Grant Conor, Duffin Emily, O'Connell Finbarr, Nadarajan Parthiban, Bergin Colm, Keane Joseph, O'Sullivan Mary P
Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, the University of Dublin, Dublin, Ireland.
Department of Infectious Diseases, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, the University of Dublin, Dublin, Ireland.
Immunology. 2025 Jul;175(3):391-401. doi: 10.1111/imm.13922. Epub 2025 May 4.
Alveolar macrophages (AMs) are the most numerous immune cells of the lung and are the resident, sentinel lung immunocytes that summon trafficking immune cells to the compartment. Immune profiling of AMs from COVID-19 patients implicates AMs in the immune circuits that drive pulmonary inflammation in severe COVID-19 infection. However, little is known about human AM responses to SARS-CoV-2 proteins, such as the spike protein and envelope protein. We aimed to understand if human AMs recognize SARS-CoV-2 proteins and how they respond. We found that human AMs do not sense SARS-CoV-2 spike protein but do sense envelope protein via the pattern recognition receptors TLR2 and TLR4, secreting IL-1β, IFNγ, IL-12p70, IL-6, and TNFα in response. AMs from donors over the age of 70 years produced significantly more cytokines than those from younger patients following stimulation with SARS-CoV-2 envelope protein. AMs from current smokers had lower cytokine secretion. This is the first report of human AMs producing cytokines in response to SARS-CoV-2 proteins and the first to correlate those responses with clinical risk factors. These results may partly explain why older adults are at such high risk of severe lung inflammation in COVID-19.
肺泡巨噬细胞（AMs）是肺中数量最多的免疫细胞，是驻留的、哨兵样的肺免疫细胞，可召集游走免疫细胞至该区域。对新冠病毒病（COVID-19）患者的AMs进行免疫分析表明，AMs参与了在严重COVID-19感染中驱动肺部炎症的免疫回路。然而，关于人类AMs对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）蛋白（如刺突蛋白和包膜蛋白）的反应知之甚少。我们旨在了解人类AMs是否能识别SARS-CoV-2蛋白以及它们如何做出反应。我们发现人类AMs无法感知SARS-CoV-2刺突蛋白，但能通过模式识别受体Toll样受体2（TLR2）和Toll样受体4（TLR4）感知包膜蛋白，并相应地分泌白细胞介素-1β（IL-1β）、干扰素γ（IFNγ）、白细胞介素-12p70（IL-12p70）、白细胞介素-6（IL-6）和肿瘤坏死因子α（TNFα）。在接受SARS-CoV-2包膜蛋白刺激后，70岁以上供体的AMs产生的细胞因子明显多于年轻患者的AMs。目前吸烟者的AMs细胞因子分泌较低。这是关于人类AMs对SARS-CoV-2蛋白产生细胞因子反应的首次报告，也是首次将这些反应与临床风险因素相关联的报告。这些结果可能部分解释了为什么老年人在COVID-19中发生严重肺部炎症的风险如此之高。
