NALP3 inflammasome activation in protein misfolding diseases

Shi, Fushan; Kouadir, Mohammed; Yang, Yang

doi:10.1016/j.lfs.2015.05.011

Cited by 35 publications

(25 citation statements)

References 78 publications

(96 reference statements)

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“…Prion diseases are caused by the conversion of cellular prion protein (PrP C ) to the pathological isoform PrP Sc through conformational changes (Shi F. et al, 2015). Aggregated PrP Sc peptides lead to the activation of microglia and astrocytes, which results in the release of pro-inflammatory cytokines and neurotoxic factors (Tribouillard-Tanvier et al, 2009).…”

Section: Nlrp3 Inflammasome and Neurological Diseasesmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

353

275

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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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Section: Nlrp3 Inflammasome and Neurological Diseasesmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

353

275

View full text Add to dashboard Cite

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“…This process leads to the maturation of the pro-inflammatory cytokines (IL-1β, . Secretion of IL-1β by glial cells contributes towards the destruction of dopaminergic neurons in the brain of PD patients [15] and the initiation of cell pyroptotic death [16,17]. Hence, suppression of NLRP3 inflammasomederived IL-1β production may be beneficial to PD patients.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2 receptor restricts astrocytic NLRP3 inflammasome activation via enhancing the interaction of β-arrestin2 and NLRP3

et al. 2018

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Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1β (IL-1β) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. β-arrestin2-mediated dopamine D2 receptor (Drd2) signal transduction has been regarded as a potential anti-inflammatory target. Our previous study revealed that astrocytic Drd2 suppresses neuroinflammation in the central nervous system. However, the role of Drd2 in astrocytic NLRP3 inflammasome activation and subsequent IL-1β production remains unclear. In the present study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model to investigate whether Drd2 could suppress astrocytic NLRP3 inflammasome activation. We showed that Drd2 agonist inhibited NLRP3 inflammasome activation, evidenced by decreased caspase-1 expression and reduced IL-1β release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in β-arrestin2 knockout and β-arrestin2 small interfering RNA-injected mice, suggesting a critical role of β-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1β expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that β-arrestin2 mediated the inhibitory effect of Drd2 on NLRP3 inflammasome activation via interacting with NLRP3 and interfering the inflammasome assembly. Collectively, our study illustrates that astrocytic Drd2 inhibits NLRP3 inflammasome activation through a β-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.

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“…Then caspase‐1 was activated to promote maturation and release of interleukin 1β (IL‐1β) and IL‐18, causing a variety of inflammatory responses. Changes in NLRP3 itself or NLRP3 inflammasome have been implicated in infection (such as human immunodeficiency virus infection and chlamydial infection), autoinflammation (such as cryoprin‐associated periodic syndrome), autoimmune (such as ulcerative colitis, Crohn's disease) and gout, Alzheimer's as well as Parkinson's diseases …”

Section: Introductionmentioning

confidence: 99%