Necroptosis: an emerging type of cell death in liver diseases

Abstract

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.

Keywords: Apoptosis; Cell death; Liver disease; Necroptosis; Programmed necrosis.

Figure 1

Diagrammatic representation of necroptosis pathway. Apoptosis and necroptosis can share the same death inducers molecules such as tumor necrosis factor-α (TNF-α), FasL, and TNF-related apoptosis-inducing ligand (TRAIL). The intracellular domain of TNF receptor (TNFR)1 further recruits many intracellular proteins including TNF receptor-associated death domain protein (TRADD), TNF receptor associated factor (TRAF), and receptor-interacting serine-threonine kinase 1 (RIP1). RIP1 phosphorylates and activates RIP3 which later forms the complex together with mixed lineage kinase domain-like (MLKL). C-Jun N-terminal kinase (JNK) and MLKL act downstream of RIP3. There is a possibility that some other unknown kinases might be acting between RIP1 and RIP3 which could explain why certain liver diseases do not show the protective effects of necrostatin-1.

Figure 2

Types of cell deaths. The classification shown in not generalized and is presented only for descriptional purpose. RIP: Receptor interacting proteins.