cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 9, 2024

Abstract Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression organ degeneration, but the mechanism regulation of crosstalk network remain unclear. Main body abstract Cellular stress disrupts mitochondrial homeostasis, facilitates opening permeability transition pore leakage DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, subsequently induces activation onset pyroptosis. Meanwhile, inflammasome-associated protein caspase-1, Gasdermin D, CARD domain ASC potassium channel are involved in regulating pathway. Importantly, this has a cascade amplification effect that exacerbates immuno-inflammatory response, worsening pathological process autoimmune diseases. Given importance innate immunity, it is emerging new avenue explore mechanisms multiple disease pathogenesis. Therefore, efforts define strategies selectively modulate different settings have been or ongoing. In review, we will describe how mechanistic understanding driving possible therapeutics targeting network, focusing on interacting regulatory proteins, pathways, hub between inflammasomes, Short conclusion This review aims provide insight into roles pyroptosis, highlight some promising directions future research intervention.

Language: Английский

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The gasdermin family: emerging therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Language: Английский

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Itaconate in host inflammation and defense

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(7), P. 586 - 606

Published: March 5, 2024

Language: Английский

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Mitochondrial (mt)DNA–cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 27, 2024

Abstract Background Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate cellular immune suppression during process SAP, where cyclic GMP–AMP synthase (cGAS)–stimulator interferon genes (STING) plays an important role. However, function mechanism cGAS–STING in SAP-induced lung injury (LI) remains unknown. Methods Lipopolysaccharide (LPS) was combined with caerulein-induced SAP wild type, cGAS −/− sting mice . Primary macrophages were extracted via bronchoalveolar lavage peritoneal lavage. Ana-1 cells pretreated LPS stimulated nigericin sodium salt induce pyroptosis vitro. Results triggered NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated alveolar mouse model. Knockout / STING could ameliorate NLRP3 pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria induced a cGAS- dose-dependent manner. Upregulated signal promote inflammasome-mediated increase serum interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α levels thus, SAP-associated LI (SAP-ALI). Downstream molecules STING, IRF7, IRF3 connect mtDNA–cGAS–STING axis NLRP3–pyroptosis axis. Conclusions Negative regulation any molecule mtDNA–cGAS–STING–IRF7/IRF3 pathway affect inflammasomes, thereby reducing improving SAP-ALI

Language: Английский

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CMPK2 promotes NLRP3 inflammasome activation via mtDNA‐STING pathway in house dust mite‐induced allergic rhinitis

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 1, 2025

Abstract Background House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, molecular mechanisms driving this process remain incompletely elucidated. Objective This study aimed elucidate underlying HDM‐induced AR. Methods We examined expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and NLRP3 inflammasome in both AR patients mice. Additionally, we investigated role CMPK2 activation Results The CMPK2, was significantly increased nasal mucosa compared non‐AR controls. A positive correlation found between levels STING, NLRP3, ASC, CASP1 IL‐1β. HDM treatment up‐regulated overexpression enhanced human epithelial cells (HNEPCs). mitochondrial reactive oxygen species (mtROS) production following exposure contributed dysfunction release DNA (mtDNA), which activated cyclic GMP‐AMP synthase (cGAS)‐STING pathway. Remarkably, depletion mtDNA or inhibition signalling reduced HNEPCs. In vivo, genetic knockout alleviated ameliorated clinical symptoms Conclusions Our results suggest that promotes through up‐regulation ensuing mtDNA‐STING pathway, hence revealing additional therapeutic target Key points Cytidine/uridine (CMPK2) mice with caused via (mtDNA)‐STING Blocking house (HDM)‐challenged

Language: Английский

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cGAS-STING targeting offers therapy choice in lung diseases

