cells. Moreover, tumor exosomal ENPP1 also can hydrolyze 2'3'-cGAMP bound to LL-37 (an effective transporter of 2'3'-cGAMP) to inhibit STING signaling. Furthermore, high expression of ENPP1 in exosomes is observed isolated from human breast and lung cancer tissue, and tumor exosomal ENPP1 inhibited the immune infiltration of CD8+ T cells and CD4+ T cells. The results elucidate the essential function of tumor exosomal ENPP1 in the cGAS-STING pathway, furthering understanding of the crosstalk between the tumor cells and immune system.

Interleukin-1ß promotes human metapneumovirus replication via activating the cGAS-STING pathway.

BACKGROUND: Human metapneumovirus(hMPV) is one of the most common viruses that cause acute lower respiratory tract infections. Interleukin-1ß (IL-1ß) has been reported to play an important role in multiple virus replication. Patients with hMPV infection have increased levels of IL-1ß which reminds IL-1ß is associated with hMPV infection. However, the mechanism by which IL-1ß affects hMPV replication remains unclear. In this study, we explore the effect of IL-1ß on hMPV replication and investigate its specific mechanism of action. METHODS: We established an hMPV infection model through Human bronchial epithelial cells (16HBE). qRT-PCR and Western Blot were used to detect the expression levels of IL-1ß, cyclic GMP-AMP synthase (cGAS), and interferon stimulating factor (STING). Regulating IL-1ß expression by small interfering RNA (siRNA) or exogenous supplementary to study the influence of hMPV replication. The selective cGAS inhibitor RU.521, G150, and STING inhibitor H-151 were utilized to detect hMPV replication in 16HBE cells. RESULTS: The level of IL-1ß protein increased in a time-dependent and dose-dependent manner after hMPV infection. The mRNA and protein levels of cGAS and STING were significantly up-regulated. Knockdown of IL-1ß could contribute to the decreased viral loads of hMPV. While the exogenous supplement of recombinant human IL-1ß in cells, replication of hMPV was significantly increased. Additionally, the level of cGAS-STING protein expression would be affected by regulating IL-1ß expression. Inhibitors of the cGAS-STING pathway led to a lower level of hMPV replication. CONCLUSION: This study found that IL-1ß could promote hMPV replication through the cGAS-STING pathway, which has the potential to serve as a candidate to fight against hMPV infection, targeting IL-1ß may be an effective new strategy to restrain virus replication.

Effect of Application of Autologous Conditioned Serum on Wound Healing in Diabetic Mice Through Inhibition of STING Pathway Activation.

Slow wound healing in diabetic patients is a common complication of diabetes. Autologous conditioned serum (ACS) therapy is an emerging and safe biological therapy, and may accelerate the wound healing in diabetes. To investigate the effect of ACS in promoting wound healing in diabetic mice and its possible mechanism. Twenty-four six-week-old male C57BL/6 J mice were selected and divided into 5 groups, including control group (Ctrl), diabetic wound group (DW), ACS treatment group (DW+ACS) and STING pathway validation group (DW+ACS+DMXAA), with six mice in each group. Intervention was initiated after the back incision was performed, and wound healing was assessed on day 0, day 7, and day 14, and wound healing was assessed by hematoxylin and eosin (HE) staining of skin tissue on day 14. At the same time, the wound healing of the fibroblast markers collagen I and α-SMA was measured by immunohistochemistry and western blot. ACS treatment significantly accelerated the diabetic wound according to the wound area and HE staining results. Meanwhile, collagen I and α-SMA concentration evaluated by immunohistochemistry and western blot were remarkably elevated under the ACS interference. The STING signaling pathway was obviously activated in diabetic wound tissues. After the addition of DMXAA, an agonist of STING, the healing function of ACS was dramatically reversed. The application of ACS promotes wound healing in diabetic mice by enhancing fibroblasts. Meanwhile, the STING signaling pathway was inactivated by ACS interference. Hence, ACS can be used in the treatment of wound healing of Diabetes.

Perillaldehyde ameliorates lipopolysaccharide-induced acute lung injury via suppressing the cGAS/STING signaling pathway.

Acute lung injury (ALI) is a common life-threatening illness characterized by a lung inflammatory response and oxidative stress, and effective agent therapies are currently lacking. mtDNA can be recognized by cGAS/STING, the dysregulation of which leads to inflammatory diseases, such as ALI. Perillaldehyde(PAH), one of the major active components of traditional Chinese medicine made from Perilla frutescens, has antioxidant and antiinflammatory effects. The aim of this study was to explore whether PAH can protect against lipopolysaccharide (LPS)-induced ALI and whether its protective effect is exerted through the regulation of cGAS/STING signaling. We found that PAH significantly inhibited lung histological changes, inflammatory cell infiltration, and the overproduction of inflammatory cytokines induced by LPS. Moreover, PAH inhibited LPS-induced oxidative stress, as shown by the deceases in superoxide dismutase (SOD) and glutathione(GSH) levels and increased in malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels. In addition, PAH markedly downregulated the expression of cGAS, STING, p-TBK, p-IRF3, p-P65, and p-IκB, and pharmacological inhibition of cGAS/STING inhibited ALI- induced by LPS. Furthermore, the levels of mitochondrial ROS (mROS) and mtDNA were increased, and cGAS/STING-mediated IRF3/NF-κB signaling was activated during the inflammatory response- induced by LPS in RAW264.7 cells. In addition, pretreatment with the STING activator partially abolished the inhibitory effect of PAH on the inflammation and activation of STING-mediated IRF3/NF-κB signaling induced by LPS. Overall, the results revealed that PAH can effectively alleviate ALI by inhibiting cGAS/STING-mediated IRF3/NF-κB signaling, and that PAH may be a potential candidate agent for the treatment of ALI.

