Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke

Abstract

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.

Keywords: Inflammation; Ischemic stroke; NLRP3 inflammasome; Reactive oxygen species; Signaling pathway.

Fig. 1

Mechanisms of NLRP3 inflammasome activation. Decreases in intracellular K⁺ concentrations, increases in intracellular Ca²⁺ concentrations, and excessive ROS production activate the NLRP3 inflammasome. As an inhibitor of the TRX system, TXNIP has been proven to mediate generation of large amounts of ROS and to activate the NLRP3 inflammasome. The activation of P2X7R caused by elevated ATP concentrations leads to increased intracellular Ca²⁺ concentrations and K⁺ outflow, resulting in activation of the NLRP3 inflammasome. Cathepsin is released into the cytoplasm after lysosomal membrane rupture, which induces activation of the NLRP3 inflammasome via cleavage of NLRP3 receptor-associated inhibitory domains or inhibitory proteins. dsRNA, increased intracellular Ca²⁺ levels, K⁺ outflow, increased ROS and other cellular stress factors activate PKR, and PKR activates the NLRP3 inflammasome. Anaerobic glycolysis results in the accumulation of large amounts of H⁺ and lactic acid, causing acidosis and ultimately activating the NLRP3 inflammasome

Fig. 2

Metabolic changes in the intracellular and extracellular environments activate the NLRP3 inflammasome, leading to pyroptosis. Pyroptosis is characterized by GSDMD-mediated cell death. Extracellular and intracellular environments undergo metabolic changes, including reductions in ATP, efflux of intracellular K⁺, increases in intracellular Ca²⁺, and production of large amounts of ROS by mitochondria; the ROS cannot be normally removed, and the NLRP3 inflammasome is activated, prompting pro-caspase-1 to self-cleave into caspase-1. Then, caspase-1 lyses and activates GSDMD, leading to pore formation, membrane lysis, and DNA breakage.

Fig. 3

Possible drug actions targeting the different mechanisms of NLRP3 inflammasome activation. EPA: eicosapentaenoic acid; MNS: 3,4-methylenedioxy-beta-nitrostyrene; ω-3FAs: omega-3 fatty acids; ARC: arctigenin; SINO: sinomenine; Nrf2: nuclear factor erythrocyte 2–related factor 2; BHB: β-hydroxybutyrate; NM: nafamostat mesilate; IFN-β: interferon-β; UMB: umbelliferone; Eze: ezetimibe; IVIG: intravenous immunoglobulin; GDL: ginkgo diterpene lactones; DAMP: damage-associated molecular pattern; GPR40/GPR20: G protein–coupled receptor (GPCR) 40/20; ASIC: acid-sensing ion channel; CasR/GPR6CA: Ca²⁺-sensing receptor/GPCR family C group 6 member A; NCX: Na⁺/Ca²⁺ exchanger; IL-18R: interleukin-18 receptor; IL-1R: interleukin-1 receptor; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa B; MAPK: mitogen-activated protein kinase; PIP2: phosphatidylinositol-4,5-diphosphate; PLC: phospholipase C; DAG: diacylglycerol; InsP3: inositol triphosphate 3; ROS: reactive oxygen species; ASC: apoptosis-associated speck-like protein with a CARD; PKR: protein kinase R; TXNIP: thioredoxin-interacting protein; Bcl-2: B-cell lymphoma 2; Casp 1: caspase-1; GSDMD: gasdermin D

Fig. 4

Crosstalk among several physiological and pathological processes leads to neuronal death after stroke. Misfolded proteins and paraproteins trigger ER stress and the UPR to activate the NLRP3 inflammasome and aggravate inflammatory responses; the NLRP3 inflammasome can also promote the UPR and ER stress. ROS accumulation, Ca²⁺ dyshomeostasis, and ER stress excessively activate autophagy. Autophagy normally inhibits the NLRP3 inflammasome but can induce NLRP3 inflammasome activation when it is excessive. The NLRP3 inflammasome can also act on autophagy. Lipid peroxide accumulation results in ferroptosis, and there is probably crosstalk between ferroptosis and NLRP3 inflammasome activation. ER stress, excessive autophagy, ferroptosis, and the NLRP3 inflammasome together form an LNAS