NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Abstract

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

Quercetin protects against diabetic encephalopathy via SIRT1/NLRP3 pathway in db/db mice

“…In a previous study, NLRP3 inflammasome is activated in the neurons of hippocampus in db/db mice . NLRP3 catalyzes the activation of caspase‐1, thereby promoting the maturation and secretion of IL‐1β and IL‐18 . Studies have found that inhibiting NLRP3 inflammasome activation can reduce IL‐1β levels in hippocampus of DM rats, and the expression level of hippocampal IL‐1β is related to cognitive function in DM mice .…”

Ginkgolide B ameliorates NLRP3 inflammasome activation after hypoxic‐ischemic brain injury in the neonatal male rat

“…Further studies of the cell‐type specificity of NLRP3 expression revealed that NLRP3 expression was mainly localized to microglia, while there was only a few activated astrocyte that showed NLRP3 expression. As the most well‐known inflammasome, the NLRP3 inflammasome is present in microglia and astrocytes in the central nervous system (Song et al, 2017). Microglia is a major source of NLRP3 activation and can produce IL‐1β in response to different classical inflammasome activators, such as such as ATP and nigericin.…”

“…Hypoxia ischemia induces an inflammatory response in the brain and peripheral organs, resulting in the release of a number of pro‐ and anti‐inflammatory cytokines and chemokines, including cytokines interleukin (IL)‐1β and IL‐18 (Ziemka‐Nalecz et al, 2017; Li et al, 2017). In particular, the secretion of IL‐1β and IL‐18 requires the NOD (nucleotide‐binding oligomerization domain)‐like receptor (NLR) Pyrin domain containing 3 (NLRP3) inflammasome (Singh and Jha, 2018; Song et al, 2017). NLRP3 activation has been reported to mediate injury in various CNS disorders including HIE (Ystgaard et al, 2015; Chen et al, 2018).…”

Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen

“…Even so, other small compounds (ie MCC950) block ASC oligomerisation . Besides, there are several other substances that show an inhibitory potential either on inflammasome assembly or up‐stream signalling pathways (pannexin channel 1, P2X7 receptors, NF‐κB, NSAIDs) that activate inflammasomes …”