Can NLRP3 (Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3) activate cytoplasmic DNA?

From the Guidelines

NLRP3 can activate in response to cytoplasmic DNA, as it plays a crucial role in the innate immune response, particularly in the recognition of danger-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA) released into the cytosol 1.

Key Points

• NLRP3 inflammasome is activated by various stimuli, including cytoplasmic DNA, which leads to the cleavage of pro-inflammatory cytokines like IL-1β and IL-18 1.
• Mitochondrial DNA can be released into the cytosol and activate the NLRP3 inflammasome, triggering an inflammatory response 1.
• Pattern recognition receptors (PRRs), such as cyclic GMP-AMP synthase (CGAS), recognize cytosolic DNA and activate downstream signaling pathways, including the NLRP3 inflammasome 1.
• Immunogenic cell death (ICD) inducers can lead to the activation of NLRP3, resulting in the release of immunostimulatory molecules like ATP, HMGB1, and type I IFN, which promote the recruitment and activation of antigen-presenting cells (APCs) and T cells 1.

Relevant Mechanisms

• The activation of NLRP3 by cytoplasmic DNA involves the recognition of DAMPs by PRRs, leading to the assembly of the inflammasome complex and the cleavage of pro-inflammatory cytokines.
• The NLRP3 inflammasome plays a critical role in the innate immune response, particularly in the recognition of microbial and host-derived DAMPs.

From the Research

NLRP3 Activation

• The NLRP3 inflammasome is a cytoplasmic protein complex that mediates inflammatory responses to a broad array of danger signals 2.
• NLRP3 senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense 3.

Role of DNA in NLRP3 Activation

• Intracellular mitochondrial DNA (mtDNA) can be oxidized and transferred to the cytoplasm, where it directly binds to NLRP3 to activate the NLRP3 inflammasome 4.
• The NLRP3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells, with Nlrp3(-/-) DCs experiencing significantly less oxidative DNA damage mediated by ROS 2.
• There is no direct evidence that NLRP3 can activate cytoplasmic DNA, but it can be activated by mitochondrial DNA and other danger signals.

Mechanism of NLRP3 Activation

• The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages, with deletion of the LRR domain inhibiting NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7 5.
• The endoplasmic reticulum (ER) plays a critical role in NLRP3 inflammasome activation, with ER-mitochondria contact sites providing a location for NLRP3 activation and ER-stress signaling contributing to NLRP3 inflammasome activation 3.