AIM 2 inflammasomes regulate neuronal morphology and influence anxiety and memory in mice

Abstract

Inflammasomes are the protein assemblies that consist of inflammasome sensors, adaptor apoptosis-associated speck-like proteins containing a CARD (ASC) and inflammasome caspase. Inflammasomes sense multiple danger signals via various inflammasome sensors and consequently use caspase to trigger proteolytic processing and secretion of IL-1β cytokines. Recent studies have suggested that neurons use their own innate immune system to detect danger signals and regulate neuronal morphology. Here, we investigate whether inflammasomes, the critical components of innate immunity, participate in regulation of neuronal morphology and function. Among various sensors, Absent in melanoma 2 (Aim2) expression in neurons is most prominent. Adding synthetic double-stranded DNA (dsDNA) to cultured neurons induces IL-1β secretion in an AIM2-dependent manner and consequently downregulates dendritic growth but enhances axon extension. The results of Aim2 knockout and knockdown show that AIM2 acts cell-autonomously to regulate neuronal morphology. Behavioral analyses further reveal that Aim2−/− mice exhibit lower locomotor activity, increased anxious behaviors and reduced auditory fear memory. In conclusion, our study suggests that AIM2 inflammasomes regulate neuronal morphology and influence mouse behaviors.

Deletion of the Inflammasome Sensor <b><i>Aim2</i></b> Mitigates Aβ Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model

“…Quantitative RT-PCR (Q-RT-PCR) was carried out as described previously [28,39] . Briefly, the experiments were performed with a LightCycler480 (Roche) and Universal ProbeLibrary system (UPL; Roche) using the Assay Design Center Web Service (http://qpcr.probefinder.com/roche3.html).…”

“…Dead cells in cultures or those generated by aging or tissue injury in vivo can be internalized and serve as endogenous ligands to activate AIM2 inflammasomes and promote IL-1 processing and secretion [29][30][31] . Compared with other inflammasome sensors, expression levels of Aim2 are highest in cultured cortical and hippocampal neurons, as well as in young mouse brains (<3 months of age) [28] . In neurons, activation of AIM2 restricts dendritic growth but promotes axonal extension in a cell-autonomous manner [28] .…”

“…Compared with other inflammasome sensors, expression levels of Aim2 are highest in cultured cortical and hippocampal neurons, as well as in young mouse brains (<3 months of age) [28] . In neurons, activation of AIM2 restricts dendritic growth but promotes axonal extension in a cell-autonomous manner [28] . IL-1 is required for the function of AIM2 in regulating neuronal morphology because deletions of the IL-1 receptor IL-1R1 and its critical downstream signaling molecule MYD88 completely abolish the function of AIM2 in controlling neuronal morphology [28] .…”

“…In neurons, activation of AIM2 restricts dendritic growth but promotes axonal extension in a cell-autonomous manner [28] . IL-1 is required for the function of AIM2 in regulating neuronal morphology because deletions of the IL-1 receptor IL-1R1 and its critical downstream signaling molecule MYD88 completely abolish the function of AIM2 in controlling neuronal morphology [28] . Together, accumulated studies have indicated roles for AIM2 in neuronal innate immunity, cell death, and morphology.…”

“…The AIM2 inflammasome plays a role in brain injury [27] and the regulation of dendritic and axonal growth of neurons [28] . AIM2 recognizes double-stranded DNA (dsDNA) in the cytoplasm.…”