The role of the NLRP3 inflammasome in neuroinflammation after neonatal hypoxic-ischemic brain injury

Abstract

Worldwide, neonates are suffering from hypoxic-ischemic encephalopathy. The pathology can lead to neurological impairments and neonatal death and has an incidence of 1-3/1000 neonates in developed countries and 10-20 times as many in developing countries. Inflammation in the brain is one of the factors deciding the severity of disease progression. <br/> The NLRP3 inflammasome senses and reacts to stress signals and is known to be activated following hypoxia-ischemia. However, the detailed mechanism of the NLRP3 regulation after hypoxia-ischemia and the cell-specific involvement needs further investigation. <br/> As microglia are dominantly mediating inflammation in the brain and are known to express NLRP3, this study investigated the role of microglial cells in NLRP3 activation following hypoxia-ischemia. <br/> The role of NLRP3 in hypoxic-ischemic encephalopathy was characterized by using the hypoxia-ischemia model after Rice and Vannucci in the neonatal rat and establishing an oxygen-glucose deprivation model in primary microglia. <br/> This study presents the relevance of the NLRP3 activation following hypoxia-ischemia. Furthermore, the study demonstrates the beneficial effect of inhibiting NLRP3 on biomolecular level and on long-term outcomes in the animal. Microglia were presented as major drivers of NLRP3 regulation following hypoxia-ischemia. With the focus on microglial NLRP3, it was shown how activated NLRP3 is impacting the fate of neuronal cells. These results provide insight into the mechanisms of NLRP3 regulation and present a potential cell-specific target for therapeutic interventions.