Transcriptional regulation of IRF3, MEF2A, and MEF2C by cGAS-STING activation in mouse microglia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE289830 | GEO | 2026/10/01
REPOSITORIES: GEO
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2026-10-01 | GSE288063 | GEO
Project description:Aging is the strongest risk factor for Alzheimer’s disease (AD), yet the mechanisms by which aging promotes AD progression remain incompletely understood. Chronic neuroinflammation is a hallmark of both brain aging and AD, with microglia undergoing progressive inflammatory and functional changes, but how these age-associated changes contribute to disease progression is unclear. Here, we profiled gene expression and chromatin accessibility in the hippocampus across aging and amyloid-β (Aβ) pathology, and identified progressive activation of cGAS-STING pathway and interferon-responsive microglial states that are markedly accelerated in the process. Pharmacological inhibition of STING in aged mice improved spatial memory, reduced Aβ plaque burden and shifted microglia from interferon-responsive states towards a phagocytic program associated with enhanced Aβ clearance. Mechanistically, STING activation reduced MEF2 activity and occupancy at enhancers of phagocytosis-associated genes, whereas STING inhibition restored MEF2 activity. Human AD hippocampal microglia similarly exhibited elevated IRF3 activity together with reduced MEF2C activity and nuclear availability. STING inhibition failed to preserve Aβ phagocytosis in MEF2C-deficient human iPSC-derived microglia. Together, these findings identify a cGAS–STING–MEF2 regulatory axis through which aging-associated innate immune signaling impairs microglial Aβ clearance and suggest that targeting cGAS–STING may restore protective microglial function in AD.
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Project description:Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer’s disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS-STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed “Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)”. ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.
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Project description:The innate immune cGAS-STING pathway is activated by cytosolic doubled-stranded DNA (dsDNA) to induce type I interferon response, which is essential for antiviral and antitumor immunity. However, intrinsic STING activation during viral infection or within the tumor microenvironment is often insufficient to achieve complete viral clearance or tumor regression, indicating the presence of additional mechanisms that evades its activity. Here, we identified COX2/PGE2 as an intrinsic negative regulator of STING activation, particularly in response to cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, we demonstrated that PGE2 signals through the EP4-PKA axis to induce mitophagy and facilitate the clearance of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated antiviral response. Furthermore, we discovered STOML2 as a direct downstream target of PKA, thereby linking mitochondrial quality control to innate immune signaling. Together, our findings established the COX2/PGE2/PKA axis as an intrinsic negative regulator of STING signaling, which may be targeted to potentiate STING-mediated antiviral and antitumor immunity.
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Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.
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