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Review
. 2018 Jul 6;15(1):199.
doi: 10.1186/s12974-018-1235-0.

Necroptosis: a regulated inflammatory mode of cell death

Yogesh K Dhuriya  1   2 , Divakar Sharma  3   4
Affiliations
Review

Necroptosis: a regulated inflammatory mode of cell death

Yogesh K Dhuriya et al. J Neuroinflammation. .

Abstract

Programmed cell death has a vital role in embryonic development and tissue homeostasis. Necroptosis is an alternative mode of regulated cell death mimicking features of apoptosis and necrosis. Necroptosis requires protein RIPK3 (previously well recognized as regulator of inflammation, cell survival, and disease) and its substrate MLKL, the crucial players of this pathway. Necroptosis is induced by toll-like receptor, death receptor, interferon, and some other mediators. Shreds of evidence based on a mouse model reveals that deregulation of necroptosis has been found to be associated with pathological conditions like cancer, neurodegenerative diseases, and inflammatory diseases. In this timeline article, we are discussing the molecular mechanisms of necroptosis and its relevance to diseases.

Keywords: Inflammation; MLKL; Necroptosis; Neurodegenerative disease; RIPK3.

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The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Molecular mechanism of apoptosis and necroptosis. Death receptor mediates both extrinsic apoptosis as well as necroptosis; RIPK1 plays a key role in apoptosis and necroptosis. Activation of caspase-8 drives the pathway towards apoptosis while its inhibition leading to necroptosis. During necroptosis, RIPK1 and RIPK3 interact with each other resulting in the formation of functional heterodimer complex; this complex promotes oligomerization of MLKL by phosphorylating it. Oligomeric form of MLKL translocates towards the plasma membrane from cytosol resulting in the formation of the pore, causing an inflammatory response. In spite of pore formation, MLKL also mediates its effect after interacting with ion channels
Fig. 2
Fig. 2
RIPK-dependent inflammation. RIPK3 kinase activity, critical for oligomerization of MLKL that culminates with inflammation. Activation of RIPK3 is mediated by RIPK1 as well as other mediators like TLR3/TLR4 and interferon
See this image and copyright information in PMC

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