Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury.

Traumatic brain injury (TBI) pathology is significantly mediated by an inflammatory response involving inflammasome activation, resulting in the release of interleukin (IL)-1β and pyroptotic cell death through gasdermin-D (GSDMD) cleavage. Inflammasome components are transported through extracellular vesicles (EVs) to mediate systemic inflammation in peripheral organs, including the gut. The purpose of this study was to determine the protective effect of GSDMD knockout (KO) on TBI-induced inflammasome activation, EV signaling, and gut function. GSDMD-KO and C57BL6 (WT) mice were subjected to the controlled cortical impact model of TBI. Cytokine expression was assessed with electrochemiluminescent immunoassay and immunoblotting of the cerebral cortex and gut. EVs were examined for pathology-associated markers using flow cytometry, and gut permeability was determined. GSDMD-KO attenuated IL-1β and IL-6 expression in the cerebral cortex and reduced IL-1β and IL-18 in the gut 3 days post-injury. GSDMD-KO mice had decreased neuronal- and gut-derived EVs compared to WT mice post-TBI. GSDMD-KO EVs also had decreased IL-1β and different surface marker expression post-TBI. GSDMD-KO mice had decreased gut permeability after TBI. These data demonstrate that GSDMD ablation improves post-TBI inflammation and gut pathology, suggesting that GSDMD may serve as a potential therapeutic target for the improvement of TBI-associated pathologies.