AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment

Abstract

Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by a period of massive cell death where over half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and byproducts of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this collateral damage influences brain maturation and function currently remains poorly understood. Here we show that the AIM2 inflammasome contributes to proper brain development and that disruptions in this immune sensor of genotoxic stress lead to behavioral abnormalities. The AIM2 inflammasome has been most extensively studied in the context of infection, where its activation in response to double-stranded DNA (dsDNA) is known to trigger cytokine production as well as a Gasdermin-D-mediated form of cell death commonly referred to as pyroptosis 1-4 . We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this DNA damage surveillance sensor result in anxiety-related behaviors. We further show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of the cell death executioner Gasdermin-D, and not via its involvement in IL-1 and/or IL-18 production. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, we report that

Bacterial-induced maternal interleukin-17A pathway promotes autistic-like behaviors in mouse offspring

“…In particular, MIA on the window from E12.5 to E14.5 during gestation may be critical stage for neurodevelopment in fetus. In fact, poly(I:C) injection on E12.5 results in strong induction of IL-17A at E14.5 that promotes ASD-like phenotypes of offspring [4,12]. In this study, we induced MIA on E14.0 by injecting LPS and demonstrated that bacterial-induced maternal IL-17A pathway by LPS promoted ASD-like behaviors of offspring.…”

“…MIA model to mimic viral infection has been frequently used by injecting one dose of poly(I:C) on embryonic day 12.5 (E12.5), which corresponds to the first trimester stage in human [5]. Recent MIA model by poly(I:C) injection has shown that pro-inflammatory cytokine interleukin 17A (IL-17A) produced by T helper 17 (Th17) cells plays a critical role in ASD-like phenotypes of offspring [4,10,12] and affects fetal brain development by generating cortical patches on cerebral cortex, which is associated with ASD-like behavioral abnormalities [32]. In addition, recent reports have indicated that maternal intestinal bacteria that promote Th17 cell differentiation regulate ASD-like phenotypes of MIA offspring [10,12].…”

The role of innate immunity in Alzheimer's disease

“…Interestingly, our laboratory and others have shown the loss of Aim2 impacts neuronal morphology and negatively influences several behaviors such as anxiety and memory. 217,218 Furthermore, our recent studies demonstrate that defects in the AIM2 inflammasome can alter neurodevelopment. 217 Thus, it is feasible that changes in brain development existing before Aβ deposition may influence disease outcomes in AD mouse models.…”

“…217,218 Furthermore, our recent studies demonstrate that defects in the AIM2 inflammasome can alter neurodevelopment. 217 Thus, it is feasible that changes in brain development existing before Aβ deposition may influence disease outcomes in AD mouse models. Moving forward, it will be interesting to revisit the role of the AIM2 inflammasome in AD using approaches that conditionally ablate AIM2 signaling following neurodevelopment.…”

AIM2 in health and disease: Inflammasome and beyond

“…AIM2 inflammasome activation in response to genotoxic stress during neurodevelopment contributes to normal brain development by purging unfit neurons via GSDMDmediated pyroptosis. As a result, AIM2 deficiency leads to the retention of more cells (damaged as well as normal) in the brain and the development of anxiety-related behaviors in mice 67. In addition to cell-intrinsic DNA, cell-extrinsic DNA can also become mislocalized in the cytosol, thus becoming a ligand for AIM2.Phagocytic cells, such as macrophages, internalize cell-free DNA released upon cellular damage, self-DNA-immune complexes, and apoptotic bodies containing DNA.…”