NOD-like receptor protein 3 (NLRP3) inflammasome activation in macrophages requires two signals. Which of the following represents the SECOND signal ('Signal 2') that directly activates the NLRP3 complex?
- A TLR4 ligation by LPS activating NF-κB and upregulating NLRP3 and pro-IL-1β expression
- B Potassium efflux, lysosomal disruption by uric acid crystals, or mitochondrial ROS ✓
- C ASC (apoptosis-associated speck-like protein) phosphorylation by IRAK4
- D Caspase-8 activation via the extrinsic apoptosis pathway
Explanation
NLRP3 inflammasome activation requires a two-signal model: Signal 1 (priming) is NF-κB-mediated transcriptional upregulation of NLRP3 and pro-IL-1β/pro-IL-18 via TLR/cytokine receptor activation. Signal 2 (activation) consists of diverse danger signals that directly oligomerize NLRP3: potassium efflux (the most conserved signal, reduced intracellular K+ is the proximal trigger), lysosomal damage and cathepsin B release (from uric acid, cholesterol crystals, silica particles), mitochondrial ROS, and extracellular ATP (via P2X7 receptor-driven K+ efflux). NLRP3 oligomerization recruits ASC through PYD-PYD interactions, which then recruits pro-caspase-1 through CARD-CARD interactions, leading to caspase-1 autoactivation and cleavage of pro-IL-1β, pro-IL-18, and GSDMD.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.