Fig. 3.

Regulation of NLRP3 Inflammasome Activation by Reactive Oxygen Species. In response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which are stimuli that indicate a disruption in cellular homeostasis, NLRP3, ASC, and caspase-1 assemble into a supramolecular complex, the inflammasome, that processes the inactive form of the pro-inflammatory cytokine interleukin-1β (pro-IL-1β) into its active form (IL-1β) and promotes inflammation. NLRP3 inflammasome stimuli induce mitochondrial reactive oxygen species (ROS) production. ROS might act directly on inflammasome components by oxidizing thiols. Super oxide dismutase (SOD) prevents the accumulation of excess levels of ROS that inhibit inflammasome activation. ROS-mediated release and/or damage of mitochondrial molecules produce mitochondrial DAMPs (mtDAMPs) that bind to NLRP3 (see Fig.4 for more details). ROS promote calcium (Ca²⁺) influx by activating plasma membrane cation channels. Mitochondrial dysfunction caused by Ca²⁺ uptake further promotes mitochondrial ROS release. ROS have been implicated in potassium (K⁺) efflux, which activates the inflammasome via a mechanism that might enhance Ca²⁺ influx. Oxidation of thioredoxin (TRX) by ROS causes dissociation of thioredoxin-interacting protein (TXNIP) from TRX. Subsequent binding of NLRP3 by TXNIP, possibly at the mitochondria, leads to inflammasome activation. In response to lipopolysaccharide (LPS) detection, NF-κB upregulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) that can inhibit inflammasome activation. TXNIP inhibits the transcriptional activity of NF-κB to attenuate this upregulation and thus prevent inhibition of inflammasome activation. Under no/low oxidative stress conditions, Nrf2 is in a complex comprising Keap1 and the mitochondrial outermembrane protein PGAM5. Oxidation of thiols in Keap1 releases Nrf2 from the complex and leads to Nrf2 association with and activation of the inflammasome. Some Nrf2 translocates to the nucleus and upregulates heme oxygenase-1 (HO-1) expression, which in turn activates the inflammasome. Nrf2 also upregulates expression of anti-oxidant genes, which attenuate ROS levels, and mitophagy-activating genes, which decrease ROS produced by dysfunctional mitochondria. Nrf2 further modulates inflammasome activation by repressing TXNIP expression.