Review Article | Published:

The diverse role of RIP kinases in necroptosis and inflammation

Nature Immunology volume 16, pages 689697 (2015) | Download Citation

  • An Erratum to this article was published on 21 July 2015

This article has been updated

Abstract

Inflammation is a healthy response to infection or danger and should be rapid, specific and terminated once the threat has passed. Inflammatory diseases, where this regulation fails, cause considerable human suffering. Treatments have successfully targeted pro-inflammatory cytokines, such as tumor-necrosis factor (TNF), that directly induce genes encoding inflammatory products. Inflammatory signals, including TNF, may also directly induce caspase-independent cell death (necroptosis), which can also elicit inflammation. Necroptosis was originally defined as being dependent on the kinase RIPK1 but is now known to be dependent on RIPK3 and the pseudo-kinase MLKL. Therefore, RIPK1, RIPK3 and MLKL are potential therapeutic targets. RIPK1 and RIPK3 also directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility. This Review examines the role of cell death, particularly necroptosis, in inflammation, in the context of recent insights into the roles of the key necroptosis effector molecules RIPK1, RIPK3 and MLKL.

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Change history

  • 26 June 2015

    In the version of this article initially published, the following were incorrect and should be corrected as stated here. In Fig 1, ref. 84 should be ref. 82, and "pers. comm." should be cited one line below (aligned with Mlkl-/-). The middle of the third sentence of the Fig. 2 legend should include not a period but a comma, to read "phosphorylation of RIPK3, which leads to" and the end of fifth sentence should not include "RIPK" but should read "which leads to RIPK1-independent necroptosis...." The fifth sentence of final paragraph of the subsection "RIPK1-, RIPK3- and MLKL-induced necroptosis" should not include "cIAP" but should begin "First, mice deficient in both cIAP1 and cIAP2...." The middle of the sixth sentence of first paragraph in the subsection "Evidence for necroptotic DAMPS" should not state this as "concentration" but should read "however, HMGB1 levels are not higher" and final sentence should include citation of ref. 49 to read "...do not49." In Fig. 4, the arrow from pro-IL-1β should be a solid line, not a dashed line. The third sentence of the first paragraph of the subsection "RIP kinases and MLKL as therapeutic targets" should cite ref. 74 instead of ref. 76 (to read "mutation74."), and the final sentence of that subsection should be deleted. Fig. 5 should include the following revisions: in the top right section (Brain), the text should not include a parenthetical element but read "brain injury117,118, controlled cortical impact trauma119 and"; in the upper left section (Skin), the first sentence should not end with "RIPK" but should end "RIPK1 (refs. 48,49,57)"; in the middle left section (Liver), "no effect on" should be orange in both places (not only the first); and in the bottom section (Systemic), the second line should read "TNFand Z-VAD-induced hyper-acute shock" (not "TNF- or Z-VAD-"). The errors have been corrected in the HTML and PDF versions of the article.

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Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

    • John Silke
    •  & James A Rickard
  2. Department of Medical Biology, University of Melbourne, Parkville, Australia.

    • John Silke
    •  & James A Rickard
  3. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Motti Gerlic

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Competing interests

J.S. is involved with Catalyst Therapeutics, which is trying to develop a drug targeting MLKL for use in inflammatory diseases.

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Correspondence to John Silke or Motti Gerlic.

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https://doi.org/10.1038/ni.3206

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