What can activate the NLRP3 (Nucleotide-binding domain, Leucine-rich Repeat-containing family, Pyrin domain-containing 3) inflammasome?

From the Guidelines

The NLRP3 inflammasome can be activated by a diverse range of stimuli, including mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA), as well as other pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) 1.

Key Activators of NLRP3 Inflammasome

• Mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) play important roles in triggering the innate immune response via the NLR family pyrin-domain-containing protein 1/3 (NLRP1/3) and p38/NF-κB signaling pathways, respectively 1
• Bacterial components like lipopolysaccharide (LPS) can also activate the NLRP3 inflammasome, as seen in the context of nonalcoholic fatty liver disease (NAFLD) 1
• Endogenous danger signals, such as ATP, uric acid crystals, cholesterol crystals, amyloid-β fibrils, and glucose, can activate NLRP3 1
• Cellular stress conditions, including potassium efflux, calcium signaling disruption, mitochondrial dysfunction, and reactive oxygen species (ROS) production, can trigger NLRP3 activation 1

Clinical Implications

The activation of the NLRP3 inflammasome has been implicated in various diseases, including inflammatory disorders, cardiovascular disease, and cancer 1. Understanding the mechanisms of NLRP3 activation is crucial for the development of therapeutic strategies to modulate the inflammatory response and prevent disease progression.

Evidence Quality and Recommendations

The evidence for NLRP3 inflammasome activation is based on a range of studies, including those published in reputable journals such as Redox Biology 1, Gastroenterology 1, and British Journal of Pharmacology 1. The most recent and highest-quality study, published in 2024, highlights the importance of inflammation in the pathogenesis of atrial fibrillation and the role of the NLRP3 inflammasome in this process 1. Based on this evidence, it is clear that the NLRP3 inflammasome plays a critical role in the inflammatory response and that its activation can have significant clinical implications.

From the Research

Activation of NLRP3 Inflammasome

The NLRP3 inflammasome can be activated by various stimuli, including:

• Microbial toxins 2
• ATP 2, 3
• Particulate matter 2
• Nigericin 3
• Uric acid crystals 3
• Amyloid-β fibrils 3
• Extracellular ATP 3
• Lysosomal rupture 2
• Ion influx 4
• Mitochondrial dysfunction 4
• Reactive oxygen species production 4
• Lysosomal damage 4

Role of NEK7 in NLRP3 Inflammasome Activation

The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase 3. The structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells 3.

Activation Pathways

There are three types of activation pathways for the NLRP3 inflammasome:

• "Classical" activation pathway 5
• "Non-canonical" activation pathway 5
• "Alternative" activation pathway 5

Factors that Activate NLRP3 Inflammasome

A variety of factors can activate the NLRP3 inflammasome, including:

• Genetic factors 5
• Environmental factors 5
• Chemical factors 5
• Viral infection 5