Age-Dependent Reduction in Asthmatic Pathology through Reprogramming of Postviral Inflammatory Responses.
Age-Dependent Reduction in Asthmatic Pathology through Reprogramming of Postviral Inflammatory Responses.
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DOI：
10.4049/jimmunol.2101094
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Haspel J
中科院分区：
文献类型：
--
作者：
Hazan G;Eubanks A;Gierasch C;Atkinson J;Fox C;Hernandez-Leyva A;Rosen AL;Kau AL;Agapov E;Alexander-Brett J;Steinberg D;Kelley D;White M;Byers D;Wu K;Keeler SP;Zhang Y;Koenitzer JR;Eiden E;Anderson N;Holtzman MJ;Haspel J
哮喘是一种儿童慢性疾病，但由于未知的原因，疾病活动有时会随着儿童的成熟而消退。在这里，我们提出的临床和动物模型的证据表明，儿童哮喘的年龄依赖性源于不断演变的主机响应呼吸道病毒感染。使用临床数据，我们表明在COVID-19封锁期间对呼吸道病毒传播的社会抑制打破了儿童哮喘急性发作的传统年龄梯度，将哮喘缓解现象与病毒暴露联系起来。在小鼠中，我们发现仙台病毒（SeV）或甲型流感病毒（IAV）引发的哮喘肺病理学具有高度的年龄敏感性：在幼年小鼠（4-6周龄）中很强，但在成熟小鼠（>3个月大）中减弱。有趣的是，相同哮喘特征的过敏原诱导比病毒更少依赖于实际年龄。对SeV的特异性应答包括对感染早期出现的2型气道炎症的青少年偏好，而成熟小鼠表现出更受限制的细支气管感染分布，产生了独特的2型低炎症细胞因子谱。在基础状态下，老化导致肺白细胞负荷的变化，包括肺泡巨噬细胞（AM）的数量和转录景观。重要的是，耗尽成熟小鼠中的AM将SeV后病理恢复到幼年水平。因此，衰老通过调节AM隔室和对病毒的2型炎症反应来影响呼吸道病毒感染的慢性结果。我们的数据提供了关于哮喘缓解如何在儿童中发展的见解。
Asthma is a chronic disease of childhood, but for unknown reasons disease activity sometimes subsides as children mature. Here, we present clinical and animal model evidence suggesting that the age-dependency of childhood asthma stems from an evolving host response to respiratory viral infection. Using clinical data, we show that societal suppression of respiratory virus transmission during COVID-19 lockdown disrupted the traditional age gradient in pediatric asthma exacerbations, connecting the phenomenon of asthma remission to virus exposure. In mice, we show that asthmatic lung pathology triggered by Sendai virus (SeV) or influenza A virus (IAV) is highly age-sensitive: robust in juvenile mice (4–6 weeks old) but attenuated in mature mice (>3 months old). Interestingly, allergen induction of the same asthmatic traits was less dependent on chronological age than viruses. Age-specific responses to SeV included a juvenile bias towards type-2 airway inflammation that emerged early in infection, while mature mice exhibited a more restricted bronchiolar distribution of infection that produced a distinct type-2 low inflammatory cytokine profile. In the basal state, aging produced changes to lung leukocyte burden, including the number and transcriptional landscape of alveolar macrophages (AMs). Importantly, depleting AMs in mature mice restored post-SeV pathology to juvenile levels. Thus, aging influences chronic outcomes of respiratory viral infection through regulation of the AM compartment and type-2 inflammatory responses to viruses. Our data provide insight into how asthma remission might develop in children.
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影响因子：
5.8
作者：
Eichinger KM;Egaña L;Orend JG;Resetar E;Anderson KB;Patel R;Empey KM
通讯作者：
Empey KM
影响因子：
1.4
作者：
Apprill, Amy;McNally, Sean;Weber, Laura
通讯作者：
Weber, Laura
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
9.6
作者：
Byers, Derek E.;Wu, Kangyun;Holtzman, Michael J.
通讯作者：
Holtzman, Michael J.
影响因子：
16.6
作者：
Angelidis, Ilias;Simon, Lukas M.;Schiller, Herbert B.
通讯作者：
Schiller, Herbert B.