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.

中文翻译：

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叉头转录因子 Foxo3 负向调节心肌炎中的自然杀伤细胞功能和病毒清除

目的 Foxo3 是一种参与细胞代谢、存活和炎症疾病的转录因子。然而，对 Foxo3 效应的机械洞察仍然有限。在这里，我们研究了 Foxo3 在自然杀伤 (NK) 细胞反应中的作用及其在病毒性心肌炎中的作用。方法和结果 在野生型 (WT) 和 Foxo3 缺陷小鼠的柯萨奇病毒 B3 心肌炎模型中研究了 Foxo3 对病毒载量和免疫反应的影响。在感染 (pi) 后 7 天，在 Foxo3-/- 小鼠中观察到心脏组织中免疫细胞浸润减少、病毒滴度和促炎细胞因子减少。在第 3 天，Foxo3-/- 小鼠心脏中的病毒滴度也减弱，而干扰素-γ（IFNγ）和 NKp46 表达上调，表明通过增强 NK 细胞活性进行早期病毒控制。NK细胞的CD69表达，与 WT 同窝仔鼠相比，CD11b+CD27+ 效应 NK 细胞的频率和 Foxo3-/- 小鼠的细胞毒性增强。此外，在 NK 细胞活化中必不可少的 microRNA-155 表达在 Foxo3-/- NK 细胞中升高，而其抑制导致 IFNγ 产生减少。携带长寿相关 FOXO3 单核苷酸多态性 (SNP) rs12212067 的健康人表现出降低的 IFNγ 和 NK 细胞的细胞毒性脱颗粒。由于病毒控制效率较低，具有这种 SNP 的病毒性炎症性心肌病（病毒性 CMI）患者的预后较差。结论 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发挥重要作用。因此，