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.

Magdalena Howe,Sonja Kropp,Stefanie Scheu,Anja Schulze,Richard M Locksley,Judith Alferink,Jens Bauer,Heike Weighardt

doi:10.3390/ijms20184410

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.

Highlights

The millions of severe sepsis and septic shock cases reported worldwide represent a major public health threat and are associated with a mortality rate of 25% [1,2]
Using a model of polymicrobial sepsis combined with prior viral stimulation this study revealed novel functions of interferon β (IFNβ) that critically impact the outcome of sepsis
In our study direct comparisons between Wild type (WT), IFNβ−/− and IFNAR1−/− mice indicated that poly(I:C)-induced IFNβ production has a non-redundant, detrimental role in IFNAR-mediated sensitization leading to increased mortality rates early during polymicrobial sepsis

Summary

Introduction

The millions of severe sepsis and septic shock cases reported worldwide represent a major public health threat and are associated with a mortality rate of 25% [1,2]. During the early systemic inflammatory response excessive amounts of cytokines, e.g., type I interferons (IFNs) and tumor necrosis factor (TNF) are released by activated leukocytes and contribute to septic shock and tissue injury [6,7,8]. This is accompanied by the production of other proinflammatory cytokines, including IL-12 and IFNγ shown to have protective functions by inducing effector mechanisms essential for early bacterial clearance [9,10]. The cell type(s) responsible for type I IFN production remain undefined thereby preventing a better understanding of the cellular immune mechanisms associated with sepsis development

Methods

Results

Conclusion