The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling.
The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling.
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DOI：
10.1007/s10753-022-01736-8
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发表时间：
2023-02
期刊：
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
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对病毒感染最显著的宿主反应是产生1型干扰素（T1 IFN）。T1 IFN的一种宿主调节因子是丝氨酸-苏氨酸激酶，肿瘤进展基因座2（TPL 2）。我们先前已经证明Tp 12 −/−小鼠死于低致病性甲型流感病毒株（x31）感染，与干扰素-β（IFN-β）、趋化因子CCL 2的肺水平增加以及单核细胞和中性粒细胞过度肺浸润相关。IFN-β的TPL 2依赖性过表达与结核分枝杆菌易感性增强有关;因此，我们研究了T1 IFN在Tp 12 −/−小鼠对流感易感性中的作用。在Ifnar 1 −/− Tpl 2 −/−小鼠中，CCL 2过表达和单核细胞募集正常化，证实Tpl 2通过抑制T1 IFN/CCL 2轴来抑制炎性单核细胞募集。出乎意料的是，Ifnar 1 −/−菌株中过度的中性粒细胞募集进一步加剧了7 dpi时Ifnar 1 −/− Tpl 2 −/−中的TPL 2基因消融，伴随着嗜中性粒细胞调节细胞因子CXCL 1和IFN-λ的过度表达。总的来说，我们的数据表明，TPL 2和T1 IFN协同抑制中性粒细胞募集。然而，用嗜中性粒细胞消耗性抗Ly 6 G抗体治疗仅显示疾病的适度改善。分类的先天性免疫群体的分析揭示了中性粒细胞、炎性单核细胞和肺泡巨噬细胞中炎性介质的冗余表达。这些发现表明，针对单一细胞类型或介质可能不足以控制以混合炎性渗出物为特征的严重疾病。未来的研究将考虑TPL 2调节途径作为严重流感进展的潜在预测因子，并研究在病毒感染期间调节TPL 2功能的新方法。在线版本包含补充材料，可通过10.1007/s10753-022-01736-8获得。
The most prominent host response to viral infection is the production of type 1 interferons (T1 IFNs). One host regulator of the T1 IFNs is the serine-threonine kinase, tumor progression locus 2 (TPL2). We have previously demonstrated that Tpl2−/− mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-β (IFN-β), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-β has been implicated in enhanced susceptibility to Mycobacterium tuberculosis; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2−/− mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1−/−Tpl2−/− mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1−/− strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1−/−Tpl2−/− by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-λ. Collectively, our data suggest that TPL2 and T1 IFNs synergize to inhibit neutrophil recruitment. However, treatment with the neutrophil-depleting anti-Ly6G antibody showed only a modest improvement in disease. Analysis of sorted innate immune populations revealed redundant expression of inflammatory mediators among neutrophils, inflammatory monocytes and alveolar macrophages. These findings suggest that targeting a single cell type or mediator may be inadequate to control severe disease characterized by a mixed inflammatory exudate. Future studies will consider TPL2-regulated pathways as potential predictors of severe influenza progression as well as investigate novel methods to modulate TPL2 function during viral infection. The online version contains supplementary material available at 10.1007/s10753-022-01736-8.
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