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Article

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

by
Erika d. l. R. M. Cabrera Ranaldi
1,
Helen M. Bramlett
1,2,
Oliver Umland
3,
Leo I. Levine
1,
Robert W. Keane
1,4,
Juan Pablo de Rivero Vaccari
1,4,
W. Dalton Dietrich
1 and
Nadine A. Kerr
1,*
1
Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA
2
Bruce W. Carter Department of Veteran Affairs Medical Center, Miami, FL 33136, USA
3
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
4
Department of Cellular Physiology and Molecular Biophysics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(8), 3512; https://doi.org/10.3390/ijms26083512
Submission received: 21 February 2025 / Revised: 28 March 2025 / Accepted: 2 April 2025 / Published: 9 April 2025
(This article belongs to the Special Issue Current Insights into the Role of Exosomes in Intercellular Communication)
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Abstract

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.
Keywords: inflammasome; pyroptosis; interleukin; IL-1β; traumatic brain injury; exosomes; extracellular vesicles; gut dysfunction inflammasome; pyroptosis; interleukin; IL-1β; traumatic brain injury; exosomes; extracellular vesicles; gut dysfunction

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MDPI and ACS Style

Cabrera Ranaldi, E.d.l.R.M.; Bramlett, H.M.; Umland, O.; Levine, L.I.; Keane, R.W.; de Rivero Vaccari, J.P.; Dietrich, W.D.; Kerr, N.A. Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury. Int. J. Mol. Sci. 2025, 26, 3512. https://doi.org/10.3390/ijms26083512

AMA Style

Cabrera Ranaldi EdlRM, Bramlett HM, Umland O, Levine LI, Keane RW, de Rivero Vaccari JP, Dietrich WD, Kerr NA. Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury. International Journal of Molecular Sciences. 2025; 26(8):3512. https://doi.org/10.3390/ijms26083512

Chicago/Turabian Style

Cabrera Ranaldi, Erika d. l. R. M., Helen M. Bramlett, Oliver Umland, Leo I. Levine, Robert W. Keane, Juan Pablo de Rivero Vaccari, W. Dalton Dietrich, and Nadine A. Kerr. 2025. "Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury" International Journal of Molecular Sciences 26, no. 8: 3512. https://doi.org/10.3390/ijms26083512

APA Style

Cabrera Ranaldi, E. d. l. R. M., Bramlett, H. M., Umland, O., Levine, L. I., Keane, R. W., de Rivero Vaccari, J. P., Dietrich, W. D., & Kerr, N. A. (2025). Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury. International Journal of Molecular Sciences, 26(8), 3512. https://doi.org/10.3390/ijms26083512

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