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Cited by 438

The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.

RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury

Open access
Newton, K, Dugger, D L, Maltzman, A, Greve, J M, Hedehus, M, Martin-McNulty, B, Carano, R A D, Cao, T C, van Bruggen, N, Bernstein, L, Lee, W P, Wu, X, DeVoss, J, Zhang, J, Jeet, S, Peng, I, McKenzie, B S, Roose-Girma, M, Caplazi, P, Diehl, L, Webster, J D, Vucic, D·2016·Cell Death & Differentiation
DOI 10.1038/cdd.2016.46
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Abstract

Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.

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Metadata

Authors
Newton, K., Dugger, D. L., Maltzman, A., Greve, J. M., Hedehus, M., Martin-McNulty, B., Carano, R. A. D., Cao, T. C., van Bruggen, N., Bernstein, L., Lee, W. P., Wu, X., DeVoss, J., Zhang, J., Jeet, S., Peng, I., McKenzie, B. S., Roose-Girma, M., Caplazi, P., Diehl, L., Webster, J. D., & Vucic, D.
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2016-05-13
Volume
23
Issue
9
Pages
1565-1576
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2016.46
OpenAlex
W2357133200
Cited by
438
References
11
FWCI
23.62
Type
journal article
Language
en
Open access
hybrid
Licence
creativecommons.org/licenses/by-nc-nd/4.0 (tdm)

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CoChat. (2026). Citation check: RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. https://app.cochat.ai/papers/10.1038/cdd.2016.46
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Newton, K., Dugger, D. L., Maltzman, A., Greve, J. M., Hedehus, M., Martin-McNulty, B., Carano, R. A. D., Cao, T. C., van Bruggen, N., Bernstein, L., Lee, W. P., Wu, X., DeVoss, J., Zhang, J., Jeet, S., Peng, I., McKenzie, B. S., Roose-Girma, M., Caplazi, P., . . . Vucic, D. (2016). RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death & Differentiation. https://doi.org/10.1038/cdd.2016.46

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