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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome

Linde Duprez1, Nozomi Takahashi, Filip Van Hauwermeiren

  • 1Department for Molecular Biomedical Research, the Flanders Institute for Biotechnology (VIB), 9052 Ghent, Belgium.

Immunity
|December 27, 2011
PubMed

Insights

Necroptosis, a form of cell death mediated by RIPK1 and RIPK3, drives mortality in systemic inflammatory response syndrome (SIRS). Inhibiting RIPK1 or deleting RIPK3 protects against lethal SIRS and sepsis.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathology

Background:

  • Tumor necrosis factor receptor 1 (TNFR1) signaling initiates survival-inflammation or cell death pathways.
  • Cell death can proceed via apoptosis or receptor-interacting protein kinase (RIPK)-mediated necrosis (necroptosis).

Purpose of the Study:

  • To investigate the roles of apoptosis and necroptosis in TNF-induced systemic inflammatory response syndrome (SIRS).
  • To identify potential therapeutic targets for SIRS and sepsis by examining the necroptotic pathway.

Main Methods:

  • Utilized genetic deletion of caspases (caspase-3, -7, -1) and RIPK3 in mouse models of SIRS.
  • Administered necrostatin-1, a RIPK1 kinase inhibitor, to assess its protective effects.
  • Evaluated SIRS mortality and levels of circulating damage-associated molecular patterns (DAMPs).
  • Tested RIPK3 deficiency in a cecal ligation and puncture (CLP) sepsis model.

Main Results:

  • Deletion of apoptotic caspases or inflammatory caspase-1 did not affect lethal SIRS.
  • Complete protection against lethal SIRS was observed in RIPK3-deficient mice.
  • RIPK3 deficiency significantly reduced circulating DAMPs and mortality in both TNF-induced SIRS and CLP sepsis models.
  • Necrostatin-1 pretreatment mimicked the protective effects of RIPK3 deficiency.

Conclusions:

  • RIPK1-RIPK3-mediated necroptosis, not apoptosis, is the primary driver of mortality in TNF-induced SIRS.
  • RIPK kinase inhibition represents a promising therapeutic strategy for SIRS and sepsis.
  • Components of the necroptotic pathway are viable therapeutic targets for inflammatory conditions.

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