Sterile inflammatory responses mediated by the NLRP3 inflammasome

Abstract

Through pattern recognition receptors the innate immune system detects disruption of the normal function of the organism and initiates responses directed at correcting these derangements. Cellular damage from microbial or non-microbial insults causes the activation of nucleotide-binding domain leucine-rich repeat containing receptors in multiprotein complexes called inflammasomes. Here we discuss the role of the NLRP3 inflammasome in the recognition of cellular damage and the initiation of sterile inflammatory responses.

Figure 1. Model for NLRP3 inflammasome activation by microbes and danger signals

Activation of the NLRP3 inflammasome results in activation of caspase-1 and the resultant processing of pro-IL-1β into biologically active IL-1β. A wide variety of stimuli including bacterial pore-forming toxins and particulate activators such as silica, asbestos, uric acid, alum and amyloid-β can activate the NLRP3 inflammasome. NLRP3 activating PAMPs and DAMPs induce a K⁺ efflux and the generation of mitochondrial-derived ROS that play a role in NLRP3 inflammasome activation by an unknown mechanism. Lysosomal damage following crystalline particulate internalization may also influence NLRP3 inflammasome activation through an unknown mechanism that is inhibited by the cathepsin B inhibitor Ca-074-me.

Figure 2. Model for NLRP3 inflammasome activation by necrotic cells

Specific types of cellular damage, such as pressure-disruption or complement lysis, hypoxic injury or treatment with chemotherapeutic agents such as oxaliplatin, result in the release of actively respiring mitochondria (1) or cellular ATP (2). ATP generated by the mitochondria or ATP released from the necrotic cell is capable of activating the NLRP3 inflammasome in macrophages via the P2X7 receptor. Additional unidentified mitochondrial factors may also activate the NLRP3 inflammasome. Cellular damage caused by 7-bromoindirubin-3′-oxime (7BIO) or osmotic lysis results in activation of the NLRP3 inflammasome within the cell undergoing cell death (3). Activation of the NLRP3 inflammasome results in caspase-1 activation followed by processing and secretion of the proinflammatory cytokine IL-1β.