Sensing damage by the NLRP3 inflammasome

Abstract

The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesis.

Fig. 1

Pathophysiological role of the NLRP3 inflammasome in sterile inflammatory diseases.

Fig. 2. Mitochondrial dysfunction triggers NLRP3 inflammasome activation

Cellular stress or damage induced by DAMPs and PAMPs in the setting of a low intracellular potassium concentrations results in mitochondrial dysfunction and the generation of ROS. An unknown intermediate, likely of mitochondrial origin, triggers the activation of the NLRP3 inflammasome. Clearance of ROS-producing mitochondria by mitophagy prevents further NLRP3 inflammasome activation.

Fig. 3. Role of the Nlrp3 inflammasome in the cycle of organ damage and dysfunction induced by ischemia reperfusion

Ischemia reperfusion injury results in tissue necrosis with the subsequent release of DAMPs into the extracellular space. These DAMPs induce the priming and activation of the NLRP3 inflammasome in both leukocytes and parenchymal cells resulting in inflammation and possible organ damage.