Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
Nat Commun. 2022 Nov 9;13(1):6759. doi: 10.1038/s41467-022-34593-y.
Aging impairs the immune responses to influenza A virus (IAV), resulting in increased mortality to IAV infections in older adults. However, the factors within the aged lung that compromise host defense to IAV remain unknown. Using a murine model and human samples, we identified prostaglandin E (PGE), as such a factor. Senescent type II alveolar epithelial cells (AECs) are overproducers of PGE within the aged lung. PGE impairs the proliferation of alveolar macrophages (AMs), critical cells for defense against respiratory pathogens, via reduction of oxidative phosphorylation and mitophagy. Importantly, blockade of the PGE receptor EP2 in aged mice improves AM mitochondrial function, increases AM numbers and enhances survival to IAV infection. In conclusion, our study reveals a key mechanism that compromises host defense to IAV, and possibly other respiratory infections, with aging and suggests potential new therapeutic or preventative avenues to protect against viral respiratory disease in older adults.
衰老大幅削弱了人体对甲型流感病毒（IAV）的免疫反应，导致老年人因 IAV 感染而死亡的风险增加。然而，导致衰老肺部宿主防御功能受损的因素仍不清楚。通过使用一种鼠类模型和人类样本，我们发现前列腺素 E（PGE）就是这样一个因素。衰老的 II 型肺泡上皮细胞（AECs）在衰老的肺部中过度产生 PGE。PGE 通过减少氧化磷酸化和线粒体自噬，损害了肺泡巨噬细胞（AMs）的增殖能力，AMs 是抵御呼吸道病原体的关键细胞。重要的是，在老年小鼠中阻断 PGE 受体 EP2 可改善 AM 的线粒体功能，增加 AM 的数量，并提高对 IAV 感染的存活率。总之，我们的研究揭示了一个关键机制，即衰老会损害人体对 IAV 及其他可能的呼吸道感染的防御能力，并为保护老年人免受病毒性呼吸道疾病提出了新的潜在治疗或预防途径。