Biology Direct, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 7, 2025

Cyclic GMP/AMP (cGAMP) synthase (cGAS), along with the endoplasmic reticulum (ER)-associated stimulator of interferon genes (STING), are crucial elements type 1 response. cGAS senses microbial DNA and self-DNA, labeling cGAS-STING as a mechanism in autoimmunity, sterile inflammatory responses, cellular senescence. However, chronic aberrant activation axis results autoimmune diseases. has emerged vital driving inflammation-related diseases, including lung Insights into biology pathway have enabled discovery small-molecule agents which potential to inhibit In this review, we first outline principal components signaling cascade. Then, discuss recent research that highlights general mechanisms by contributes focus on summarizing list bioactive compounds pathway, reviewing their mechanisms.These review novel groundbreaking therapeutic possibilities through targeting

Language: Английский

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Mitochondrial Dynamics and Metabolism in Macrophages for Cardiovascular Disease: a review

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156620 - 156620

Published: March 7, 2025

Language: Английский

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Knockdown of CENPM activates cGAS-STING pathway to inhibit ovarian cancer by promoting pyroptosis

BMC Cancer, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 1, 2024

Abstract Objective We aimed to screen novel gene signatures for ovarian cancer (OC) and explore the role of biomarkers in OC via regulating pyroptosis using bioinformatics analysis. Methods Differentially expressed genes (DEGs) were screened from GSE12470 GSE16709 datasets. Hub determined protein–protein interaction networks after The Centromeric protein M (CENPM) was assessed by subcutaneous tumor experiment hematoxylin–eosin immunohistochemical staining. Tumor metastasis evaluated detecting epithelial-mesenchymal transition-related proteins. proliferation, migration, invasion cell counting kit transwell assay. Enzyme-linked immunosorbent assay applied measure inflammatory factors. mRNA expression detected real-time quantitative PCR western blot. Results 9 hub (KIFC1, PCLAF, CDCA5, KNTC1, MCM3, OIP5, CENPM, KIF15, ASF1B) with high prediction value OC. In SKOV3 A2780 cells, levels significantly up-regulated, compared normal cells. CENPM selected as a key gene. Knockdown suppressed Subcutaneous revealed that knockdown growth metastasis. Additionally, promoted cells xenograft tumors knockdown. Furthermore, activated cGAS-STING pathway inhibitor reversed inhibitory effect on viability, Conclusion biomarker OC, inhibited progression promoting activating pathway.

Language: Английский

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Cell-cell crosstalk in the pathogenesis of acute lung injury and acute respiratory distress syndrome

Tissue Barriers, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the result of an exaggerated inflammatory response triggered by a variety pulmonary systemic insults. The tissues comprised cell types, including alveolar epithelial cells, vascular endothelial macrophages, neutrophils, others. There is mounting evidence that these diverse populations within interact to regulate inflammation in both direct indirect stimuli. aim this review provide summary discussion recent advances understanding importance cell-cell crosstalk pathogenesis ALI/ARDS, with specific focus on interactions may offer prospective therapeutic avenues for ALI/ARDS.

Language: Английский

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Elevated GFI1 in Alveolar Macrophages Suppresses ACOD1 Expression and Exacerbates Lipopolysaccharide‐Induced Lung Injury in Obesity

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

To investigate the mechanisms behind worsening of acute lung injury (ALI) in obesity, transcriptomic sequencing is performed, and significantly reduced mRNA levels Aconitate Decarboxylase 1 (ACOD1) tissue high-fat diet (HFD) mice are found. Clinical samples collected, an ALI model established HFD mice, both human mouse analyzed, revealing a significant decrease ACOD1 expression alveolar macrophages obesity. Further vivo vitro experiments show that knockdown worsens injury, inflammation, oxidative stress, while overexpression alleviates these effects. Moreover, nuclear factor erythroid 2-related 2 (Nrf2) inhibition diminishes protective effects exacerbated by Additionally, context growth independent (GFI1) protein elevated macrophages, its leads to upregulated expression. Therefore, this study suggests downregulation key likely driven GFI1 upregulation.

Language: Английский

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