The role of AIM2 inflammasome pathway-mediated pyroptosis on brain injury induced by severe acute pancreatitis in mice

This study aimed to investigate the role of the AIM2 inflammasome pathway-mediated pyroptosis in severe acute pancreatitis-induced brain injury (SAP-IBI) utilizing a murine model. A male C57BL/6 murine model of SAP-IBI was established. Mice were randomized into five groups: sham-operated controls (SO), SAP-IBI model, adeno-associated virus negative control (SAP + AAV-NC), AIM2 silencing via AAV-delivered shRNA (SAP + AAV-AIM2 shRNA), and AAV-mediated AIM2 overexpression (SAP + AAV-AIM2 OE). Assessment at 24 h included mortality rates, modified neurological severity scores (mNSS), histopathological scoring of pancreatic and hippocampal tissues, hippocampal water content, serum biomarkers (amylase, lipase, IL-1β, IL-18, PLA2), and expression of pyroptosis-related molecules (AIM2, ASC, Caspase-1, GSDMD, IL-1β, IL-18) in the hippocampus. At 24 h post-operation, the mortality rates of the SAP-IBI group, SAP + AAV-AIM2 shRNA group and SAP + AAV-AIM2 OE group did not reach statistical significance. Compared with the SAP-IBI group, the SAP + AAV-AIM2 shRNA group exhibited significantly improved outcomes including reduced neurological deficits (mNSS: 8.63 ± 1.06 vs. 13.00 ± 1.00; P < 0.05), markedly lower histopathological scores in both hippocampal and pancreatic tissues (P < 0.05), attenuated hippocampal edema (water content: 78.11 ± 0.45 vs. 80.70 ± 0.81; P < 0.05). These improvements were accompanied by a marked reduction in serum biomarkers (P < 0.05) and downregulation of hippocampal pyroptosis-related molecules (P < 0.05). Conversely, the SAP + AAV-AIM2 OE group showed significant exacerbation in all parameters compared to the SAP-IBI group (P < 0.05). This study demonstrates that the AIM2 inflammasome promotes hippocampal pyroptosis in SAP-IBI pathogenesis. Modulating this pathway may represent a promising therapeutic strategy for enhancing neurological outcomes.