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

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Abstract

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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Howe, M., Bauer, J., Schulze, A., Kropp, S., Locksley, R. M., Alferink, J., … Scheu, S. (2019). 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. International Journal of Molecular Sciences, 20(18). https://doi.org/10.3390/ijms20184410

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