As a key regulator of the innate immune system, the NLRP3 inflammasome responds to a variety of environmental insults through activation of caspase-1 and release of the proinflammatory cytokines IL-1β and IL-18. Aberrant NLRP3 inflammasome function is implicated in numerous inflammatory diseases, spurring drug discovery efforts at NLRP3 as a therapeutic target. A diverse array of small molecules is undergoing preclinical/clinical evaluation with a reported mode of action involving direct modulation of the NLRP3 pathway. However, for a subset of these ligands the functional link between live-cell target engagement and pathway inhibition has yet to be fully established. Herein we present a cohort of mechanistic assays to both query direct NLRP3 engagement in cells, and functionally interrogate different nodes of NLRP3 pathway activity. This system enabled the stratification of potency for five confirmed NLRP3 inhibitors, and identification of two reported NLRP3 inhibitors that failed to demonstrate direct pathway antagonism.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.chembiol.2023.09.016 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
ASIC1a mediated nucleus pulposus cells pyroptosis and glycolytic crosstalk as a molecular basis for intervertebral disc degeneration.
Inflamm Res
January 2025
Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
Background: One of the etiologic components of degenerative spinal illnesses is intervertebral disc degeneration (IVDD), and the accompanying lower back pain is progressively turning into a significant public health problem. Important pathologic characteristics of IVDD include inflammation and acidic microenvironment, albeit it is unclear how these factors contribute to the disease.
Purpose: To clarify the functions of inflammation and the acidic environment in IVDD, identify the critical connections facilitating glycolytic crosstalk and nucleus pulposus cells (NPCs) pyroptosis, and offer novel approaches to IVDD prevention and therapy.
Scopoletin alleviates acetaminophen-induced hepatotoxicity through modulation of NLRP3 inflammasome activation and Nrf2/HMGB1/TLR4/NF-κB signaling pathway.
Int Immunopharmacol
January 2025
Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, Yanbian University, Yanji, Jilin 133002, China. Electronic address:
Scopoleitin (SP), a bioactive compound from many edible plants and fruits, exerts a wide range of biological activities, however the role and mechanism of SP in acetaminophen (APAP)-induced hepatotoxicity remains unclear. In this study, we verified the protective effect of SP on APAP-induced liver injury (AILI) hepatotoxicity and explore the underlying molecular mechanisms. Here, we showed that SP alleviated AILI by reducing serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, hepatic histopathological damage, inflammation, and liver cell apoptosis.
View Article and Find Full Text PDFSLAMF8 Disrupts Epithelial Barrier in Chronic Rhinosinusitis with Nasal Polyps via M1 Macrophage Polarization.
Ann Allergy Asthma Immunol
January 2025
Department of Otorhinolaryngology Head and Neck Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China. Electronic address:
Background: Recent studies show that M1 macrophages accumulate predominantly in non-eosinophilic chronic rhinosinusitis with nasal polyps (neCRSwNP). However, the precise mechanisms regulating M1 macrophages and their impact on the epithelial barrier remain unclear.
Objective: We aim to investigate the expression and regulatory role of SLAMF8, a molecule exclusively expressed in myeloid cells, in M1 macrophage polarization and its potential contribution to neCRSwNP development.
Why do microplastics aggravate cholestatic liver disease? The NLRP3-mediated intestinal barrier integrity damage matter.
Environ Pollut
January 2025
Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410013, PR China. Electronic address:
Microplastics (MPs) are becoming a significant environmental and public health concern because they are present in freshwater and marine environments and are ingested by living organisms. Cholestatic liver disease (CLD) is closely related to intestinal homeostasis, but there are no data investigating the effects of MPs on CLD. In this study, we used Mdr2 mice (a model of CLD) to investigate the effects of polystyrene microplastics (PS-MPs, 0.
View Article and Find Full Text PDFThe absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy-induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation.
Int Immunopharmacol
January 2025
Department of Endocrinology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China. Electronic address:
The immune-responsive gene 1 (IRG1) protein plays a role in various pathological processes by connecting cellular metabolism to a range of cellular activities through the production of itaconate. Recent studies have highlighted the significance of IRG1 and itaconate in bone metabolism and homeostasis. However, the precise role of IRG1 in osteoporosis remains inadequately documented.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!