Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke

Abstract

Stroke is one of the major devastating diseases with no effective medical therapeutics. Because of the high rate of disability and mortality among stroke patients, new treatments are urgently required to decrease brain damage following a stroke. In recent years, the inflammasome is a novel breakthrough point that plays an important role in the stroke, and the inhibition of inflammasome may be an effective method for stroke treatment. Briefly, inflammasome is a multi-protein complex that causes activation of caspase-1 and subsequent production of pro-inflammatory factors including interleukin (IL)-18 and IL-1β. Among them, the NLRP3 inflammasome is the most typical inflammasome, which can detect cell damage and mediate inflammatory response to tissue damage in ischemic stroke. The NLRP3 inflammasome has become a key mediator of post-ischemic inflammation, leading to a cascade of inflammatory reactions and cell death eventually. Thus, NLRP3 inflammasome is an ideal therapeutic target due to its important role in the inflammatory response after ischemic stroke. In this mini review article, we will summarize the structure, assembly, and regulation of NLRP3 inflammasome, the role of NLRP3 inflammasome in ischemic stroke, and several treatments targeting NLRP3 inflammasome in ischemic stroke. The further understanding of the mechanism of NLRP3 inflammasome in patients with ischemic stroke will provide novel targets for the treatment of cerebral ischemic stroke patients.

Targeting Inflammasomes to Treat Neurological Diseases

“…In this context, following ischemic stroke, several mediators have potentially been found to induce NLRP3 inflammasome activation in in vitro and in vivo studies including mitochondrial dysfunction and generation of ROS, thioredoxin-interacting protein (TXNIP), serum amyloid A, bromodomaincontaining protein 4, and increased zinc levels. 58 In transient middle cerebral artery occlusion murine models, microglial cells were reported to be the first to show NLRP3 inflammasome activation in the ischemic core area, although other cell types such as neurons and endothelial cells also expressed NLRP3. 59,60 NLRP3 deficiency or treatment with MCC950 was associated with reduction in infarct volume and edema, and with improvement of neurological outcomes.…”

“…There is increasing evidence that the NLRP3 inflammasome plays an important role in the pathogenesis and progression of ischemic stroke. In this context, following ischemic stroke, several mediators have potentially been found to induce NLRP3 inflammasome activation in in vitro and in vivo studies including mitochondrial dysfunction and generation of ROS, thioredoxin‐interacting protein (TXNIP), serum amyloid A, bromodomain‐containing protein 4, and increased zinc levels 58 …”

LncRNA TUG1 Demethylated by TET2 Promotes NLRP3 Expression, Contributes to Cerebral Ischemia/Reperfusion Inflammatory Injury

“…TUG1 could promote myocardial ischemic injury-induced cardiomyocyte cell apoptosis by directly targeting miR-9a-5p and upregulation of Krüppel-like factor 5 (KLF5) ( Yang et al., 2019 ). The NLRP3/Caspase-1/IL-1β pathway is believed as a promising avenue against ischemic stroke ( Gao et al., 2017 ; Zhang et al., 2017 ; Guo et al., 2018 ; Feng et al., 2020 ; Wang et al., 2020 ). Previous studies confirmed that miR-200a-3p mediated NLRP3 inflammasome activation in inflammation and brain injury ( Ding et al., 2018 ; Yu, 2019).…”

The Role of NF-κB Triggered Inflammation in Cerebral Ischemia

“…Among the different receptor proteins that can form inflammasomes, NLRP3 is one of the best characterized component of an NLR family (Wen et al, 2013 ; Broz and Dixit, 2016 ). NLRP3 inflammasome is formed by NACHT, a nucleotide binding and oligomerization domain, a C-terminal leucine-rich repeat (LRR), N-terminal adaptor protein ASC [that contains a pyrin domain (PYD)] and procaspase-1 (Schroder and Tschopp, 2010 ; Voet et al, 2019 ; Feng et al, 2020 ).…”