The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Blevins, Hallie; Xu, Yiming; Biby, Savannah; Zhang, Shijun

doi:10.3389/fnagi.2022.879021

Cited by 119 publications

(83 citation statements)

References 339 publications

(407 reference statements)

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“…Dysfunctional RPE cells by oxidative stress drives inflammation. ROS in RPE cells promote NF-κB signaling and nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome [ 36 , 37 ], which further upregulates IL-1β and IL-18 through the activation of caspase-1 [ 38 ]. ROS is also associated with angiogenesis in the retina and choroid [ 39 ].…”

Section: Oxidative Stress and Cellular Dysfunction In The Eyementioning

confidence: 99%

Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration

et al. 2022

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Aging leads to a gradual decline of function in multiple organs. Cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) are age-related ocular diseases. Because their pathogenesis is unclear, it is challenging to combat age-related diseases. Cellular senescence is a cellular response characterized by cell cycle arrest. Cellular senescence is an important contributor to aging and age-related diseases through the alteration of cellular function and the secretion of senescence-associated secretory phenotypes. As a driver of stress-induced premature senescence, oxidative stress triggers cellular senescence and age-related diseases by inducing senescence markers via reactive oxygen species and mitochondrial dysfunction. In this review, we focused on the mechanism of oxidative stress-induced senescence in retinal cells and its role in the pathogenesis of AMD.

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Section: Oxidative Stress and Cellular Dysfunction In The Eyementioning

confidence: 99%

Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration

et al. 2022

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“…This requires a system that is tightly regulated to allow for activation but also to ensure a limited amount of collateral damage. Dysregulation of the inflammasome can result in aberrant or excessive stimulation, contributing to pathologies related to auto-inflammatory conditions, cancer, cardiometabolic disorders, and neurodegenerative diseases (Anderson, Biggs, Rankin, & Havrda, 2022;Blevins, Xu, Biby, & Zhang, 2022;Boxberger, Hecker, & Zettl, 2019;Holbrook et al, 2021). Thus, genetic or environmental conditions that stimulate, alter, or disrupt inflammasome activation can have significant effects upon the organism.…”

Section: Examining Modifications To Inflammasome Activation By Test S...mentioning

confidence: 99%

Imaging Inflammasome Activation in Microglia

Martin

Harry

2022

Current Protocols

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Inflammasomes are multiprotein complexes that play key roles in the host's innate immune response to insult. The assembly of an inflammatory complex is initiated with the oligomerization of the upstream inflammasome-forming sensor and then follows a well-orchestrated multi-step process leading to downstream effector functions that are critical in the innate immune response. The final assembly of these steps provides a detectable readout of inflammasome complex activation in the form of an apoptosis-associated speck-like protein containing a CARD (ASC) speck. Inflammasome activation-and the release of IL-1β and ASC specks from the microglia, the brain resident immune cellhave been implicated in various neurological and neurodegenerative disorders. Protocols exist for the generation of fluorescent inflammasome indicator peripheral macrophages. Building upon these protocols, we describe here a protocol that details the generation of fluorescent inflammasome indicator microglia cells using recombinant retroviruses to transduce murine BV-2 cells. In this protocol, the cells are established in a manner to allow for experimental control of the initial priming step of the inflammasome activation process. We then provide a series of steps for using these reporter cells within an inflammasome activation assay and use real-time imaging of ASC-speck formation as an indicator of inflammasome activation. In addition, we describe strategies for using these cells for examining the effects of a test substance on inflammasome activation. This protocol offers an effective approach conducive to screening for and examining modifications of microglia inflammasome activation due to exposure to chemicals or pharmacological agents.

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“…The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is a multiple protein complex, consisting of NLRP3 protein as a sensor, apoptosis-associated speck-like protein (ASC) as an adaptor and caspase-1 as an effector. 81 Typically, the assembly of NLRP3 inflammasome requires a priming stage and activation. The priming of the formation of NLRP3 inflammasome needs upstream signals as the first signal from the engagement of pathogenassociated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) with TLR, NOD2, IL-1R, or tumor necrosis factor receptor (TNFR), which subsequently triggers the upregulation of NLRP3 and pro-inflammatory cytokines: pro-interleukin (IL)-1β and pro-IL-18 via NF-κB pathway.…”

Section: Targeting Nlrp3 Inflammasomementioning

confidence: 99%

Section: The Immune-related Mechanisms Of Btk Inhibition In the Centr...mentioning

confidence: 99%

“…After receiving stimuli as the second signal, NLRP3 oligomerizes and the NACHT domain of NLRP3 is activated by ATP and NEK7 binding. 81 , 82 Next, the PYD domain recruits the adaptor ASC through PYD-PYD interaction. The caspase recruitment domain (CARD) of ASC binds to pro-caspase-1 via CARD–CARD interaction, converting pro-caspase-1 to caspase-1, which finally forms the NLRP3–ASC–caspase-1 protein complex, known as NLRP3 inflammasome.…”

Section: The Immune-related Mechanisms Of Btk Inhibition In the Centr...mentioning

confidence: 99%

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The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

Cao¹,

Wang²,

Zhu³

2022

JIR

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Bruton's tyrosine kinase (BTK) is a central signaling node in B cells. BTK inhibition has witnessed great success in the treatment of B-cell malignancies. Additionally, in the immune system, BTK is also a prominent component linking a wide variety of immune-related pathways. Therefore, more and more studies attempting to dissect the role of BTK in autoimmune and inflammation progression have emerged in recent years. In particular, BTK expression was also found to be elevated within the central nervous system (CNS) during neuroinflammation. BTK inhibitors are capable of crossing the blood-brain barrier rapidly to modulate B cell functions, attenuate microglial activities and affect NLRP3 inflammasome pathways within the CNS to improve the outcome of diseases. Thus, BTK inhibition appears to be a promising approach to modulate dysregulated inflammation in the CNS and alleviate destruction caused by excessive inflammatory responses. This review will summarize the immunomodulatory mechanisms in which BTK is involved in the development of neurological diseases and discuss the therapeutic potential of BTK inhibition for the treatment of neuroinflammatory pathology.

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The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Cited by 119 publications

References 339 publications

Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration

Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration

Imaging Inflammasome Activation in Microglia

The Immunomodulatory Functions of BTK Inhibition in the Central Nervous System

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