African swine fever virus early protein pI73R suppresses the type-I IFN promoter activities.

African swine fever virus is known to suppress type-I interferon (IFN) responses. The main objective of this study was to screen early-expressed viral genes for their ability to suppress IFN production. Out of 16 early genes examined, I73R exhibited robust suppression of cGAS-STING-induced IFN-ß promoter activities, impeding the function of both IRF3 and NF-κB transcription factors. As a result, I73R obstructed IRF3 nuclear translocation following the treatment of cells with poly(dA:dT), a strong inducer of the cGAS-STING signaling pathway. Although the I73R protein exhibits structural homology with the Zα domain binding to the left-handed helical form of DNA known as Z-DNA, its ability to suppress cGAS-STING induction of IFN-ß was independent of Z-DNA binding activity. Instead, the α3 and ß1 domains of I73R played a significant role in suppressing cGAS-STING induction of IFN-ß. These findings offer insights into the protein's functions and support its role as a virulence factor.

Carbon ion irradiation exerts antitumor activity by inducing cGAS-STING activation and immune response in prostate cancer-bearing mice.

BACKGROUND AND PURPOSE: As an advanced radiotherapy technique, carbon ion radiotherapy has demonstrated good efficacy and low toxicity for prostate cancer patients, but the radiobiological mechanism of killing tumor cells has not been fully elucidated. This study aims to explore the antitumor effects of carbon ion irradiation (CIR) through investigating the immune response induced by CIR in prostate cancer-bearing mice and the underlying molecular mechanism. MATERIALS AND METHODS: We established subcutaneous transplantation tumor models of prostate cancer to evaluate the tumor inhibition effect of CIR. Investigation of immunophenotype alterations were assessed by flow cytometry. Immunofluorescence, western blot, and real-time quantitative PCR was employed to analyze the activation of cGAS-STING pathway. RESULTS: CIR showed more powerful tumor growth control than photon irradiation in immunocompetent syngeneic C57BL/6 mice. CIR exerts antitumor effect by triggering immune response, characterized by increased CD4+ T cells and macrophages in tumor, enhanced CD8+ T cells and T effector memory cells in spleen, improved IFN-γ production of CD8+ tumor-infiltrating lymphocytes, and reduced exhausted T cells in tumor and spleen. Additionally, production of cytoplasmic double-stranded DNA, protein levels of p-TBK1 and p-IRF3 in the cGAS-STING pathway, and gene expression levels of downstream interferon-stimulated genes were significantly increased after CIR in a dose-dependent manner. Treatment of RM1 tumor-bearing mice with the STING inhibitor C-176 impaired the antitumor effect of CIR. CONCLUSION: The excellent antitumor activity of CIR in immunocompetent prostate cancer-bearing C57BL/6 mice may be attributed to stronger induction of antitumor immune response and higher activation of cGAS-STING pathway.

Role of micronucleus-activated cGAS-STING signaling in antitumor immunity. / å¾®æ ¸æ¿€æ´»cGAS-STINGä¿¡å·é€šè·¯çš„æœºåˆ¶åŠå ¶è‚¿ç˜¤å ç–«åŠŸèƒ½.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalyzes the formation of a second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type Ⅰ interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, is also a significant contributor to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type Ⅰ interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type Ⅰ interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.

Outer Membrane Vesicles Released from Garlic Exosome-like Nanoparticles (GaELNs) Train Gut Bacteria that Reverses Type 2 Diabetes via the Gut-Brain Axis.

Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet-derived exosome-like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high-fat diet-induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high-fat diet-induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc-1100, P9, and phosphatidylcholines. Increasing the levels of Amuc-1100 and P9 leads to increasing the GLP-1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING-mediated inflammation and GLP-1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle-trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.

Advances in crosstalk among innate immune pathways activated by mitochondrial DNA.

Mitochondria are not only the power plant for intracellular oxidative phosphorylation and ATP synthesis, but also involved in cell proliferation, differentiation, signaling and apoptosis. Recent studies have shown that mitochondria play an important role in other pathophysiological functions in addition to cellular energy metabolism. Mitochondria release mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) to activate Toll-like receptor 9 (TLR9), NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune signaling pathways against foreign pathogenic microorganisms. The innate immune response not only promotes antimicrobial immune defense and regulates antiviral signaling, but their overactivation also induces the onset and progression of inflammatory diseases. In this paper, we review the role of mtDNA in the activation of innate immune signaling pathways and the crosstalk among innate immune signaling pathways activated by mtDNA, providing clues for the study of inflammatory diseases caused by mtDNA cytoplasmic translocation.