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. 2020 Apr 1;12(4):e11002. doi: 10.15252/emmm.201911002

Figure 8. A schematic diagram showing the pyroptosis and inflammatory cascades on dsDNA recognition during cerebral ischemia.

Figure 8

Nuclear dsDNA released into cytoplasm by several cell death pathways during brain ischemia is a damage‐associated molecular pattern, which can drive cGAS signaling and AIM2 inflammasome activation in microglia. Once activated, microglia can release both non‐inflammasome‐dependent cytokines (e.g., TNFα, IL‐6) and inflammasome‐dependent cytokines (IL‐1β and IL‐18). Furthermore, microglia also undergo pyroptosis that could subsequently amplify the inflammation through triggering the release of neurotoxic and inflammatory mediators. Moreover, cytokines secreted could further drive a persistent inflammatory cascade and activate infiltrating neutrophils, causing neuronal death. cGAS antagonizing synthetic oligonucleotide A151 attenuates the overall neuroinflammatory response caused by cytoplasmic dsDNA through reducing microglia activation, preventing microglial pyroptosis, and inhibiting the peripheral neutrophil infiltration. Inhibition of dsDAN‐sensing cGAS and AIM2 may thus exert neuroprotection and improve stroke outcomes by interrupting this inflammatory positive feedback loop.