Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

Swanton, Tessa; Cook, James; Beswick, James; Freeman, Sally; Lawrence, Catherine B.; Brough, David

doi:10.1177/2472555218786210

Cited by 20 publications

(15 citation statements)

References 316 publications

(501 reference statements)

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“…However, it is important to determine whether the same mechanisms occur in cells that may experience tissue-specific disease conditions. Recent research has demonstrated that microglia form inflammasomes during Alzheimer's disease (19), and inflammasomes are implicated in the progression of a number of other neurological and neurodegenerative conditions (20). Thus, we investigated the relationship between IL-1β release and membrane permeability and cell death in cultures of glial cells (astrocytes and microglia) isolated from the brains of mice.…”

Section: Resultsmentioning

confidence: 99%

“…All animal procedures were performed with appropriate personal and project licenses in place, in accordance with the Home Office (Animals) Scientific Procedures Act (1986) and approved by the Home Office and the local Animal Ethical Review Group, University of Manchester. As described previously (20), brain tissue was mechanically digested, and cells were maintained in DMEM, 10% FBS, PenStrep until 80% confluence was reached (10–13 days in vitro ). Cultures were then reseeded at a density of 1.7 × 10 5 cells/ml.…”

Section: Methodsmentioning

confidence: 99%

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The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

Tapia

Daniels

Palazón-Riquelme

et al. 2019

Journal of Biological Chemistry

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Interleukin (IL)-1 family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the secretion of the three best-characterized members of the IL-1 superfamily, IL-1α, IL-1β, and IL-18, in a range of conditions and cell types, including murine bone marrow–derived and peritoneal macrophages, human monocyte–derived macrophages, HeLa cells, and mouse embryonic fibroblasts. We discovered that IL-1β and IL-18 share a common secretory pathway that depends upon membrane permeability and can operate in the absence of complete cell lysis and cell death. We also found that the pathway regulating the trafficking of IL-1α is distinct from the pathway regulating IL-1β and IL-18. Although the release of IL-1α could also be dissociated from cell death, it was independent of the effects of the membrane-stabilizing agent punicalagin, which inhibited both IL-1β and IL-18 release. These results reveal that in addition to their role as danger signals released from dead cells, IL-1 family cytokines can be secreted in the absence of cell death. We propose that models used in the study of IL-1 release should be considered context-dependently.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

Tapia

Daniels

Palazón-Riquelme

et al. 2019

Journal of Biological Chemistry

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“…Notably, in addition to ischemia/reperfusion diseases, inflammasomes have been implicated in the pathogenesis of many other diseases, including neurodegenerative diseases. Thus, development of small molecules that target different inflammasomes, but primarily NLRP3 inflammasome, has attracted considerable attention over the past decades [ 10 , 33 ]. MCC950 is regarded as the most specific NLRP3 inhibitor to date, as it does not inhibit the NLRP1, NLRC4, and AIM2 inflammasomes [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation

Jiang

Ran

Lyu

et al. 2020

J Neuroinflammation

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Background Cardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined. Methods Mice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated. Results Using our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced. Conclusions Our data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.

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“…This class of compounds inhibits ATP‐ and nigericin‐mediated activation of the NLRP3 inflammasome (Daniels et al, ). This mechanism of action is independent of COX enzyme inhibition and seems to involve inhibition of the volume‐regulated anion channels (Swanton et al, ). Mefenamic acid and flufenamic acid have weak potency but are specific for NLRP3 over other inflammasomes.…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

Nizami

Hall-Roberts

Warrier

et al. 2019

British J Pharmacology

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One of the largest unmet medical needs is a disease‐modifying treatment for Alzheimer's disease (AD). Recently, the role of microglia in disease, particularly AD, has gained great interest, following the identification of several disease risk‐associated genes that are highly expressed in microglia. Microglia play a critical homeostatic role in the brain, with neuroinflammatory and phagocytic mechanisms being of particular importance. Here, we review the role of NLRP3, the complement system, and the triggering receptor expressed in myeloid cells 2 (TREM2) in modulating microglial functions. We have reviewed the targets, their molecular pathways and the therapeutic interventions aimed at modulating these targets, in the hope of discovering a novel therapeutic approach for the treatment of AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

Cited by 20 publications

References 316 publications

The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation

Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets

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