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  • Opinion
  • Published:

Regulated cell death and inflammation: an auto-amplification loop causes organ failure

Abstract

Regulated cell death (RCD) is either immunologically silent or immunogenic. RCD in parenchymal cells may lead to the release of damage- associated molecular patterns that drive both tissue inflammation and the activation of further pathways of RCD. Following an initial event of regulated necrosis, RCD and inflammation can induce each other and drive a local auto-amplification loop that leads to exaggerated cell death and inflammation. In this Opinion article, we propose that such crosstalk between pro-inflammatory and RCD pathways has pathophysiological relevance in solid organ failure, transplantation and cancer. In our opinion, clinicians should not only prescribe immunosuppressive treatments to disrupt this circuit, but also implement the neglected therapeutic option of adding compounds that interfere with RCD.

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Figure 1: Signalling pathways of regulated cell death.
Figure 2: Regulated cell death triggers inflammation.
Figure 3: Model of the necro-inflammatory auto-amplification loop of regulated cell death and inflammation.
Figure 4: The auto-amplification loop of regulated cell death and inflammation in sepsis, ischaemia–reperfusion injury and solid cancer.

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Acknowledgements

The authors apologize to the authors of several important publications, which could not be cited owing to space and reference limitations. The authors thank L. Galluzzi for helpful discussions and for critically reading the manuscript. A.L. received funding from the German Society for Nephrology, the Else Kröner-Fresenius Stiftung, Pfizer and Novartis. H.-J.A's work is supported by grants from the Deutsche Forschungsgemeinschaft (AN372/9-2, AN371/12-2 and AN372/15-1) and the Else Kröner-Fresenius Stiftung. B.R.S. is an Early Career Scientist of the Howard Hughes Medical Institute and received funding from the New York State Stem Cell Science (NYSTEM; Contract No. C026715 for the CPS Facility) and the US National Institutes of Health (NIH grants R01CA097061, R01GM085081, R01CA161061 and DK34275), the Whitehall Foundation, the William Randolph Hearst Foundation, and the Baby Alex Foundation. S.K. received grants from Pfizer, Novartis, Fresenius and the Else Kröner-Fresenius Stiftung.

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Linkermann, A., Stockwell, B., Krautwald, S. et al. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol 14, 759–767 (2014). https://doi.org/10.1038/nri3743

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