Madlen Loebel1, Luise Holzhauser2, Jelka A Hartwig1, Praphulla C Shukla3, Konstantinos Savvatis3,4, Alexander Jenke3, Martina Gast3, Felicitas Escher3, Sonya C Becker1, Sandra Bauer1, Andrea Stroux5, Antje Beling6,7, Meike Kespohl6, Sandra Pinkert8, Henry Fechner8, Uwe Kuehl3, Dirk Lassner9, Wolfgang Poller3, Heinz-Peter Schultheiss9, Tanja Zeller10, Stefan Blankenberg10, Anna-Pia Papageorgiou11, Stephane Heymans11, Ulf Landmesser3,7, Carmen Scheibenbogen1,12, Carsten Skurk3,7. 1. Institute of Medical Immunology, Charité, Augustenburger Platz 1, 13353 Berlin, Germany. 2. Department of Cardiology, University of Chicago, 5841S Maryland Avenue, Chicago, IL 60637, USA. 3. Department of Cardiology, Charité, CBF, Hindenburgdamm 30, 12200 Berlin, Germany. 4. Department of Cardiology, St-Bartholomew's Hospital, West Smithfield, London EC1A7BE, UK. 5. Department of Biometry and Clinical Epidemiology, Charité, CBF, Hindenburgdamm 30, 12200 Berlin, Germany. 6. Institute of Biochemistry, Charité, Chariteplatz 1, 10117 Berlin, Germany. 7. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Oudenarder Strasse 16, 13347 Berlin, Germany. 8. Department of Biochemistry, University of Technology, Gustav-meyer Allee 25, 13355 Berlin, Germany. 9. Institute for Cardiac Diagnostics and Therapy (IKDT), Molthestrasse 31, 12203 Berlin, Germany. 10. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany-DZHK, Partner Site Hamburg/Lübeck/Kiel, Martinistrasse 52, 20246 Hamburg, Germany. 11. Cardiovascular Research Institute, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, NL, Netherlands. 12. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Südstrasse 2, 13353 Berlin, Germany.
Abstract
Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis. Methods and results: Effects of Foxo3 on viral load and immune responses were investigated in a model of coxsackie virus B3 myocarditis in wild-type (WT) and Foxo3 deficient mice. Reduced immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were observed in Foxo3-/- mice 7 days post-infection (p.i.). Viral titres were also attenuated in hearts of Foxo3-/- mice at Day 3 while interferon-γ (IFNγ) and NKp46 expression were up-regulated suggesting early viral control by enhanced NK cell activity. CD69 expression of NK cells, frequencies of CD11b+CD27+ effector NK cells and cytotoxicity of Foxo3-/- mice was enhanced compared to WT littermates. Moreover, microRNA-155 expression, essential in NK cell activation, was elevated in Foxo3-/- NK cells while its inhibition led to diminished IFNγ production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFNγ and cytotoxic degranulation of NK cells. Viral inflammatory cardiomyopathy (viral CMI) patients with this SNP showed a poorer outcome due to less efficient virus control. Conclusion: Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection.
Aims: Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight in Foxo3 effects is still limited. Here, we investigated the role of Foxo3 on natural killer (NK) cell responses and its effects in viral myocarditis. Methods and results: Effects of Foxo3 on viral load and immune responses were investigated in a model of coxsackie virus B3 myocarditis in wild-type (WT) and Foxo3 deficient mice. Reduced immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were observed in Foxo3-/- mice 7 days post-infection (p.i.). Viral titres were also attenuated in hearts of Foxo3-/- mice at Day 3 while interferon-γ (IFNγ) and NKp46 expression were up-regulated suggesting early viral control by enhanced NK cell activity. CD69 expression of NK cells, frequencies of CD11b+CD27+ effector NK cells and cytotoxicity of Foxo3-/- mice was enhanced compared to WT littermates. Moreover, microRNA-155 expression, essential in NK cell activation, was elevated in Foxo3-/- NK cells while its inhibition led to diminished IFNγ production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFNγ and cytotoxic degranulation of NK cells. Viral inflammatory cardiomyopathy (viral CMI) patients with this SNP showed a poorer outcome due to less efficient virus control. Conclusion: Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection.
Authors: Nathan A Holland; Jake T Francisco; Sean C Johnson; Joshua S Morgan; Troy J Dennis; Nishitha R Gadireddy; David A Tulis Journal: J Cardiovasc Dev Dis Date: 2018-01-23