Fig. 4

The roles of cathepsins in inflammation response. NLRP3 inflammasome activation occurs in the following ways. (1) Lysosomes ruptured by ROS and phagocytosis-derived molecules (LDL and Aβ40/42) release CTSB and CTSL into the cytoplasm, where they activate NLRP3 containing leucine-rich repeat (LRL), NACHT, and pyrin domain (PYD) domains and induce oligomerization with pro-caspase-3/-9 (pro-cas-3/-99) and apoptosisrelated speck-like protein including a caspase recruitment domain (CARD-ASC) to develop the inflammasome complex. (2) CTSB and CTSL negatively regulate NLRP3 inflammasome activation via the degradation of NLRP10. (3) CTSB can also facilitate the formation of the inflammasome NLRP3 complex induced by the free fatty acid palmitate and toll-like receptor 2/4 (TLR2/4)-mediated blood serum amyloid A (SAA) protein. The activated NLRP3 inflammasome generates the active caspase-3/-9 (cas-3/-9) form that can result in endothelial cell permeability/apoptosis or the activation of pro-interleukin (IL)-1β and pro-IL-18, thereby releasing these mature cytokines into blood. EC: endothelial cell; NLRP3: specific NACHT, LRR, and PYD domains-containing protein 3; NF-κB, nuclear factor-κB