Jiang Wei, Chen Yeying, Yu Cheng-Yun, Zou Benkun, Lu Yimeng, Yang Qian, Tang Zihui, Mao Weiying, Li Jing, Han Han, Shao Lingyun, Zeng Jiashun, Chu Yiwei, Tang Jianguo, Lu Mingfang
Department of Immunology, School of Basic Medical Sciences, Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
Department of Rheumatology and Immunology, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Eur J Immunol. 2025 Jan;55(1):e2350378. doi: 10.1002/eji.202350378. Epub 2024 Nov 5.
Alveolar macrophages (AMs) are sentinels in the airways, where they sense and respond to invading microbes and other stimuli. Unlike macrophages in other locations, AMs can remain responsive to Gram-negative lipopolysaccharides (LPS) after they have responded to LPS in vivo (they do not develop "endotoxin tolerance"), suggesting that the alveolar microenvironment may influence their responses. Although alveolar epithelial cells (AECs) normally limit AMs' innate responses, preventing inflammation induced by harmless antigens in the lung, how AECs influence the innate responses of AMs to infectious agents has been uncertain. Here we report that (1) after exposure to aspirated (intranasal instillation) LPS, AMs increase their responses to TLR agonists and elevate their phagocytic and bactericidal activities in mice; (2) Aspirated LPS pre-exposure increases host resistance to pulmonary infection caused by Gram-negative bacteria and the protection effect lasts for at least 35 days; (3) LPS stimulation of AECs both increases AMs' innate immune responses and prevents AMs from developing tolerance in vitro; (4) Upon LPS stimulation, AMs secreted TNF-α induces AECs to release GM-CSF, which potentiates AMs' response. These experiments have revealed a previously unappreciated role that AECs may play in boosting the innate responses of AMs and promoting resistance to pulmonary infections.
肺泡巨噬细胞（AMs）是气道中的哨兵，在那里它们感知并应对入侵的微生物和其他刺激。与其他部位的巨噬细胞不同，AMs在体内对革兰氏阴性脂多糖（LPS）产生反应后仍能保持对其的反应性（它们不会产生“内毒素耐受”），这表明肺泡微环境可能会影响它们的反应。尽管肺泡上皮细胞（AECs）通常会限制AMs的固有反应，防止肺部无害抗原诱导的炎症，但AECs如何影响AMs对感染因子的固有反应尚不清楚。在此我们报告：（1）在吸入（鼻内滴注）LPS后，AMs对Toll样受体（TLR）激动剂的反应增强，并且其吞噬和杀菌活性在小鼠中升高；（2）预先吸入LPS可增强宿主对革兰氏阴性菌引起的肺部感染的抵抗力，且保护作用至少持续35天；（3）LPS刺激AECs既能增强AMs的固有免疫反应，又能在体外防止AMs产生耐受；（4）在LPS刺激下，AMs分泌的肿瘤坏死因子-α（TNF-α）诱导AECs释放粒细胞-巨噬细胞集落刺激因子（GM-CSF），从而增强AMs的反应。这些实验揭示了AECs在增强AMs的固有反应和促进对肺部感染的抵抗力方面可能发挥的一个此前未被认识到的作用。
