STING immune activation of microglia aggravating neurovascular unit damage in diabetic retinopathy

Free Radical Biology and Medicine, Journal Year: 2025, Volume and Issue: 233, P. 86 - 101

Published: March 30, 2025

Language: Английский

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IFNγ preconditioning improves neuroprotection of MSC-derived vesicles on injured retinal ganglion cells by suppressing microglia activation via miRNA-dependent ribosome activity

Extracellular Vesicles and Circulating Nucleic Acids, Journal Year: 2025, Volume and Issue: 6(1), P. 87 - 111

Published: Feb. 19, 2025

Aim: Microglial activation plays a pivotal role in the pathogenesis of retinal ganglion cell (RGC) degeneration resulting from optic nerve crush (ONC). Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have potential to prevent modulating microglial activation. In this study, we elucidated specific effects sEVs derived IFN-γ-primed MSCs on phenotypic transition microglia and associated pathways ONC mice. Methods: The mice model was established administered intravitreal injection with native (native sEVs) primed IFN-γ (IFNγ-sEVs). Their respective survival (RGCs) phenotypes were determined through visual function testing immunohistochemical staining. Combined mRNA seq microRNA techniques, mechanism modulation transformation IFNγ. Results: It demonstrated that IFNγ-sEVs exhibited superior protective against RGC loss reduced inflammatory responses retina compared sEVs. Both types promoted disease-associated (DAM) phenotype, while especially suppressed interferon-responsive (IRM) during RGCs degeneration. Subsequent miRNA sequencing suggested miR-423-5p , which most significant differential expression between two elevated IFNγ-sEVs, inhibited IRM ribosomal genes. Conclusion: These findings suggest IFN-γ-preconditioned may enhance neuroprotection suppressing secretion containing microRNAs

Language: Английский

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Advances in understanding the role and mechanism of the cGAS-STING signaling pathway in ocular diseases

Immunological Medicine, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 15

Published: March 8, 2025

The cGAS-STING signaling pathway plays a critical role in the immune defense against DNA viruses and autoimmunity, coordinating cascade of events that enhance cytokine production, particularly type I interferons. This review summarizes recent advancements understanding pathway's impact on various ocular diseases, including age-related macular degeneration (AMD), diabetic retinopathy, uveitis. Activation this by cytoplasmic from either damaged retinal cells or external pathogens induces inflammatory responses may accelerate disease progression. Moreover, paper explores new therapeutic approaches target pathway, offering insights into how modulation could reduce inflammation improve clinical outcomes. emerging research area suggests potential for innovative treatments degenerative conditions.

Language: Английский

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TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

Acta Biochimica et Biophysica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial host defense, sustained activation of this contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation STING activity prevent hyperactivation. Our study identifies TRIM21 novel positive regulator SLE pathogenesis. results demonstrate that overexpression stabilizes by suppressing autophagic degradation, whereas depletion accelerates clearance process. Mechanistically, catalyzes the K63-linked polyubiquitylation selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents sequestration into autophagosomes, thereby stabilizing adaptor protein and amplifying downstream responses. findings reveal previously unrecognized regulatory circuit which orchestrates cross-talk between ubiquitin control turnover. TRIM21-p62 axis represents potential therapeutic target attenuating pathological STING-dependent disorders. work advances our understanding demonstrating how E3 ligase-mediated modifications modulate cargo recognition pathways. identified provides new insights molecular interplay ubiquitylation degradation maintaining innate balance, offering perspectives developing targeted therapies against interferonopathies associated hyperactivity.

Language: Английский

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Preserving blood-retinal barrier integrity: a path to retinal ganglion cell protection in glaucoma and traumatic optic neuropathy

Cell Regeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 2, 2025

Retinal ganglion cells (RGCs) are the visual gateway of brain, with their axons converging to form optic nerve, making them most vulnerable target in diseases such as glaucoma and traumatic neuropathy (TON). In both diseases, disruption blood-retinal barrier(BRB) is considered an important mechanism that accelerates RGC degeneration hinders axon regeneration. The BRB consists inner barrier (iBRB) outer (oBRB), which maintained by endothelial cells(ECs), pericytes(PCs), retinal pigment epithelial (RPE), respectively. Their functions include regulating nutrient exchange, oxidative stress, immune microenvironment. However, TON, structural functional integrity severely damaged due mechanical inflammatory reactions, metabolic disorders. Emerging evidence highlights leads heightened vascular permeability, cell infiltration, sustained chronic inflammation, creating a hostile microenvironment for survival. Furthermore, dynamic interplay imbalance among ECs, PCs, glial within neurovascular unit (NVU) pivotal drivers destruction, exacerbating apoptosis limiting nerve intricate molecular cellular mechanisms underlying these processes underscore BRB's critical role TON pathophysiology while offering compelling foundation therapeutic strategies targeting repair stabilization. This review provides crucial insights lays robust groundwork advancing research on neural regeneration innovative protective strategies.

