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

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          Abstract

          Background

          Nod-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.

          Methods

          In 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.

          Results

          Our 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.

          Conclusion

          Our 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 material

          The online version of this article (10.1186/s12974-018-1282-6) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke

          Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1β and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1β and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.
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            Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain.

            Iba1 is a novel calcium-binding protein and is specifically expressed in microglia in the brain. It has been suggested that Iba1 plays an important role in regulation of the function of microglia. In the present study we examined time-dependent Iba1 expression after transient middle cerebral artery occlusion and characterized microglial activation in various brain regions. Rat middle cerebral artery occlusion was induced by the intraluminal filament technique. After 1.5 hours of transient ischemia, Iba1 expression was examined by immunohistochemical and immunoblot analyses. The microglial activation in association with ischemic severity was characterized by double immunostaining with other specific markers. In the peri-ischemic area, heavily Iba1 immunoreactive cells rapidly appeared at 3.5 hours after reperfusion. Immunoreactivity was further increased and peaked at 7 days. In the ischemic core, round Iba1-positive cells, which may be blood-borne monocytes, appeared from 24 hours and reached a peak at 4 to 7 days. Double immunostaining revealed that activated microglia in the peri-ischemic area upregulated Iba1 expression but were negative for the macrophage marker ED1. ED1-positive cells were clearly restricted to the ischemic core. These findings suggest the following: (1) Iba1 expression may be associated with microglial activation in ischemic brain, and Iba1 immunostaining can be useful to evaluate the pathophysiological roles of activated microglia in ischemic injury. (2) Expression of ED1 antigen is strictly restricted to severe ischemic damage, whereas activated microglia in the peri-ischemic area showed Iba1 upregulation without ED1. Therefore, microglia may exhibit difference of antigenicity in the severity of ischemic brain injury.
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              Mitochondria: diversity in the regulation of the NLRP3 inflammasome.

              Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1-dependent secretion of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria-induced inflammasome activation centrally contributes to the inflammatory process that is responsible for obesity and associated metabolic diseases.
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                Author and article information

                Contributors
                gongzhe1415@163.com
                panjingrui06@163.com
                super-shen@126.com
                meillly@126.com
                2353352460@qq.com
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                28 August 2018
                28 August 2018
                2018
                : 15
                : 242
                Affiliations
                [1 ]ISNI 0000 0004 1791 7851, GRID grid.412536.7, Department of Neurology, , Sun Yat-sen Memorial Hospital, Sun Yat-sen University, ; Guangzhou, 510120 China
                [2 ]ISNI 0000 0004 1791 7851, GRID grid.412536.7, Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, , Sun Yat-sen Memorial Hospital, Sun Yat-sen University, ; Guangzhou, China
                Article
                1282
                10.1186/s12974-018-1282-6
                6114292
                30153825
                1eb66a66-029d-452d-864a-92fbc0679ce0
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 February 2018
                : 16 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81572481
                Award Recipient :
                Funded by: the key project of production, study and research of Guangzhou city
                Award ID: 201508020058
                Award Recipient :
                Funded by: the International Collaboration Program of Universities in Guangdong Province Grant
                Award ID: 2012 gjhz001
                Award Recipient :
                Funded by: the Science & Technique Plan fund of Guangdong Province
                Award ID: 2009B060700040
                Award Recipient :
                Funded by: the Sun Yat-Sen Scientific Research Sailing Project
                Award ID: YXQH201702
                Award Recipient :
                Funded by: the Guangdong Natural Science Foundation
                Award ID: 2017A030313655
                Award Recipient :
                Funded by: the Science &Technique Plan fund of Guangdong Province
                Award ID: 2013B021800098
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                stroke,nlrp3 inflammasome,mitochondrial dysfunction,microglia,neuron
                Neurosciences
                stroke, nlrp3 inflammasome, mitochondrial dysfunction, microglia, neuron

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