Institute of Medical Immunology, Charité, Augustenburger Platz 1, 13353 Berlin, Germany.
Department of Cardiology, University of Chicago, 5841S Maryland Avenue, Chicago, IL 60637, USA.
Eur Heart J. 2018 Mar 7;39(10):876-887. doi: 10.1093/eurheartj/ehx624.
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.
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.
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.
Foxo3 是一种参与细胞代谢、存活和炎症性疾病的转录因子。然而，Foxo3 效应的机制见解仍然有限。在这里，我们研究了 Foxo3 对自然杀伤 (NK) 细胞反应的作用及其在病毒性心肌炎中的作用。
在柯萨奇病毒 B3 心肌炎的模型中，在野生型 (WT) 和 Foxo3 缺陷型小鼠中研究了 Foxo3 对病毒载量和免疫反应的影响。感染后 7 天，Foxo3-/- 小鼠心脏组织中的免疫细胞浸润、病毒滴度和促炎细胞因子减少。Foxo3-/- 小鼠心脏中的病毒滴度也在第 3 天减弱，同时干扰素-γ (IFNγ) 和 NKp46 表达上调，表明 NK 细胞活性增强导致早期病毒控制。与 WT 同窝仔相比，Foxo3-/- 小鼠 NK 细胞的 CD69 表达、CD11b+CD27+效应 NK 细胞的频率和细胞毒性增强。此外，在 Foxo3-/- NK 细胞中，NK 细胞激活所必需的 microRNA-155 表达升高，而其抑制导致 IFNγ 产生减少。携带与长寿相关的 FOXO3 单核苷酸多态性 (SNP) rs12212067 的健康人表现出 IFNγ 和 NK 细胞细胞毒性脱颗粒减少。携带这种 SNP 的病毒性炎症性心肌病 (viral CMI) 患者由于病毒控制效率较低，预后较差。
我们的结果表明 Foxo3 参与调节 NK 细胞功能，并表明 Foxo3 在抗病毒先天免疫中起重要作用。因此，增强 Foxo3 活性，如 SNP rs12212067，可能在癌症和心血管疾病等慢性炎症中具有保护作用，但不利于急性病毒感染的控制。
