Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis
by
Magdalena Howe 1, Jens Bauer 1, Anja Schulze 1, Sonja Kropp 1, Richard M. Locksley 2, Judith Alferink 3,4, Heike Weighardt 5 and Stefanie Scheu 1,*
Magdalena Howe 1, Jens Bauer 1, Anja Schulze 1, Sonja Kropp 1, Richard M. Locksley 2, Judith Alferink 3,4, Heike Weighardt 5 and Stefanie Scheu 1,*
1
Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
2
Howard Hughes Medical Institute and Departments of Medicine and Microbiology/Immunology, University of California, San Francisco, CA 94143, USA
3
Department of Psychiatry, University of Münster, 48149 Münster, Germany
4
Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany
5
Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4410; https://doi.org/10.3390/ijms20184410
Received: 11 August 2019 / Revised: 1 September 2019 / Accepted: 5 September 2019 / Published: 7 September 2019
(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation)
Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ−/− and type I IFN receptor (IFNAR1)−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.
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Keywords:
sepsis; viral infection; type I interferons; interferon β; IL-12; dendritic cells; cytokine reporter mouse model; immunotherapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
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MDPI and ACS Style
Howe, M.; Bauer, J.; Schulze, A.; Kropp, S.; Locksley, R.M.; Alferink, J.; Weighardt, H.; Scheu, S. Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis. Int. J. Mol. Sci. 2019, 20, 4410.
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