Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype

Hou, Baohua; Zhang, Yahui; Liang, Peiyu; He, Yuan; Peng, Biwen; Liu, Wanhong; Han, Song; Yin, Jun; He, Xiaohua

doi:10.1038/s41419-020-2565-2

Cited by 138 publications

(84 citation statements)

References 66 publications

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“…Of notice, inflammasome activation has been associated with cognitive symptoms in several human diseases ( 18 ) and with cognitive deficits in autoimmune experimental models ( 19 ). As such, we further investigated inflammasome activation as a possible mechanism behind the low-grade inflammation observed and the cognitive deterioration.…”

Section: Resultsmentioning

confidence: 99%

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study

et al. 2020

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Background Cognition in the elderly is heterogeneous. Senescence of the immune system is increasingly considered as a potential player in cognitive performance. We explored here the interplay between cognitive performance and peripheral immune molecules in healthy older individuals. Methods A cross-sectional study of clinically well characterized senior healthy individuals (120; 51–87 years old) previously clustered as “Good” and “Poor” performers based on established tests that evaluate memory and executive function. A plasma concentration of 30 immune molecules was assessed by multiplex analysis and correlated with parameters of cognitive performance. Results Participants with worse cognitive performance (“Poor”) exhibited increased concentrations of IL-1β, IL-8, IL-13, and tumor necrosis factor (TNF) when compared to individuals with a better cognitive performance (“Good”). The cognitive dimensions memory and executive function, when considered separately, displayed a negative association with several immune molecules (IL-1β, IL-1RA, IL-6, IL-13, IP-10, and TNF with memory and only IL-1β with executive function), even controlling for age, sex, years of formal education, mood, and use of anti-inflammatory drugs. Regression analysis showed that several of these molecules (IL-1β, IL-6, IL-8, and IL-13) contribute to predicting whether an individual belongs to the “Good” or “Poor” cognitive performance group. Conclusion These results strengthen the hypothesis that increased concentrations of peripheral immune molecules, like IL-1β, are associated with worse cognitive performance in senior healthy individuals. It further highlights that some poorly studied immune molecules should be considered in the context of cognitive aging, such as IL-13, here revealed as a new player in such interaction.

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Section: Resultsmentioning

confidence: 99%

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study

et al. 2020

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“… 245 NLRP3 inhibition with MCC950 was shown to significantly suppress IL-1β production and airway inflammation in the lungs of mice with cystic fibrosis 246 and to prevent cognitive deficits in mice with experimental autoimmune encephalomyelitis (EAE). 247 However, recent studies have shown that MCC950/CRID3 targets wild-type NLRP3 but not NLRP3 gain-of-function point mutants related to CAPS. 248 The CFTR (inh) -172 analog CY-09 also inhibits NLRP3 ATPase activity by directly binding to the ATP-binding motif of the NLRP3 NACHT domain.…”

Section: Introductionmentioning

confidence: 99%

An update on the regulatory mechanisms of NLRP3 inflammasome activation

et al. 2021

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The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

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“…In this context, recent landmark studies have allowed the characterization of a population of neurotoxic astrocytes expressing complement component 3 (C3) in response to pro-inflammatory cytokines released by activated microglia [ 9 ]. This subset of reactive astrocytes, termed A1, exhibit transcriptional programs destructive to synapses and oligodendrocytes and inhibitory to remyelination with potential pathogenic consequences in human MS and animal models of the disease [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

et al. 2020

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The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS.

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Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype

Cited by 138 publications

References 66 publications

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study

An update on the regulatory mechanisms of NLRP3 inflammasome activation

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination

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