TY - JOUR
T1 - The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance inmyocarditis
AU - Loebel, Madlen
AU - Holzhauser, Luise
AU - Hartwig, Jelka A.
AU - Shukla, Praphulla C.
AU - Savvatis, Konstantinos
AU - Jenke, Alexander
AU - Gast, Martina
AU - Escher, Felicitas
AU - Becker, Sonya C.
AU - Bauer, Sandra
AU - Stroux, Andrea
AU - Beling, Antje
AU - Kespohl, Meike
AU - Pinkert, Sandra
AU - Fechner, Henry
AU - Kuehl, Uwe
AU - Lassner, Dirk
AU - Poller, Wolfgang
AU - Schultheiss, Heinz-Peter
AU - Zeller, Tanja
AU - Blankenberg, Stefan
AU - Papageorgiou, Anna-Pia
AU - Heymans, Stephane
AU - Landmesser, Ulf
AU - Scheibenbogen, Carmen
AU - Skurk, Carsten
PY - 2018/3/7
Y1 - 2018/3/7
N2 - 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-gamma (IFN gamma) 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 IFN gamma production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFN gamma 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.
AB - 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-gamma (IFN gamma) 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 IFN gamma production. Healthy humans carrying the longevity-associated FOXO3 single nucleotide polymorphism (SNP) rs12212067 exhibited reduced IFN gamma 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.
KW - Myocardial inflammation
KW - Infection
KW - Polymorphism
KW - Transcription factor FOXO3
KW - COXSACKIEVIRUS B3 REPLICATION
KW - IFN-GAMMA PRODUCTION
KW - T-CELLS
KW - SYNOVIAL TISSUE
KW - HUMAN LONGEVITY
KW - CARDIAC INJURY
KW - HIV-INFECTION
KW - MYOCARDITIS
KW - ACTIVATION
KW - PATHWAY
U2 - 10.1093/eurheartj/ehx624
DO - 10.1093/eurheartj/ehx624
M3 - Article
C2 - 29136142
SN - 0195-668X
VL - 39
SP - 876
EP - 887
JO - European Heart Journal
JF - European Heart Journal
IS - 10
ER -