Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders

Abstract

Inflammasomes are multiprotein complexes that trigger the activation of caspases-1 and subsequently the maturation of proinflammatory cytokines interleukin-1β and interleukin-18. These cytokines play a critical role in mediating inflammation and innate immunity response. Among various inflammasome complexes, the NLRP3 inflammasome is the best characterized, which has been demonstrated as a crucial role in various diseases. Here, we review recently described mechanisms that are involved in the activation and regulation of NLRP3 inflammasome. In addition, we summarize the recent researches on the role of NLRP3 inflammasome in central nervous system (CNS) diseases, including traumatic brain injury, ischemic stroke and hemorrhagic stroke, brain tumor, neurodegenerative diseases, and other CNS diseases. In conclusion, the NLRP3 inflammasome may be a promising therapeutic target for these CNS diseases.

Figure 1

Models of NLRP3 inflammasome activation. Signal 1 activates the Toll-like receptor (TLR)/NF-κB pathway, leading to the transcription of pro-IL-1β and pro-IL-18. Signal 2 is mediated by PAMPs or DAMPs stimulation and promotes the assembly of NLRP3 inflammasome complex. Three main mechanisms of the NLRP3 inflammasome activation have been proposed. (1) Stimuli can trigger the production of mitochondrial ROS and then induce the NLRP3 inflammasome activity. (2) Extracellular ATP or bacterial toxins can induce K⁺ efflux through the P2X purinergic receptor 7 (P2X7), which leads to the activation of the NLRP3 inflammasome. (3) The phagocytosis of specific crystalline can cause lysosomal rupture and induce the release of lysosomal contents cathepsin B, which contributes to the activation and assembly of the NLRP3 inflammasome. Consequently, these trigger the cleavage of procaspase-1 into its active and mature form caspase-1, which leads to the production of the mature IL-1β and IL-18.