New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation

Journal of Neuroimmune Pharmacology, Год журнала: 2024, Номер 19(1)

Опубликована: Фев. 29, 2024

Abstract Inflammasomes are important modulators of inflammation. Dysregulation inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related inflammatory diseases. NLRP3 an intracellular sensor that recognizes pathogen-associated molecular patterns damage-associated resulting in assembly activation inflammasome. The includes NLRP3, adaptor apoptosis-associated speck-like (ASC), effector cysteine protease procaspase-1 plays imperative role caspase-1 stimulation which further initiates a secondary response. Regulation ameliorates NLRP3-mediated Much effort has been invested studying activation, exploration specific inhibitors epigenetic mechanisms controlling This review gives overview established assembly, its brief mechanistic activations well current update on non-specific could be used We also focused recently discovered mediated by DNA methylation, histone alterations, microRNAs regulating expression inflammasome, resulted novel method gaining insight into modulate activity introducing potential therapeutic strategies for CNS Graphical "Image missing"

Язык: Английский

---

Role of NLRP3 Inflammasome in Post-Spinal-Cord-Injury Anxiety and Depression: Molecular Mechanisms and Therapeutic Implications

ACS Chemical Neuroscience, Год журнала: 2023, Номер 15(1), С. 56 - 70

Опубликована: Дек. 18, 2023

The majority of research on the long-term effects spinal cord injury (SCI) has primarily focused neuropathic pain (NP), psychological issues, and sensorimotor impairments. Among SCI patients, mood disorders, such as anxiety depression, have been extensively studied. It found that chronic stress NP negative consequences reduce quality life for individuals living with SCI. Our review examined both human experimental evidence to explore connection between changes following inflammatory pathways, a specific focus NLRP3 inflammasome signaling. We observed increased proinflammatory factors in blood, well brain tissues models. plays crucial role various diseases by controlling release molecules like interleukin 1β (IL-1β) IL-18. Dysregulation key regions associated processing, prefrontal cortex hippocampus, contributes development disorders In this review, we summarized recent expression regulation components related signaling Finally, discussed potential therapeutic approaches target regulate cytokines way treat

Язык: Английский

---

Acacetin inhibits inflammation by blocking MAPK/NF-κB pathways and NLRP3 inflammasome activation

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Фев. 8, 2024

Objective: Our preliminary research indicates that acacetin modulates the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin containing 3 (NLRP3) inflammasome, providing protection against Alzheimer’s Disease (AD) and cerebral ischemic reperfusion injury. The mechanisms of to inhibit activation NLRP3 inflammasome remain fully elucidated. This study aims investigate effects potential on various agonists induced activation. Methods: A model for was established in mouse bone marrow-derived macrophages (BMDMs) using Monosodium Urate (MSU), Nigericin, Adenosine Triphosphate (ATP), Pam3CSK4, separately. Western blot analysis (WB) employed detect Pro-caspase-1, Pro-Interleukin-1β (Pro-IL-1β) cell lysates, caspase-1, IL-1β supernatants. Enzyme-Linked Immunosorbent Assay (ELISA) used measured release IL-1β, IL-18, Tumor Necrosis Factor-alpha (TNF-α) supernatants assess impact lactate dehydrogenase (LDH) also assessed. Nuclear Factor Kappa B (NF-κB) Mitogen-Activated Protein Kinase (MAPK) signaling pathways related proteins were evaluated by WB, NF-κB nuclear translocation observed via laser scanning confocal microscopy (LSCM). Disuccinimidyl Suberate (DSS) cross-linking Apoptosis-associated Speck-like protein a Caspase Recruitment Domain (ASC), LSCM observe Reactive Oxygen Species (ROS) production. Inductively Coupled Plasma (ICP) N-(6-methoxyquinolyl) acetoethyl ester (MQAE) assays utilized determined efflux potassium (K+) chloride (Cl-) ions. Results: Acacetin inhibited agonists, reducing TNF-α, LDH. It suppressed expression Lipopolysaccharides (LPS)-activated Phosphorylated ERK (p-ERK), p-JNK, p-p38, p65 phosphorylation translocation. reduced ROS production ASC aggregation, thus suppressing Notably, did not affect K+ Cl-ions during process. Conclusion: shows inhibitory both priming assembly processes positioning it as promising new candidate treatment inflammasome-related diseases.

Язык: Английский

---

NLRP3 inflammasome in atherosclerosis: Mechanisms and targeted therapies

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июль 31, 2024

Atherosclerosis (AS) is the primary pathology behind various cardiovascular diseases and leading cause of death disability globally. Recent evidence suggests that AS a chronic vascular inflammatory disease caused by multiple factors. In this context, NLRP3 inflammasome, acting as signal transducer immune system, plays critical role in onset progression AS. The inflammasome involved endothelial injury, foam cell formation, pyroptosis Therefore, targeting offers new treatment strategy for This review highlights latest insights into pathogenesis pharmacological therapies focusing on optimal targets small molecule inhibitors. These are valuable rational drug design assessment targeted inhibitors treating

Язык: Английский

---

Can pyroptosis be a new target in rheumatoid arthritis treatment?

