Regulated necrosis: the expanding network of non-apoptotic cell death pathways

Abstract

Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Although RIPK1 (receptor-interacting protein kinase 1)- and RIPK3-MLKL (mixed lineage kinase domain-like)-mediated necroptosis is the most understood form of regulated necrosis, other examples of this process are emerging, including cell death mechanisms known as parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis. Elucidating how these pathways of regulated necrosis are interconnected at the molecular level should enable this process to be therapeutically targeted.

Exposure of phosphatidylserine on the cell surface

“…Although apoptosis has been considered to be responsible for all programmed cell death, 72 recent studies indicate that cell death can also occur by programmed necrosis 73 by 44 Schroeder et al, 45 Caputo et al 46 and Suzuki et al 40,53 The scramblase activity and tissue distribution are from Suzuki et al 53 The diseases associated with TMEM16 are from Munchau et al 127 and Charlesworth et al 128 for TMEM16C, from Tsutsumi et al…”

Tumour devascularisation as a potential immunotherapeutic strategy

“…In turn, these molecules then activate toll-like receptors (TLRs) 2 and 4 and CD91 on dendritic cells promoting endocytosis of cell debris as well as tumour antigen processing and presentation. 25–27 …”

A matter of regeneration and repair: caspases as the key molecules

“…As a result of inhibition of apoptosis-and autophagy-related specific proteins, this type of cell death can be converted into necrosis (Golstein and Kroemer, 2006;Kroemer et al, 2009). However, necroptosis is a programmed type of cell death mechanism that occurs in response to some inflammatory diseases when there is no or blocked caspase activity (Vercammen et al, 1998;Berghe et al, 2014). This type of cell death was first observed in L929 cells stimulated with TNF-α in the presence of caspase inhibitor, and thus it was demonstrated that low levels of caspase activity have a protective effect.…”