The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest

Activation of the absent in melanoma 2 (AIM2) inflammasome and impaired autophagosome clearance in neurons contribute significantly to cardiac arrest and return of spontaneous circulation (CA-ROSC) injury, while the mechanism by which the AIM2 inflammasome is regulated and relationship between the processes remain poorly understood. Recently, charged multivesicular body protein 2A (CHMP2A), a subunit of endosomal sorting complex required for transport (ESCRT), was shown to regulate phagophore closure, and its depletion led to the accumulation of autophagosomes and induced cell death. Here, we investigated whether CHMP2A-mediated autophagy was an underlying mechanism of AIM2-associated inflammation after CA-ROSC and explored the potential link between the AIM2 inflammasome and autophagy under ischemic conditions.AIM2 inflammasome activation and autophagic flux in the cortex were assessed in the CA-ROSC rat model. We injected LV-Vector or LV-CHMP2A virus into the motor cortex with stereotaxic coordinates and divided the rats into four groups: Sham, CA, CA+LV-Vector, and CA+LV-CHMP2A. Neurologic deficit scores (NDSs), balance beam tests, histopathological injury of the brain, and expression of the AIM2 inflammasome and proinflammatory cytokines were analyzed.AIM2 inflammasome activation and increased interleukin 1 beta (IL-1β) and IL-18 release were concurrent with reduced levels of CHMP2A-induced autophagy in CA-ROSC rat neurons. In addition, silencing CHMP2A resulted in autophagosome accumulation and decreased autophagic degradation of the AIM2 inflammasome. In parallel, a reduction in AIM2 contributed to autophagy activation and mitigated oxygen-glucose deprivation and reperfusion (OGD-Rep)-induced inflammation. Notably, CHMP2A overexpression in the cortex hindered neuroinflammation, protected against ischemic brain damage, and improved neurologic outcomes after CA.Our results support a potential link between autophagy and AIM2 signaling, and targeting CHMP2A may provide new insights into neuroinflammation in the early phase during CA-ROSC.