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      Inflammasomes in neuroinflammation and changes in brain function: a focused review

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          Abstract

          Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system (CNS) disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the CNS against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation, and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment, and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimer's disease (AD) and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses. It has been reported that while these inflammasomes may be activated through TNF-α dependent pathways, other cytokines, like IFN-γ, may assist in inhibiting their activation and thus delay disease progression. Furthermore, some other cytokines, including IL-6, may not have a direct role in inflammasome-mediated diseases. An array of recent research suggests that NLRP inflammasomes targeted therapies could be used for alleviating neuroinflammation and for treatment of associated psychiatric illnesses, although this still remains a challenge and necessitates further extensive research. This review examines the complex inflammatory signaling pathways involved in the activation of NLRP inflammasomes and the role they play in promoting neuroinflammation and subsequent behavioral changes.

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          Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

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            The inflammasomes.

            Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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              The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.

              Generation of Interleukin (IL)-1beta via cleavage of its proform requires the activity of caspase-1 (and caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive. Here we report the identification of a caspase-activating complex that we call the inflammasome. The inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs. Using a cell-free system, we show that proinflammatory caspase activation and proIL-1beta processing is lost upon prior immunodepletion of Pycard. Moreover, expression of a dominant-negative form of Pycard in differentiated THP-1 cells blocks proIL-1beta maturation and activation of inflammatory caspases induced by LPS in vivo. Thus, the inflammasome constitutes an important arm of the innate immunity.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                07 October 2014
                2014
                : 8
                Affiliations
                1Psychiatric Neuroscience Lab, Discipline of Psychiatry, School of Medicine, University of Adelaide Adelaide, SA, Australia
                2Discipline of Anatomy and Physiology, School of Medical Sciences, University of Adelaide Adelaide, SA, Australia
                Author notes

                Edited by: Luba Sominsky, RMIT University, Australia

                Reviewed by: Trisha Anne Jenkins, RMIT University, Australia; Ruth M. Barrientos, University of Colorado, USA

                *Correspondence: Bernhard T. Baune, Psychiatric Neuroscience Lab, Discipline of Psychiatry, School of Medicine, University of Adelaide, Level 4, Eleanor Harrald Building, North Terrace, Adelaide, SA - 5005, Australia e-mail: bernhard.baune@ 123456adelaide.edu.au

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience.

                Article
                10.3389/fnins.2014.00315
                4188030
                Copyright © 2014 Singhal, Jaehne, Corrigan, Toben and Baune.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 4, Tables: 0, Equations: 0, References: 164, Pages: 13, Words: 11227
                Categories
                Endocrinology
                Review Article

                Neurosciences

                depression, alzheimer's disease, neuroinflammation, cytokines, il-1, aging, inflammasomes, nlrp

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