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июнь 22, 2023

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of undefined etiology, with persistent synovial inflammation and destruction articular cartilage bone. Current clinical drugs for RA mainly include non-steroidal anti-inflammatory (NSAIDs), glucocorticoids, modifying anti-rheumatic (DMARDs) so on, which can relieve patients’ joint symptoms. If we want to have complete cure RA, there are still some limitations these drugs. Therefore, need explore new mechanisms prevent treat radically. Pyroptosis newly discovered programmed cell death (PCD) in recent years, characterized by the appearance holes membranes, swelling rupture, release intracellular pro-inflammatory factors into extracellular space, resulting strong inflammatory response. The nature pyroptosis pro-inflammatory, whether it participating development has attracted wide interest among scholars. This review describes discovery mechanism pyroptosis, main therapeutic strategies role development. From perspective study may provide potential target treatment clinics.

Язык: Английский

---

Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression

Neural Regeneration Research, Год журнала: 2023, Номер 19(9), С. 1890 - 1898

Опубликована: Дек. 14, 2023

Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to pathogenesis various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding role that inflammasome-mediated neuroinflammation plays in depression may be beneficial for future therapeutic strategies. this review, we aimed elucidate mechanisms lead activation as well provide insight into strategies target inflammasome. Moreover, outlined inflammasome, including inflammatory pathway inhibitors, natural compounds, other compounds been shown effective treating Additionally, summarized application inhibitors clinical trials Currently, there scarcity dedicated investigating applications treatment. The modulation microglia holds promise management Further investigations necessary ascertain efficacy safety these approaches potential novel antidepressant treatments.

Язык: Английский

---

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(11), С. 6078 - 6078

Опубликована: Май 31, 2024

Epilepsy is one of the most prevalent and serious brain disorders affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms prevent occurrence future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing multifaceted nature epileptogenesis its association with Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires comprehensive understanding underlying mechanisms these for development targeted therapeutic strategies beyond conventional antiseizure treatments. Several types NLRP3 inhibitors been developed their has validated both vitro vivo models In this review, we discuss advances regulatory activation as well progress made, challenges faced treatment epilepsy.

Язык: Английский

---

NOD-like receptor protein 3 inhibitors in St. John's wort and their potential antidepressant effects

International Journal of Biological Macromolecules, Год журнала: 2025, Номер 306, С. 141721 - 141721

Опубликована: Март 3, 2025

Язык: Английский

---

NLRP3 inflammasome in neuroinflammation and central nervous system diseases

Cellular and Molecular Immunology, Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Abstract Neuroinflammation plays an important role in the pathogenesis of various central nervous system (CNS) diseases. The NLRP3 inflammasome is intracellular multiprotein complex composed innate immune receptor NLRP3, adaptor protein ASC, and protease caspase-1. activation can induce pyroptosis release proinflammatory cytokines IL-1β IL-18, thus playing a inflammatory responses. Recent studies have revealed that activated brain to neuroinflammation, leading further neuronal damage functional impairment, contributes pathological process neurological diseases, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s stroke. In this review, we summarize neuroinflammation course CNS diseases discuss potential approaches target for treatment

Язык: Английский

---

Modulating the NLRP3 Inflammasome: Acitretin as a potential treatment for Sepsis-induced acute lung injury

International Immunopharmacology, Год журнала: 2025, Номер 153, С. 114504 - 114504

Опубликована: Апрель 1, 2025

Acitretin, a well-established dermatological drug primarily used for psoriasis treatment, has been clinically several decades. However, its potential role in modulating inflammation sepsis remains unexplored. This study seeks to explore the impact of acitretin on sepsis-induced acute lung injury (ALI) and elucidate underlying mechanisms involved. In mouse model induced by lipopolysaccharide (LPS), we assessed effects ALI. Transcriptome sequencing tissue was performed identify relevant signaling pathways. vitro, bone marrow-derived macrophages (BMDMs) were treated with (1 μM, 5 μM 10 μM) evaluate NOD-, LRR- pyrin domain-containing protein 3(NLRP3) inflammasome activation pyroptosis. vivo, wild-type, Nlrp3 knockout, Gsdmd knockout mice confirm NLRP3 mediating acitretin's effects. Acitretin significantly mitigated ALI, reducing mortality LPS-challenged mice. analysis revealed that suppressed pathway tissue. dose-dependently inhibited interleukin (IL)-1β release, caspase-1 p20 production, GSDMD cleavage BMDMs. Furthermore, preventing ASC oligomerization interaction NLRP3. reduced inflammation, IL-1β levels bronchoalveolar lavage fluid, ratio wet dry wide-type mice, but these abolished demonstrated significant anti-inflammatory properties through suppression inflammasome, suggesting as therapeutic strategy related complications.

Язык: Английский

---