Complex Roles of Caspases in the Pathogenesis of Inflammatory Bowel Disease  Christoph Becker, Alastair J. Watson, Markus F. Neurath  Gastroenterology  Volume 144, Issue 2, Pages 283-293 (February 2013) DOI: 10.1053/j.gastro.2012.11.035 Copyright © 2013 AGA Institute Terms and Conditions

Figure 1 Caspases mediate extrinsic and intrinsic apoptosis. The extrinsic apoptosis pathway is activated when death receptor ligands such as TNF-α bind their receptor. The activated receptor recruits FADD. This interaction forms a death-inducing signaling complex, which recruits pro-caspase-8, leading to its autocatalytic cleavage and activation. Activated caspase-8 cleaves and activates caspase-3 and other effector caspases that mediate the cell death pathway (the caspase cascade). The intrinsic apoptosis pathway is induced at the mitochondria by cellular stress (such as DNA damage or oxidative or endoplasmic reticulum (ER) stress). The initiator pro-caspase-9 forms a complex with the mitochondrial protein cytochrome c and apoptotic protease activating factor (APAF)-1 to form the apoptosome. Activated caspase-9 cleaves and activates caspase-3. The extrinsic and intrinsic pathways interact, as caspase-8 cleaves the BH3 interacting-domain death agonist (Bid); truncated BID (tBid) disrupts the outer mitochondrial membrane to cause release of cytochrome c, which activates caspase-9. Together, these pathways lead to apoptotic processing of the cell. Gastroenterology 2013 144, 283-293DOI: (10.1053/j.gastro.2012.11.035) Copyright © 2013 AGA Institute Terms and Conditions

Figure 2 Activation and function of caspase-1 in the inflammasome. Pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) are recognized by NLRs in the cytoplasm. On activation, NLRs recruit the adaptor ASC and pro-caspase-1 into the inflammasome protein complex. Formation of the inflammasome induces self-cleavage and activation of pro-caspase-1. Activated caspase-1 subsequently cleaves the pro-forms of IL-1β and IL-18. Mature IL-1β and IL-18 are secreted to promote inflammation. Gastroenterology 2013 144, 283-293DOI: (10.1053/j.gastro.2012.11.035) Copyright © 2013 AGA Institute Terms and Conditions

Figure 3 Regulation of necroptosis by caspase-8 in the ripoptosome. Heterodimers of cFLIP and caspase-8 mediate survival and cell death. The reduced catalytic activity of caspase-8 in the heterodimer of caspase-8 and cFLIP is not sufficient to induce apoptosis but is sufficient to prevent RIP3-dependent necroptosis by cleaving RIP1 and RIP3. In contrast, if FADD is absent or caspase-8 activity is fully blocked, RIP3 is recruited to RIP1, resulting in the phosphorylation and activation of each. RIP3 phosphorylates PGAM5L and MLKL, which disrupts mitochondrial function and leads to membrane damage and necroptosis. Gastroenterology 2013 144, 283-293DOI: (10.1053/j.gastro.2012.11.035) Copyright © 2013 AGA Institute Terms and Conditions

Figure 4 A model for the role of necroptosis of IECs and Paneth cells in development of Crohn's disease. In the normal terminal ileum, Paneth cells activate caspase-8 to prevent necroptosis. In contrast, during development of Crohn's disease, inflammatory cytokines such as TNF promote necroptosis and death of IECs and Paneth cells. Loss of these cells impairs antimicrobial defense and barrier function, leading to translocation of bacteria and immune activation. Gastroenterology 2013 144, 283-293DOI: (10.1053/j.gastro.2012.11.035) Copyright © 2013 AGA Institute Terms and Conditions