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      Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury


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          Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated.


          Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice.


          The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr −/− mice and cultured Ldlr −/− neuron after experimental stroke.


          These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.

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          Most cited references69

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          Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

          Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.
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            Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death.

            Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies identified the pyroptosis executioner, gasdermin D (GSDMD), a substrate of both caspase-1 and caspase-11/4/5. GSDMD represents a large gasdermin family bearing a novel membrane pore-forming activity. Thus, pyroptosis is redefined as gasdermin-mediated programmed necrosis. Gasdermins are associated with various genetic diseases, but their cellular function and mechanism of activation (except for GSDMD) are unknown. The gasdermin family suggests a new area of research on pyroptosis function in immunity, disease, and beyond.
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              Pore-forming activity and structural autoinhibition of the gasdermin family.

              Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.

                Author and article information

                zwsemail@sina.com , zwsemail@sina.com
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                5 November 2020
                5 November 2020
                : 17
                : 330
                [1 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Neurology, , Jinling Clinical College of Nanjing Medical University, ; 305 East Zhongshan Road, Nanjing, 210002 Jiangsu Province China
                [2 ]GRID grid.73113.37, ISNI 0000 0004 0369 1660, Department of Neurology, Shanghai Changhai Hospital, , Second Military Medical University/Naval Medical University, ; Shanghai, 200433 China
                [3 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, Department of Neurology, Jinling Hospital, , Medical School of Nanjing University, ; Nanjing, 210002 China
                [4 ]GRID grid.59053.3a, ISNI 0000000121679639, Stroke Center & Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, , University of Science and Technology of China, ; Hefei, 230036 Anhui China
                [5 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Neurology, Jinling Hospital, the First School of Clinical Medicine, , Southern Medical University, ; Nanjing, 210002 China
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                : 23 December 2019
                : 7 October 2020
                Funded by: National Nature Science Foundation of China
                Award ID: 81671170
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003995, Natural Science Foundation of Anhui Province;
                Award ID: No. 2008085QH368
                Award Recipient :
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                © The Author(s) 2020

                low-density lipoprotein receptor (ldlr),inflammasome,pyroptosis,neuroinflammation,ischemia/reperfusion


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