From the Guidelines
DAMPs activate the NLRP3 inflammasome. The relationship between Damage-Associated Molecular Patterns (DAMPs) and NLRP3 is that DAMPs, such as mitochondrial DNA (mtDNA), can activate the NLRP3 inflammasome, leading to the production of pro-inflammatory cytokines like IL-1β and IL-18 1.
Key Points
- MtDNA acts as a DAMP: MtDNA can be released into the cytosol due to stress, injury, or necrosis, and activate the NLRP3 inflammasome 1.
- NLRP3 activation: The activation of NLRP3 leads to the cleavage of pro-IL-1β and pro-IL-18 by caspase-1, resulting in pyroptotic cell death 1.
- Mitochondrial dysfunction: Mitochondrial dysfunction due to excessive oxidative stress can also elicit NLRP3 oligomerization or induce α-tubulin acetylation to bring mitochondria to the proximity of NLRP3 1.
- MtROS augmentation: MtROS can augment the effect of mtDNA on NLRP3 activation as well as the downstream processes 1.
Evidence
The study published in Redox Biology in 2018 provides evidence for the role of DAMPs in activating the NLRP3 inflammasome 1. Another study published in the Journal for ImmunoTherapy of Cancer in 2020 discusses the sources of immunogenic cell death adjuvanticity, including DAMPs and their role in activating the NLRP3 inflammasome 2.
Clinical Implications
Understanding the relationship between DAMPs and NLRP3 can provide insights into the development of innovative therapeutic approaches for diseases involving inflammation and cell death, such as ischemic stroke 1.
From the Research
Relationship between DAMP and NLRP3
- The NLRP3 inflammasome is activated by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) 3, 4, 5.
- Upon activation by DAMPs, NLRP3 oligomerizes and activates caspase-1, which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18 4.
- DAMPs play a crucial role in the activation of the NLRP3 inflammasome, leading to the production of inflammatory mediators and the promotion of inflammation 3, 5.
- The NLRP3 inflammasome is a key player in antiviral responses, and DAMPs generated during viral replication trigger the NLRP3 inflammasome-dependent antiviral immune responses 5.
Role of DAMPs in Inflammatory Diseases
- DAMPs contribute to the host's defense but can also promote pathological inflammatory responses 6.
- Various DAMPs, such as high-mobility group box 1 (HMGB1), S100 proteins, and heat shock proteins (HSPs), are increased and considered to have a pathogenic role in inflammatory diseases 6.
- DAMPs play an important role in inflammation and inflammatory diseases, and targeting DAMP-sensing receptors may be a clinical strategy to treat DAMP-associated diseases 7.
Mechanism of NLRP3 Activation
- The activation of the NLRP3 inflammasome is tightly regulated by various positive and negative signaling pathways to respond to stimuli without damaging the host itself while maintaining homeostasis 3.
- The NLRP3 inflammasome is regulated by multiple signaling pathways, including TLRs, MAPK, mTOR, autophagy, PKA, AMPK, and IFNR 3.