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Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis

Mucosal Immunologyvolume 11pages11911202 (2018) | Download Citation



Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8∆IEC mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8∆IEC mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8∆IECTnfr1−/− mice showed improved survival after infection, tissue destruction was similar to Casp8∆IEC mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.

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The authors thank H. Dorner, M. Zeitler, S. Gößwein, S. Wallmüller and V. Thonn for excellent technical assistance. The authors thank James Murphy (Associated Professor at the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia) for providing us with Mlkl-/- mice. This research has received funding from DFG projects within SPP1656 and SFB1181-A08. Further support was given by the Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen-Nuremberg.

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  1. Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany

    • Manuela Hefele
    • , Iris Stolzer
    • , Barbara Ruder
    • , Gui-Wei He
    • , Mousumi Mahapatro
    • , Stefan Wirtz
    • , Markus F. Neurath
    •  & Claudia Günther


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C.G. and M.H. designed the research. M.H., I.S., C.G., and B.R. performed the experiments. M.M., SW, G.W.H., M.F.N. provided material that made this study possible. M.H., M.F.N. and C.G. analysed the data and wrote the paper.

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The authors declare no competing financial interests.

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Correspondence to Claudia Günther.

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