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Cited by 469Inflammasome and immune disordersNeuroinflammation and Neurodegeneration MechanismsImmune Response and Inflammation

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NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

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Song, Limin, Pei, Lei, Yao, Shanglong, Wu, Yan, Shang, You·2017·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2017.00063PMC PMC5343070
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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.

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Figures

Figure 1 NLRP3 inflammasome: structure and function. The NLRP3 inflammasome mainly consists of the cytosolic sensor molecule NLRP3, the adaptor protein ASC, and the effector molecule pro-caspase-1. The assembly and activation of NLRP3 inflammasome results in caspase-1 activation. Activated caspase-1 subsequently leads to the maturation of IL-1β and IL-18, as well as mediates a form of inherent inflammatory cell death termed as pyroptosis. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; CARD, caspase activation and recruitment domain; GSDMD, gasdermin D; GSDMD-NT, gasdermin-N domain of GSDMD; IL, interleukin; LRR, leucine-rich repeat; NACHT (NOD), nucleotide binding and oligomerization domain; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; PYD, pyrin-only domain.
Figure 1 NLRP3 inflammasome: structure and function. The NLRP3 inflammasome mainly consists of the cytosolic sensor molecule NLRP3, the adaptor protein ASC, and the effector molecule pro-caspase-1. The assembly and activation of NLRP3 inflammasome results in caspase-1 activation. Activated caspase-1 subsequently leads to the maturation of IL-1β and IL-18, as well as mediates a form of inherent inflammatory cell death termed as pyroptosis. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; CARD, caspase activation and recruitment domain; GSDMD, gasdermin D; GSDMD-NT, gasdermin-N domain of GSDMD; IL, interleukin; LRR, leucine-rich repeat; NACHT (NOD), nucleotide binding and oligomerization domain; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; PYD, pyrin-only domain.CC BY · PubMed Central
Figure 2 NLRP3 inflammasome activation-mediated neuroinflammation. Upon activation by a wide range of exogenous and endogenous stimuli, the NLRP3 inflammasome located in microglia and astrocytes trigger the maturation of IL-1β and IL-18 and induce pyroptotic cell death. The high levels IL-1β and IL-18 bind to their receptors on glial cells, neurons, macrophages and endothelial cells, as well as cooperate with other cytokines to initiate Th-cell signaling, thereby triggering a complex spectrum of signaling events, which results in exacerbation of inflammatory cascade responses within the central nervous system (CNS). Aβ, β-amyloid; ATP, adenosine triphosphate; BBB, blood–brain barrier; IL, interleukin; MSU, monosodium urate; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; Th, T helper.
Figure 2 NLRP3 inflammasome activation-mediated neuroinflammation. Upon activation by a wide range of exogenous and endogenous stimuli, the NLRP3 inflammasome located in microglia and astrocytes trigger the maturation of IL-1β and IL-18 and induce pyroptotic cell death. The high levels IL-1β and IL-18 bind to their receptors on glial cells, neurons, macrophages and endothelial cells, as well as cooperate with other cytokines to initiate Th-cell signaling, thereby triggering a complex spectrum of signaling events, which results in exacerbation of inflammatory cascade responses within the central nervous system (CNS). Aβ, β-amyloid; ATP, adenosine triphosphate; BBB, blood–brain barrier; IL, interleukin; MSU, monosodium urate; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; Th, T helper.CC BY · PubMed Central
Figure 3 Therapeutic approaches to targeting the NLRP3 inflammasome. The cartoon depicts the schematic mode of various therapeutic approaches described in detail in the text. Several steps in NLRP3 activation and the IL-1 pathway have been identified as targets for anti-neuroinflammatory therapies. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; BBG, brilliant blue G; BHB, β-hydroxybutyrate; IL, interleukin; IL-1R, interleukin-1 receptor; MNS, 3,4-methylenedioxy-β-nitrostyrene; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; P2X7R, P2X purinergic receptor 7; TLR, Toll-like receptor.
Figure 3 Therapeutic approaches to targeting the NLRP3 inflammasome. The cartoon depicts the schematic mode of various therapeutic approaches described in detail in the text. Several steps in NLRP3 activation and the IL-1 pathway have been identified as targets for anti-neuroinflammatory therapies. ASC, apoptosis-related speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; BBG, brilliant blue G; BHB, β-hydroxybutyrate; IL, interleukin; IL-1R, interleukin-1 receptor; MNS, 3,4-methylenedioxy-β-nitrostyrene; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3; P2X7R, P2X purinergic receptor 7; TLR, Toll-like receptor.CC BY · PubMed Central

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  1. Becher, 2000, Brain-immune connection: immuno-regulatory properties of CNS-resident cells, Glia, 29, 293, 10.1002/(SICI)1098-1136(20000215)29:4293::AID-GLIA13.3.CO;2-1 · DOI

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Metadata

Authors
Song, L., Pei, L., Yao, S., Wu, Y., & Shang, Y.
Affiliations
  • Wuhan Union Hospital (CN)
  • Huazhong University of Science and Technology (CN)
Corresponding author
  • Wu, Yan
  • Shang, You
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2017-03-09
Volume
11
Pages
63-63
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2017.00063
PMC
PMC5343070
OpenAlex
W2591960163
Cited by
467
References
255
Citations by year
2026: 29 · 2025: 42 · 2024: 52 · 2023: 66 · 2022: 60 · 2021: 74 · 2020: 51 · 2019: 41 · 2018: 35 · 2017: 13
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81270018, 81471202, 81271270)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
NLRP3 inflammasome, neuroinflammation, neurological disorders, caspase-1, IL-1β, IL-18, neurodegenerative diseases, brain infection, acute brain injury, NLRP3 inhibitors, anti-IL-1 therapy, conditional knockout mice

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