Necroptosis and Inflammation

Annu Rev Biochem. 2016 Jun 2:85:743-63. doi: 10.1146/annurev-biochem-060815-014830. Epub 2016 Feb 8.


Necroptosis is a regulated form of necrosis, with the dying cell rupturing and releasing intracellular components that can trigger an innate immune response. Toll-like receptor 3 and 4 agonists, tumor necrosis factor, certain viral infections, or the T cell receptor can trigger necroptosis if the activity of the protease caspase-8 is compromised. Necroptosis signaling is modulated by the kinase RIPK1 and requires the kinase RIPK3 and the pseudokinase MLKL. Either RIPK3 deficiency or RIPK1 inhibition confers resistance in various animal disease models, suggesting that inflammation caused by necroptosis contributes to tissue damage and that inhibitors of these kinases could have therapeutic potential. Recent studies have revealed unexpected complexity in the regulation of cell death programs by RIPK1 and RIPK3 with the possibility that necroptosis is but one mechanism by which these kinases promote inflammation.

Keywords: MLKL; RIPK1; RIPK3.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 8 / genetics
  • Caspase 8 / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Immunity, Innate
  • Inflammation
  • Necrosis / genetics*
  • Necrosis / immunology
  • Necrosis / pathology
  • Protein Kinases / genetics*
  • Protein Kinases / immunology
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology
  • Signal Transduction
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Tumor Necrosis Factor-alpha
  • MLKL protein, human
  • Protein Kinases
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • CASP8 protein, human
  • Caspase 8