Astrocyte inflammasomes

Abstract

Neuronal synaptic plasticity in the hippocampus is required for the formation of new neuronal connections during memory formation. In Immunity, Zengeler et al. report that inflammasome activation in hippocampus astrocytes regulates hippocampal plasticity, synaptic protein density, neuronal activity, extracellular matrix abundance and IL-33 production. ASC specks and cleaved caspase-1 and IL-18 — but not cleaved IL-1β, cleaved GSDMD or markers of pyroptosis — were detected in GFAP⁺S100β⁺ astrocytes, but not IBA1⁺ microglia, in the hippocampus of healthy mice. Hippocampi from Casp1^ΔAst mice had diminished activity and firing and increased density of synaptic markers (VGLUT1 and GABA_ARα1) in neurons; upregulated memory-related and neurogenesis pathways (with minimal effects on astrocyte transcriptomes); increased production of IL-33 (known to induce engulfment of extracellular matrix to allow synapse rearrangement) in astrocytes and neurons; increased production of the phagolysosome marker CD68 on microglia; and reduced abundance of extracellular matrix. Astrocyte-derived IL-18 restrained the production of IL-33 in neurons. ASC specks and IL-18 expression in the hippocampus were reduced by environmental enrichment and spatial task learning, which suggests that inflammasome activation is integrated in hippocampus physiology.

Original reference: Immunity https://doi.org/10.1016/j.immuni.2025.04.007 (2025)