Inhibiting Caspase-12 Mediated Inflammasome Activation protects against Oxygen-Glucose Deprivation Injury in Primary Astrocytes

Abstract

Stroke is one of the leading causes of death worldwide. Accumulating evidence suggests that NLRP3 inflammasome activation plays an important role in ischemic stroke injury. However, the existence of the NLRP3 inflammasome in astrocytes remains controversial. In this study, we demonstrated the presence of the NLRP3 inflammasome in primary mouse astrocytes and investigated the role of caspase-12 in NLRP3 inflammasome activation and cell injury in an in vitro astrocyte oxygen-glucose deprivation (OGD) model. Astrocytes exposed to 2, 3, and 4 h of OGD exhibited increased cell injury and apoptosis, and the protein levels of caspase-12, cleaved caspase-3, NLRP3 inflammasome components, and IL-1β were also significantly elevated. Interestingly, pretreatment with the caspase-12-specific inhibitor Z-ATAD-FMK attenuated cell injury and apoptosis and decreased the levels of NLRP3, caspase-1, IL-1β, and cleaved caspase-3 in the OGD group. In conclusion, Z-ATAD-FMK protected astrocytes against OGD-induced cell death and inhibited NLPR3-inflammasome activation. Our results indicate that caspase-12 and its potential regulation of NLRP3 inflammasome activation might be a promising target for treatment of ischemic stroke.

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures

“…An emerging body of research has supported the role of caspase-4, caspase-5, and caspase-11 in regulating caspase-1 activation and inducing the inflammatory form of cell death called pyroptosis [92,93]. Moreover, the role of caspase-12, which is expressed by astrocytes and is important for caspase-1 and NLRP3 activation, should also be considered [94].…”

Analysis of specific lipid metabolites in cord blood of patients with gestational diabetes mellitus

“…Based on LC-MS tandem analysis, lysophosphatidylcolines was evaluated as a potential biomarker of cancer (Zhang et al, 2019). Lysophosphatidylcolines derived from adipocytes activate Nod-like receptor protein 3 (NLPR3) inflammasomes in adipocytes and macrophages in adipose tissue that mediate homocysteine-induced insulin resistance, resulting a decrease in the efficiency of insulin in promoting glucose uptake and utilization (Liu et al, 2020;Wan et al, 2019). The insulin resistance is often accompanied by hyperinsulinemia, which can easily lead to metabolic syndrome and type 2 diabetes mellitus (Ahmed et al, 2020b;Giraud-Billoud et al, 2018).…”

“…Glycophorophosphocholine is an ether lipid with a 1-o-alk-1'-alkenyl ether bond at the sn-1 position of the main chain of glycerol. Abnormal levels of ether glycerophosphatidylcholine (ether PCs) have been associated with cell dysfunction and various human diseases (Liu et al, 2020). Glycerophosphocholine (GPC) metabolites can promote atherosclerosis and increase cardiovascular disease risk (Tuboly et al, 2019).…”

Caspases help to spread the message via extracellular vesicles

“…Both small and large EVs have been demonstrated to be produced under such pyroptotic, as well as necrotic, conditions, but their functional significance as intercellular communicators is yet to be studied in detail [143,144]. Beyond the inflammatory caspases, additional caspase members have been implicated in immune regulation in both mammalian and nonmammalian organisms, via mechanisms that are incompletely understood [145][146][147][148][149][150]. In Caenorhabditis elegans, Weaver et al determined that CED-3 (equivalent to mammalian caspase-9) limited PMK-1 (p38 MAPK) signalling in a non-apoptotic manner to provide a balance point between development and the stress-response [150].…”