Apoptosis, Necrosis, and Necroptosis in the Gut and Intestinal Homeostasis

Abstract

Intestinal epithelial cells (IECs) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is critical for electrolyte passage, nutrient absorption, and interaction with commensal microbiota. Moreover, IECs are strongly involved in the intestinal mucosal inflammatory response as well as in mucosal innate and adaptive immune responses. Cell death in the intestinal barrier is finely controlled, since alterations may lead to severe disorders, including inflammatory diseases. The emerging picture indicates that intestinal epithelial cell death is strictly related to the maintenance of tissue homeostasis. This review is focused on previous reports on different forms of cell death in intestinal epithelium.

Figure 1

Cell death pathways. Apoptosis, necroptosis, and pyroptosis are programmed forms of cell death, while necrosis represents an unregulated cell death. Autophagy is a survival pathway that if it is excessive or uncontrolled, it promotes cell death. Fas-associated protein with a death domain (FADD); receptor-interacting interacting protein 1 (RIP1); receptor-interacting interacting protein (RIP3); mixed lineage kinase domain-like (MLKL); danger-associated molecular patterns (DAMPs); pathogen-associated molecular patterns (PAMPs); nod-like receptor family, pyrin domain containing (NLRP)3; apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); autophagy-related genes (ATG); autophagy related 16-like 1 (ATG16L1); light chain 3 (LC3II); ER: endoplasmic reticulum.

Figure 2

TNF-induced programmed cell death pathways. Cell death is induced by various stimuli that are recognized by specific sensors. These receptors recruit the complex I protein platform (TRADD, RIP1, TRAF2, and cIAP1/2), activating the inflammatory response and survival. Deubiquitination of RIP1 induces complex II (FADD and caspase-8), activating the apoptotic pathway. Inhibition of caspase-8 and increase of RIP3 expression induces complex IIb (necrosome), activating the necroptotic pathway. TNF receptor 1 (TNFR1); TNFR-associated death domain (TRADD); receptor-interacting interacting protein 1 (RIP1); receptor-interacting interacting protein (RIP3); TNFR-associated factor 2 (TRAF2); inhibitor of apoptosis proteins 1 and 2 (cIAP1/2); linear ubiquitin chain assembly complex (LUBAC); Lys63-linked polyubiquitination (Lys63-Ub); LUBAC; TAB-transforming growth factor-activated kinase 1 (TAK1); cylindromatosis (CYLD); Fas-associated protein with a death domain (FADD); mixed lineage kinase domain-like (MLKL); Dynamin-related protein (Drp1); dendritic cells (DCs); Damage-Associated Molecular Patterns (DAMPS).