Language: Английский

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cGAS, an innate dsDNA sensor with multifaceted functions

Cell Insight, Journal Year: 2025, Volume and Issue: 4(3), P. 100249 - 100249

Published: April 17, 2025

Cyclic GMP-AMP synthase (cGAS) functions as a pivotal intracellular sensor for the innate immune sensing of double-stranded DNA (dsDNA), monitoring those nucleic acids from foreign and endogenous sources. Upon assembling into cellular condensates with dsDNA regulators, cGAS synthesizes 2'3'-cGAMP that activates downstream STING signaling. This activation triggers variety responses, including autophagy, mRNA translation, interferon signaling, inflammatory responses. Context-dependently, resides in diverse compartments, nucleus, micronuclei, plasma membrane, organelle surfaces. Beyond its DNA-sensing role, can play complex roles these locations, such damage repairing, membrane restoration, chromatin condensation, angiogenesis, aging regulation. comprehensive review summarizes recent advances activation, regulation, pharmacological management cGAS, focusing on molecular mechanisms, post-translational modifications (PTMs), therapeutic interventions. The functional implications various disease contexts, infectious diseases, autoinflammatory autoimmune aging, cancers, are also covered.

Language: Английский

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cGAS/STING signalling in macrophages aggravates obliterative bronchiolitis via an IFN‐α‐dependent mechanism after orthotopic tracheal transplantation in mice

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(5)

Published: April 28, 2025

Abstract Background Our previous findings have underscored the role of innate immunity in obliterative bronchiolitis (OB). However, despite central importance cyclic GMP‒AMP synthase (cGAS)/stimulator interferon genes (STING) signalling pathway immune responses, its specific contribution to OB progression remains largely unexplored. Methods A murine orthotopic tracheal transplantation model was established replicate pathogenesis. RNA sequencing and single‐cell data were analysed investigate mechanisms underlying OB. Key molecules cGAS/STING assessed using immunofluorescence staining. Macrophage‐specific Sting1 knockout mice generated Haematoxylin eosin staining Masson's trichrome utilised evaluate allograft stenosis fibrosis. Immune cell infiltration cytokine expression qRT‐PCR. Flow cytometry used characterise splenic T‐cell subsets assess co‐stimulatory molecule macrophages. Results The upregulated macrophages infiltrating allografts. significantly attenuated alloreactive responses alleviated Furthermore, deletion reduced inflammatory marker NOS2, antigen‐presenting MHC class II (CD80 CD86) Mechanistically, inhibited production interferon‐α2 (IFN‐α2), while protective effect macrophage‐specific Sting reversed by IFN‐α2 administration. Importantly, STING inhibition enhanced tolerance‐promoting effects cytotoxic T‐lymphocyte‐associated antigen 4‐Ig (CTLA4‐Ig), leading preservation airway epithelium. Conclusions study demonstrated that exacerbated rejection an IFN‐α2‐dependent manner. These provide insights into potential novel strategies for prolonging survival. points activated rejection, promoted ability potentiated therapeutic efficacy CTLA4‐Ig

Language: Английский

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Microglia remodeling in the visual thalamus of the DBA/2J mouse model of glaucoma

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(5), P. e0323513 - e0323513

Published: May 15, 2025

Microglia are the resident immune cells of central nervous system and mediate a broad array adaptations during disease, injury, development. Typically, microglia morphology is understood to provide window into their function have capacity adopt spectrum functional phenotypes characterized by numerous morphologies gene expression profiles. Glaucoma, which leads blindness from retinal ganglion cell (RGC) degeneration, commonly associated with elevated intraocular pressure (IOP) triggers responses within layers, at optic nerve head, in projection targets brain. The goal this study was determine relationship loss RGC output synapses dorsolateral geniculate nucleus (dLGN), target thalamus that conveys information primary visual cortex. We accomplished analyzing dLGN sections DBA/2J mice, develop form inherited glaucoma, 4, 9, 12 months age, representing distinct time points disease progression. analyzed using skeletonized Iba1 fluorescence images fractal analyses individually reconstructed cells. found older mice adopted simplified morphologies, fewer endpoints less total process length per cell. There an age-dependent shift tissue control (DBA/2J Gpnmb+ ) accelerated mice. Measurements correlated cumulative IOP, immunofluorescence labeling for complement component C1q, vGluT2-labeled axon terminal density. Additionally, analysis revealed clear distinction between glaucomatous dLGN, ocular hypertensive showing elongated rod-like morphology. RNA-sequencing showed upregulation system-related genes. These results suggest alter physiology respond degeneration potentially contributing CNS neurodegenerative vision loss.

Language: Английский

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Targeting Mitochondrial Dysfunction: Innovative Strategies to Combat Glaucoma Neuroinflammation

Experimental Eye Research, Journal Year: 2025, Volume and Issue: unknown, P. 110441 - 110441

Published: May 1, 2025

Language: Английский

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STING deletion protects against amyloid β–induced Alzheimer's disease pathogenesis

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate signaling molecules have yet be explored in AD pathogenesis using genetic targeting approaches. METHODS To investigate a role for the key adaptor molecule, stimulator of interferon genes (STING), AD, we deleted Sting1 5xFAD mouse model AD‐related amyloidosis and evaluated effects on pathology, neuroinflammation, gene expression, cognition. RESULTS Genetic ablation STING mice led improved control amyloid beta (Aβ) plaques, alterations microglial activation status, decreased levels neuritic dystrophy, protection against cognitive decline. Moreover, rescue neurological STING‐deficient was characterized by reduced expression type I both microglia excitatory neurons. DISCUSSION These findings reveal critical roles Aβ‐driven suggest that STING‐targeting therapeutics may offer promising strategies treat AD. Highlights Stimulator (STING) deficiency disease‐related results deposition altered status. Protection is associated with involved IFN signaling, neuronal health, oxidative stress. Loss leads spatial learning memory.

Language: Английский

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