Immunological consequences of necrotic cell death

Cell death is fundamental for all living organisms. Originally, cell death was divided into two basic forms, termed apoptosis (programmed cell death) and necrosis (accidental cell death), which were distinguished primarily by their morphology as observed by pathologists. While originally considered to be unprogrammed, necrosis is now understood to also be a regulated process that can be genetically and chemically manipulated. Many pathways of regulated necrosis have now been discovered, including necroptosis, pyroptosis, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, parthanatos, and NETosis. Despite advances in the understanding of regulated necrosis, further advancements in knowledge are hindered by a lack of appropriate technologies.For example, the cleavage events during necroptosis are not yet known at the single-cell level, nor is it known how necroptotic cells communicate with their environment.

My laboratory has, in recent years, pioneered studies on necroptotic mechanisms, showing how these dying cells are recognised by neighbouring cells by an ‘eat me’ and ‘find me’ signals. Furthermore, we found that necroptotic cell may also stimulate neighbouring cells by releasing either specific extracellular vesicles (‘necroptotic bodies’) or specific danger associated molecular patterns (DAMPs). Here, I will discuss these results in the context of our suggested model of three necroptotic immunological waves: (i) generation of extracellular vesicles (EVs), (ii) release of cytoplasmic molecules, and (iii) release of nuclei molecules.