Fig. 2

Mechanisms by which NLRP3 inflammasome activation increases the susceptibility to post-traumatic epileptogenesis. (1) TBI causes neuronal damage resulting in DAMP generation. (2) TBI also causes BBB breakdown resulting in infiltration of peripheral inflammatory cells causing cytokine release and further neuronal damage. (3) DAMPs initiate TLR-mediated NFκB activation and subsequent expression of the inflammasome genes within microglia. (4) Synthesis of mature IL-1β and Gasdermin D by activated caspase-1. (5) Plasma membrane rupture causing pyroptotic cell death by Gasdermin D and release of IL-1β in extracellular space.6) Reduced synaptic density and abnormal synapse formation 7) Alteration of NMDA and GABA receptors by extracellular IL-1β 8) Imbalance between excitation and inhibition ultimately contributing to epileptogenesis. BBB- blood-brain barrier, DAMP- Damage associated molecular patterns, NMDAR- N-methyl-D-aspartate receptor, AMPAR- α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, GABAR- Gamma-aminobutyric acid receptor, GSDMD- Gasdermin D, IL-1β - Interleukin-1β