Research Progress on the Role of Inflammasomes in Kidney Disease

Figure 1

Canonical NLRPs can be activated by a variety of PAMPs and DAMPs, including influenza viruses, Listeria monocytogenes, extracellular ATP, hyaluronic acid, glucose, amyloid-β, silicon, and cholesterol crystals. These stimuli activate NLRP inflammasomes by triggering several common activation mechanisms, resulting in NLRP oligomerization. Active NLRPs interact with ASC to induce oligomerization, thereby forming protein complexes, further recruiting procaspase-1 to ASC to form inflammasomes, and leading to the cleavage of procaspase-1 into active caspase-1. Activated caspase-1 causes the cleavage of pro-IL-1β and pro-IL-18, leading to the maturation and secretion of various proinflammatory cytokines, including IL-1β and IL-18, inducing inflammatory responses. The cleavage of GSDMD and caspase-1 produces an N-terminal fragment (GSDMD-NT) that has affinity for phosphatidylinositol, phosphatidylserine, and cardiolipin. This fragment creates pores on the cell membrane, resulting in pyroptosis. The formation of pores also allows the extracellular release of active IL-1β and IL-18, thereby promoting an inflammatory response. After AIM2 and pyrin are activated by dsDNA and Rho GTPase, respectively, ASC and caspase-1 are also recruited to form canonical inflammasomes. Lysis of pro-IL-1β, pro-IL-18, and GSDMD results in the release of inflammatory factors and pyroptosis. Noncanonical inflammasomes activate caspase-11, caspase-4, and caspase-5 by directly binding to intracellular LPS and its component lipid A via their CARD domain. GSDMD is subsequently cleaved, and pyroptosis is induced. Activation of noncanonical inflammasomes may also lead to the assembly of canonical NLRP3 inflammasomes and induce the canonical inflammasome pathway, the mechanism of which may be related to mitochondrial ROS production and intracellular K+ efflux.