Influenza-induced Tpl2 expression within alveolar epithelial cells is dispensable for host viral control and anti-viral immunity.
Influenza-induced Tpl2 expression within alveolar epithelial cells is dispensable for host viral control and anti-viral immunity.
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DOI：
10.1371/journal.pone.0262832
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Watford WT
中科院分区：
文献类型：
--
作者：
Wyatt KD;Sarr D;Sakamoto K;Watford WT
肿瘤进展基因座2（Tpl 2）是一种丝氨酸/苏氨酸激酶，其响应于Toll样受体（TLR）和细胞因子受体调节炎性介质的表达。Tpl 2的整体消融导致响应于甲型流感病毒（IAV）感染的严重疾病，其特征在于呼吸窘迫，并且骨髓嵌合小鼠中的研究涉及非造血细胞中的Tpl 2。肺上皮细胞是流感病毒的主要靶标和复制小生境;然而，尚未研究肺上皮细胞内Tpl 2对抗病毒应答的特异性调节。在本文中，我们显示Tp 12在原代气道上皮细胞中基本表达，并且其表达在I型和II型气道上皮细胞（AECI和AECII）中响应于流感感染而增加。我们使用Nkx2.1-cre来驱动肺上皮细胞内的Tpl 2缺失，以描绘小鼠流感感染期间Tpl 2的上皮细胞特异性功能。虽然发病率和死亡率的适度增加归因于肺上皮细胞中的cre依赖性缺失，但未观察到宿主细胞因子产生或肺病理学的改变。在体外，I型气道上皮细胞系LET 1内的Tp 12抑制以及原代气道上皮细胞中的遗传消融不改变细胞因子产生。总的来说，这些发现确定了除了AEC之外的细胞中的Tpl 2依赖性缺陷是在具有整体Tpl 2消融的流感感染小鼠中观察到的发病率和死亡率的主要原因。
Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that regulates the expression of inflammatory mediators in response to Toll-like receptors (TLR) and cytokine receptors. Global ablation of Tpl2 leads to severe disease in response to influenza A virus (IAV) infection, characterized by respiratory distress, and studies in bone marrow chimeric mice implicated Tpl2 in non-hematopoietic cells. Lung epithelial cells are primary targets and replicative niches of influenza viruses; however, the specific regulation of antiviral responses by Tpl2 within lung epithelial cells has not been investigated. Herein, we show that Tpl2 is basally expressed in primary airway epithelial cells and that its expression increases in both type I and type II airway epithelial cells (AECI and AECII) in response to influenza infection. We used Nkx2.1-cre to drive Tpl2 deletion within pulmonary epithelial cells to delineate epithelial cell-specific functions of Tpl2 during influenza infection in mice. Although modest increases in morbidity and mortality were attributed to cre-dependent deletion in lung epithelial cells, no alterations in host cytokine production or lung pathology were observed. In vitro, Tpl2 inhibition within the type I airway epithelial cell line, LET1, as well as genetic ablation in primary airway epithelial cells did not alter cytokine production. Overall, these findings establish that Tpl2-dependent defects in cells other than AECs are primarily responsible for the morbidity and mortality seen in influenza-infected mice with global Tpl2 ablation.
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影响因子：
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作者：
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