Inflammasome Signaling in Astrocytes Modulates Hippocampal Plasticity
Academic Background
In recent years, the role of immune signaling pathways in nervous system homeostasis has garnered increasing attention. Traditionally, the inflammasome, a core complex of innate immunity, was thought to activate only during infection or tissue damage, participating in pathological processes through caspase-1-mediated pyroptosis and the release of pro-inflammatory cytokines (e.g., IL-1β, IL-18). However, growing evidence suggests that immune molecules also play critical roles in the physiological functions of the healthy brain. For example, the alarmin IL-33, while pro-inflammatory in certain contexts, has been found essential for hippocampal synaptic plasticity.
This study aimed to address the following key questions:
1. Is the inflammasome physiologically activated in the healthy adult brain?
2. How does inflammasome signaling in astrocytes influence hippocampal function?
3. Do downstream effector molecules (e.g., IL-18, IL-33) participate in regulating neuronal activity?
Source of the Paper
The study was led by Kristine E. Zengeler and John R. Lukens at the University of Virginia, with collaborators from disciplines including anesthesiology, neuroscience, and nephrology. The paper was published on June 10, 2025, in the top-tier immunology journal Immunity (DOI: 10.1016/j.immuni.2025.04.007).
Research Process and Results
1. Dynamic Regulation of the Inflammasome in the Healthy Brain
Experimental Design:
- Used ASC-Citrine reporter mice (fluorescent labeling of inflammasome complex formation).
- Analyzed expression of inflammasome sensors (NLRP1/3, AIM2) and effectors (caspase-1, IL-18) in the hippocampus, cerebellum, and cortex via whole-brain imaging and Western blot.
- Stimulated primary CNS cells in vitro with CaCl₂ or etoposide to observe ASC fluorescence changes.
Key Findings:
- Regional Distribution: The hippocampus and cerebellum exhibited the highest density of ASC specks, with significant enrichment of activated caspase-1 and IL-18 (Figures 1a-e).
- Neuronal Activity Negatively Regulates the Inflammasome: Environmental enrichment (EE) or Morris water maze (MWM) training reduced hippocampal ASC speck counts (Figures 1i-o), while aging increased them (Figures 1k-l).
- Reversible Regulation: CaCl₂-induced neuronal activity reversibly suppressed inflammasome assembly (Figures 1f-h).
Significance: First evidence of physiological activity-dependent inflammasome regulation in the healthy brain.
2. Impact of Inflammasome Loss on Hippocampal Plasticity
Experimental Design:
- Pharmacological Inhibition: Treated mice with the caspase-1 inhibitor VX765, labeling activated neurons via TRAP2;tdTomato and analyzing dendritic spine density with Thy1-YFP.
- Genetic Model: Generated astrocyte-specific caspase-1 knockout mice (Casp1δast).
Key Findings:
- Increased Synaptic Proteins: Upregulation of synaptophysin, vGLUT1, and GABAARα1 in the hippocampus of VX765-treated or Casp1δast mice (Figures 2i-n, 3c-f).
- Reduced Neuronal Activity: Fewer c-Fos+ neurons and decreased intrinsic firing frequency of CA1 pyramidal neurons (Figures 3k-n).
- Transcriptomic Changes: Single-cell RNA sequencing (scRNA-seq) revealed upregulation of synaptic (e.g., Snap25) and myelin-related genes (e.g., Mbp) in Casp1δast hippocampi (Figures 4a-c).
Significance: Astrocytic caspase-1 maintains hippocampal homeostasis by regulating synaptic proteins and neuronal activity.
3. Central Role of the IL-18/IL-33 Axis
Experimental Design:
- Cellular Localization: Validated IL-33 expression in astrocytes (SOX9+) and neurons (MAP2+) via immunofluorescence and MACS sorting.
- Exogenous Interventions: Treated ex vivo hippocampal slices with IL-18 or neuronal activity inducers (forskolin, glutamate) to measure IL-33 release.
Key Findings:
- Bidirectional Regulation: IL-18 suppressed hippocampal IL-33 release, while neuronal activity (e.g., forskolin) reduced IL-18 levels (Figures 5q-u).
- Behavioral Phenotypes: Casp1δast mice showed impaired long-term memory due to elevated IL-33 (Figures 4e-g), whereas astrocyte-specific IL-33 knockout (Il33δast) increased synaptic puncta and c-Fos+ neurons (Figures 5h-k).
Significance: The inflammasome regulates synaptic plasticity and memory persistence via the IL-18/IL-33 axis.
4. Pathological Role of the Inflammasome in Epilepsy
Experimental Design:
- Epilepsy Model: Induced acute seizures in mice using kainic acid (KA) and evaluated the impact of global or cell-specific caspase-1 knockout on seizure severity.
Key Findings:
- Astrocyte-Specific Protection: Casp1δast mice exhibited shorter seizure duration and reduced mortality (Figures 6e-h), while neuron- or microglia-specific knockouts showed no such effects (Figures S6r-y).
Significance: Targeting astrocytic inflammasomes may offer novel therapeutic strategies for epilepsy.
Research Value and Highlights
Scientific Value:
- Reveals the physiological role of the inflammasome in the healthy brain, challenging its traditional “pathological” paradigm.
- Elucidates the molecular mechanism by which astrocytes regulate neuronal activity via the caspase-1/IL-18/IL-33 axis.
- Reveals the physiological role of the inflammasome in the healthy brain, challenging its traditional “pathological” paradigm.
Translational Potential:
- Provides new therapeutic targets (e.g., astrocyte caspase-1) for neurological disorders like epilepsy and Alzheimer’s disease.
- Provides new therapeutic targets (e.g., astrocyte caspase-1) for neurological disorders like epilepsy and Alzheimer’s disease.
Innovative Methods:
- Integrates ASC-Citrine reporters, single-cell transcriptomics, and cell-specific knockout models for multidimensional analysis.
- Integrates ASC-Citrine reporters, single-cell transcriptomics, and cell-specific knockout models for multidimensional analysis.
Key Conclusion:
> “Astrocytic inflammasome signaling is a bidirectional modulator of hippocampal plasticity: moderate activation maintains homeostasis, while excessive activation promotes pathological hyperexcitability.”
Future Directions: Further exploration is needed to dissect the contributions of distinct inflammasome sensors (e.g., NLRP3 vs. AIM2) and their spatiotemporal roles in neurodegenerative diseases.