Pathogenesis of acute stroke and the role of inflammasomes
TL;DR: The molecular structure, cellular signaling pathways and current evidence for inflammasome activation following cerebral ischemia, and the potential for future treatments for stroke that may involve targeting inflammaome formation or its products in the ischemic brain are described.
About: This article is published in Ageing Research Reviews.The article was published on 2013-09-01. It has received 258 citations till now. The article focuses on the topics: NLRP6 & Inflammasome.
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TL;DR: An overview of the cellular and molecular biology of brain aging, how those processes interface with disease-specific neurodegenerative pathways, and how metabolic states influence brain health is provided.
586 citations
Cites background from "Pathogenesis of acute stroke and th..."
...In addition, some neurons in the ischemic penumbra may die by another recently described type of death called pyroptosis, which involves caspase 1 activation, formation of pores in the plasma membrane, and release of IL-1b (Fann et al., 2013; Adamczak et al., 2014)....
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...Glial cells, particularly microglia, often exhibit an activated state in the aged brain that is characterized by the acquisition of an ameboid morphology and the production of pro-inflammatory cytokines including interleukin 1b (IL-1b), IL-6, and tumor necrosis factor a (TNF-a) (Cribbs et al., 2012; Norden and Godbout, 2013)....
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TL;DR: This review summarizes recent progress concerning the mechanisms involved in brain damage, repair and regeneration related to microglia/macrophage activation and phenotype transition after stroke and argues that future translational studies should be targeting multiple key regulating molecules to improve brain repair.
445 citations
Cites background from "Pathogenesis of acute stroke and th..."
...In particular, the NLRP1 and NLRP3 inflammasomes mediate the production of proinflammatory mediators that play crucial roles in stroke-induced brain injury (Fann et al., 2013a)....
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...In addition, intravenous immunoglobulin can suppress NLRP1 and NLRP3 inflammasome activity and result in the protecting of neurons in experimental stroke models (Fann et al., 2013b)....
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...Moreover, NLRP1 andNLRP3 inflammasome suppression by intravenous immunoglobulin reduced neuronal cell death and behavioural deficits related to stroke (Fann et al., 2013b)....
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...Inflammatory mechanisms mediated by inflammasomes provide a better insight into neuronal and glial cell death in stroke (Fann et al., 2013a)....
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TL;DR: In this Review, many of the numerous distinct mechanisms for the self-regulation and cross-regulation of innate immune receptor signalling are described.
Abstract: In the initiation of innate immune responses against pathogens, pattern-recognition receptors (PRRs) have an essential role in recognizing specific components of microorganisms and triggering responses that eliminate the invading microorganisms. However, inappropriate activation of PRRs can lead to prolonged inflammation and even to autoimmune and inflammatory diseases. Thus, PRR-triggered responses are regulated through the degradation or translocation of the innate receptors themselves and through the involvement of intracellular regulators or amplifiers. In addition, a complex interplay between PRRs and/or other immune pathways finely tunes the outcome of host immune defence responses. In this Review, I describe many of the numerous distinct mechanisms for the self-regulation and cross-regulation of innate immune receptor signalling.
422 citations
TL;DR: In this article, the authors present the currently available data on redox biology in physiological/pathophysiological conditions and in OSA/IH, in order to better understand the apparently contradictory findings on damage vs. repair.
385 citations
TL;DR: A series of promising therapeutic approaches that target theNLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds are reviewed, however, these approaches are still experimental in neurological diseases.
Abstract: Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.
313 citations
Cites background from "Pathogenesis of acute stroke and th..."
...Moreover, emerging studies have revealed the involvement of NLRP3 signaling in several neurological disorders (Gris et al., 2010; Hoegen et al., 2011; Fann et al., 2013b; Heneka et al., 2013; Johann et al., 2015)....
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...Interference of NLRP3 activation improved cerebral ischemia outcomes, as evidenced by reduced infarction volumes and decreased levels of neurovascular damage (Fann et al., 2013b; Yang et al., 2014)....
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...It remains debated whether neurons express NLRP3 (Fann et al., 2013a; Yang et al., 2014; Kaushal et al., 2015)....
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References
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TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
10,685 citations
TL;DR: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; altePlase was more frequently associated with symptomatic intracranial hemorrhage.
Abstract: Background Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke. Methods After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. Results We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alte plase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P = 0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P = 0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P = 0.008). Mortality did not differ significant ly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P = 0.68). There was no significant difference in the rate of other serious adverse events. Conclusions As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)
5,491 citations
TL;DR: In this article, the inflammasome is identified as a caspase-activating complex that comprises caspases-1, casp-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs.
5,032 citations
TL;DR: This work has shown that tissue stress or malfunction induces an adaptive response that is intermediate between the basal homeostatic state and a classic inflammatory response, which is referred to here as para-inflammation.
Abstract: Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
4,832 citations