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Figure 5 | Journal of Neuroinflammation

Figure 5

From: Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus

Figure 5

A schematic linking the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation to status epilepticus (SE) pathogenesis. Activation of the NLRP3 inflammasome typically requires a bimodal signaling pathway. A Toll-like receptor (TLR)-dependent priming step activates the NF-κB-dependent transcription of NLRP3 and the pro-forms of the proinflammatory cytokines (which are IL-1β and IL-18). NLRP3-activating stimulation agents provide a second signal in the form of K+ efflux, cytosolic release of mitochondria-derived factors such as reactive oxygen species (ROS), cardiolipin, and oxidized mitochondrial DNA (mtDNA). Note that acidic extracellular pH represents a novel stimulation agent for triggering NLRP3 inflammasome activation. Oligomerization of NLRP3 is followed by recruitment of the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the pro-form of caspase-1, leading to the activation (cleavage) of caspase-1. Activated caspase-1 in turn catalyzes the cleavage of IL-1β and IL-18. This event may lead to changes in brain parenchyma such as leakage of the blood-brain barrier (BBB), neuronal hyperexcitability and excitotoxicity as well as neuronal damage which contribute to lowering the threshold for seizure induction and thus to trigger epileptogenesis. Activation of innate immune mechanisms during epileptogenesis can recruit inflammatory cells from the periphery which perpetuate inflammation, thus activating a vicious cycle that in turn fosters aberrant hyperexcitability. The onset of SE can in turn further promote inflammation via the production of proinflammatory cytokines.

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