Production of IFNß by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNß-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis.

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 ß (IFNß) 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 IFNß-/- and type I IFN receptor (IFNAR1)-/- mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(IC). Wild type (WT) mice treated with poly(IC) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNß 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 IFNß and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNß and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(IC) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNß and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.