ArticleJournal of neuroinflammation2025
Microglial NLRC5 drives lysosomal dysfunction to disrupt autophagic flux and promote post-stroke neuroinflammation.
Article in Journal of neuroinflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.Journal of neuroinflammation · 2026Article
- PIP4K2A Attenuates Cerebral Ischemia/Reperfusion Injury by Reducing the TRIB3-p62 Complex Burden and Modulating AKT/mTOR Signaling.Translational stroke research · 2026Article
- Paraventricular oxytocin neurons attenuate post-ischemic brain injury by suppressing microglia-mediated neuroinflammation.Cell communication and signaling : CCS · 2026Article
- HighCancers · 2026Article
- Ketogenic Strategies in Neonatal Hypoxic-Ischemic Encephalopathy-The Road to Opening Up: A Scoping Review.Neurology international · 2026Review
- Inflammation-centered neurovascular-immune-metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation.Frontiers in immunology · 2026Review
- Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses.Frontiers in immunology · 2026Review
- Exploring the molecular mechanism of dexmedetomidine in alleviating blood-brain barrier disruption in rats with cerebral ischemia reperfusion injury based on network pharmacology.Frontiers in molecular neuroscience · 2026Article
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12 authors.
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Abstract
backgroundIschemic stroke triggers excessive microglial activation and sustained neuroinflammation, driving secondary neuronal injury. Recent evidence suggests that dysfunction of the autophagy-lysosome system may be a crucial factor sustaining microglial pro-inflammatory responses, yet the underlying regulatory mechanisms remain unclear. NOD-like receptor family caspase recruitment domain-containing protein 5 (NLRC5) has been widely studied in various immune and inflammatory diseases and exhibits functional heterogeneity under different pathological conditions. However, the role of NLRC5 in modulating post-stroke neuroinflammation remains unclear.
methodsNLRC5 expression and localization was examined in a mouse transient middle cerebral artery occlusion (tMCAO) model and postmortem brain tissue from stroke patients. A microglia-specific Nlrc5 knockout (mCKO) mice line was generated to evaluate the effects of Nlrc5 deletion on neurological function, infarct volume, neuronal apoptosis, and inflammatory response after ischemic stroke. Proteomics, mass spectrometry, and molecular biology assays were conducted to elucidate the mechanisms.
resultsNLRC5 expression was upregulated in the ischemic penumbra of mouse models and appeared higher in postmortem brain tissues from stroke patients, specifically in activated microglia. Strikingly, mCKO mice exhibited significantly improved neurological outcomes, reduced infarct volumes, and attenuated neuronal apoptosis post-stroke. In vitro studies demonstrated that NLRC5 induction by various stimuli, including oxygen-glucose deprivation/reperfusion (OGD/R), lipopolysaccharide (LPS), as well as neuronal debris and supernatant, promoted pro-inflammatory cytokine release and microglia-mediated neurotoxicity, whereas Nlrc5 deletion exerted protective effects. Mechanistically, NLRC5 did not influence autophagosome formation but profoundly disrupted autophagic flux by impairing lysosomal function. Proteomic and biochemical analyses revealed that NLRC5 binds interferon-stimulated gene 15 (ISG15) via its CARD domain, shielding ISG15 from autophagy-lysosomal degradation. Furthermore, NLRC5-induced lysosomal defects and inflammatory responses were abolished in the absence of Isg15.
conclusionNLRC5 promotes microglial inflammation and exacerbates post-stroke brain injury by stabilizing ISG15 and disrupting lysosomal function and autophagic flux. NLRC5-ISG15 axis is a therapeutic target for immune modulation in ischemic stroke.
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