FOXO3a 调节气道上皮细胞中鼻病毒诱导的先天免疫反应。,Scientific Reports

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FOXO3a 调节气道上皮细胞中鼻病毒诱导的先天免疫反应。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-03 , DOI: 10.1038/s41598-019-54567-3
Joao Gimenes-Junior ₁ , Nicole Owuar ₁ , Hymavathi Reddy Vari ₁ , Wuyan Li ₁ , Nathaniel Xander ₁ , Sudhir Kotnala ₁ , Uma S Sajjan _{1,

2}

Affiliation

还发现 Forkhead 转录因子 O 类 (FOXO)3a 在多种细胞过程中发挥关键作用，可调节细胞类型特异性抗病毒反应。气道上皮细胞表达 FOXO3a，并通过启动抗病毒 I 型和 III 型干扰素 (IFN) 反应在清除鼻病毒 (RV) 中发挥重要作用。为了阐明 FOXO3a 在调节抗病毒反应中的作用，我们生成了气道上皮细胞特异性 Foxo3a 敲除 (Scga1b1-Foxo3a-/-) 小鼠和稳定的 FOXO3a 敲除人气道上皮细胞系。与野生型相比，Scga1b1-Foxo3a-/- 小鼠在 RV 或双链 (ds) RNA 模拟物、聚肌苷酸-多胞苷酸的攻击下表现出减少的 IFN-α、IFN-β、IFN-λ2/3。 Poly I:C) 表明有缺陷的 dsRNA 受体信号。RV 感染的 Scga1b1-Foxo3a-/- 小鼠也表现出病毒持续存在、肺部炎症增强和促炎细胞因子水平升高。FOXO3a K/O 气道上皮细胞对 RV 感染的 IFN 反应减弱，这与线粒体抗病毒信号蛋白 (MAVS) 的构象变化有关，但与未受刺激条件下 dsRNA 受体表达的减少无关。MitoTEMPO 是一种线粒体特异性抗氧化剂，可纠正 MAVS 构象，并恢复对 FOXO3a K/O 细胞中随后 RV 感染的抗病毒 IFN 反应。氧化应激的抑制也降低了 FOXO3a K/O 细胞中对 RV 的促炎细胞因子反应。总之，我们的结果表明 FOXO3a 在调节抗病毒反应以及限制促炎细胞因子表达方面起着关键作用。

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FOXO3a regulates rhinovirus-induced innate immune responses in airway epithelial cells.

Forkhead transcription factor class O (FOXO)3a, which plays a critical role in a wide variety of cellular processes, was also found to regulate cell-type-specific antiviral responses. Airway epithelial cells express FOXO3a and play an important role in clearing rhinovirus (RV) by mounting antiviral type I and type III interferon (IFN) responses. To elucidate the role of FOXO3a in regulating antiviral responses, we generated airway epithelial cell-specific Foxo3a knockout (Scga1b1-Foxo3a-/-) mice and a stable FOXO3a knockout human airway epithelial cell line. Compared to wild-type, Scga1b1-Foxo3a-/- mice show reduced IFN-α, IFN-β, IFN-λ2/3 in response to challenge with RV or double-stranded (ds)RNA mimic, Poly Inosinic-polycytidylic acid (Poly I:C) indicating defective dsRNA receptor signaling. RV-infected Scga1b1-Foxo3a-/- mice also show viral persistence, enhanced lung inflammation and elevated pro-inflammatory cytokine levels. FOXO3a K/O airway epithelial cells show attenuated IFN responses to RV infection and this was associated with conformational change in mitochondrial antiviral signaling protein (MAVS) but not with a reduction in the expression of dsRNA receptors under unstimulated conditions. Pretreatment with MitoTEMPO, a mitochondrial-specific antioxidant corrects MAVS conformation and restores antiviral IFN responses to subsequent RV infection in FOXO3a K/O cells. Inhibition of oxidative stress also reduces pro-inflammatory cytokine responses to RV in FOXO3a K/O cells. Together, our results indicate that FOXO3a plays a critical role in regulating antiviral responses as well as limiting pro-inflammatory cytokine expression. Based on these results, we conclude that FOXO3a contributes to optimal viral clearance and prevents excessive lung inflammation following RV infection.

更新日期：2019-12-03

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