Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

Abstract

BackgroundNod-like receptor protein 3 (NLRP3) inflammasome is a crucial factor in mediating inflammatory responses after cerebral ischemia/reperfusion (I/R), but the cellular location of NLRP3 inflammasome in cerebral I/R has yet come to a conclusion, and there is still no specific evidence to state the relationship between mitochondria and the NLRP3 inflammasome in cerebral I/R.MethodsIn the present study, we detected the cellular localization of NLRP3 inflammasomes in a transient middle cerebral artery occlusion (tMCAO) rat model and a transwell co-culture cell system under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Then, we investigated the relationship between mitochondrial dysfunction and the activation of NLRP3 inflammasomes in different cell types after OGD/R and cerebral I/R injury.ResultsOur results showed that NLRP3 inflammasomes were first activated in microglia soon after cerebral I/R injury onset and then were expressed in neurons and microvascular endothelial cells later, but they were mainly in neurons. Furthermore, mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R, and mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats.ConclusionOur findings may provide novel insights into the cell type-dependent activation of NLRP3 inflammasomes at different stages of cerebral I/R injury and the role of mitochondrial dysfunction in activating the NLRP3 inflammasome pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1282-6) contains supplementary material, which is available to authorized users.

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

“…Meng et al (2019) demonstrated that PPARγ activation exerts an anti-inflammatory effect by suppressing NLRP3 inflammasome activation in spinal cord-derived neurons. Further, NLRP3 inflammasome activation has been reported in microglia and neurons after OGD/reperfusion in vitro and during cerebral ischemia/reperfusion (Gong et al, 2018;Guo et al, 2018). Therefore, we speculated that NLRP3 inflammasome might be a promising therapeutic target for SCI.…”

“…NLRP3 inflammasome is assembled by NLRP3, ASC, and Caspase-1 after exogenous infection and endogenous signal stimulation; subsequently, there is Caspase-1 activation and the release of downstream inflammatory factors, such as IL-1β and IL-18 (Yan et al, 2015). Studies have reported NLRP3 inflammasome activation in microglia and neurons after oxygen-glucose deprivation (OGD)/reperfusion in vitro and in cerebral ischemia/reperfusion (Gong et al, 2018;Guo et al, 2018). There is post-SCI activation of NLRP3 inflammasome in an animal model involving microglia and spinal cord tissue (Grace et al, 2016;Jiang et al, 2016;Zendedel et al, 2016).…”

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Although inflammasome signaling in the CNS is mainly attributed to microglia, the key innate immune cells of the brain, expression of inflammasome components has also been reported in other cell types of the CNS, including neurons (Kaushal et al , ), astrocytes (Freeman et al , ), perivascular CNS macrophages (Kawana et al , ), oligodendrocytes (Mckenzie et al , ), and endothelial cells (Gong et al , ) (Fig ). However, current understanding of inflammasome activation in microglia and its role in CNS inflammation and disease is still fragmentary and primarily based on in vitro studies with primary microglia and microglial cell lines, and in vivo studies with transgenic knockout mice that lack expression of specific inflammasome components throughout the body.…”

Effects of Thymoquinone on Small-Molecule Metabolites in a Rat Model of Cerebral Ischemia Reperfusion Injury Assessed using MALDI-MSI

“…A cerebral ischemia reperfusion model was established using the tMCAO method [28], i.e., reperfusion for 24 h following ischemia for 2 h. Rats were intraperitoneally injected with 60 mg/kg pentobarbital sodium, following which the right common carotid artery, external carotid artery, and internal carotid artery were exposed. The silicone-coated MCAO filament (wire diameter: 0.28 mm; head diameter: 0.38 ± 0.02 mm; and wire length: 45 mm) was inserted into the internal carotid artery through the external carotid artery incision and was directed to the start point of the anterior artery to block the blood flow to the middle cerebral artery.…”