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      Inflammasomes in neuroinflammatory and neurodegenerative diseases


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          Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin ( IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.

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          Most cited references106

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          Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome.

          Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 inflammasome-driven diseases.
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            Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.

            Macrophages respond to Salmonella typhimurium infection via Ipaf, a NACHT-leucine-rich repeat family member that activates caspase-1 and secretion of interleukin 1beta. However, the specific microbial salmonella-derived agonist responsible for activating Ipaf is unknown. We show here that cytosolic bacterial flagellin activated caspase-1 through Ipaf but was independent of Toll-like receptor 5, a known flagellin sensor. Stimulation of the Ipaf pathway in macrophages after infection required a functional salmonella pathogenicity island 1 type III secretion system but not the flagellar type III secretion system; furthermore, Ipaf activation could be recapitulated by the introduction of purified flagellin directly into the cytoplasm. These observations raise the possibility that the salmonella pathogenicity island 1 type III secretion system cannot completely exclude 'promiscuous' secretion of flagellin and that the host capitalizes on this 'error' by activating a potent host-defense pathway.
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              Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease

              The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

                Author and article information

                EMBO Mol Med
                EMBO Mol Med
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                23 April 2019
                June 2019
                : 11
                : 6 ( doiID: 10.1002/emmm.v11.6 )
                : e10248
                [ 1 ] VIB Center for Inflammation Research Ghent Belgium
                [ 2 ] Department of Biomedical Molecular Biology Ghent University Ghent Belgium
                [ 3 ] Department of Internal Medicine Ghent University Ghent Belgium
                [ 4 ] Janssen Immunosciences, World without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson Beerse Belgium
                Author notes
                [*] [* ] Corresponding author. Tel: +32 14 605 343; E‐mail: mlamkanf@ 123456its.jnj.com

                Corresponding author. Tel: +32 93313761; Fax: +32 92217673; E‐mail: geert.vanloo@ 123456irc.vib-ugent.be

                Author information
                © 2019 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 26 December 2018
                : 21 March 2019
                : 03 April 2019
                Page count
                Figures: 3, Tables: 2, Pages: 16, Words: 13908
                Funded by: Queen Elisabeth Medical Foundation
                Funded by: CBC Banque Prize
                Funded by: Concerted Research Actions (GOA) of the Ghent University
                Funded by: European Research Council
                Award ID: 683144
                Funded by: Charcot Foundation
                Funded by: FWO
                Funded by: Belgian Foundation Against Cancer
                Custom metadata
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:07.06.2019

                Molecular medicine
                Molecular medicine
                disease, inflammasome, inflammation, microglia, neurodegeneration, immunology, neuroscience


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