Aryl Hydrocarbon Receptor Activation by Benzo[<i>a</i>]pyrene Prevents Development of Septic Shock and Fatal Outcome in a Mouse Model of Systemic <i>Salmonella enterica</i> Infection
Christiane Fueldner,
Sina Riemschneider,
Janine Haupt,
Harald Jungnickel,
Felix Schulze,
Katharina Zoldan,
Charlotte Esser,
Sunna Hauschildt,
Jens Knauer,
Andreas Luch,
Stefan Kalkhof,
Jörg Lehmann
Affiliations
Christiane Fueldner
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Sina Riemschneider
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Janine Haupt
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Harald Jungnickel
Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany
Felix Schulze
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Katharina Zoldan
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Charlotte Esser
Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany
Sunna Hauschildt
Faculty of Life Sciences, University of Leipzig, 04103 Leipzig, Germany
Jens Knauer
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Andreas Luch
Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany
Stefan Kalkhof
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
Jörg Lehmann
Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
This study focused on immunomodulatory effects of aryl hydrocarbon receptor (AhR) activation through benzo[a]pyrene (BaP) during systemic bacterial infection. Using a well-established mouse model of systemic Salmonella enterica (S.E.) infection, we studied the influence of BaP on the cellular and humoral immune response and the outcome of disease. BaP exposure significantly reduced mortality, which is mainly caused by septic shock. Surprisingly, the bacterial burden in BaP-exposed surviving mice was significantly higher compared to non-exposed mice. During the early phase of infection (days 1–3 post-infection (p.i.)), the transcription of proinflammatory factors (i.e., IL-12, IFN-γ, TNF-α, IL-1β, IL-6, IL-18) was induced faster under BaP exposure. Moreover, BaP supported the activity of antigen-presenting cells (i.e., CD64 (FcγRI), MHC II, NO radicals, phagocytosis) at the site of infection. However, early in infection, the anti-inflammatory cytokines IL-10 and IL-22 were also locally and systemically upregulated in BaP-exposed S.E.-infected mice. BaP-exposure resulted in long-term persistence of salmonellae up to day 90 p.i., which was accompanied by significantly elevated S.E.-specific antibody responses (i.e., IgG1, IgG2c). In summary, these data suggest that BaP-induced AhR activation is capable of preventing a fatal outcome of systemic S.E. infection, but may result in long-term bacterial persistence, which, in turn, may support the development of chronic inflammation.
